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Approaches to avermectin assembly: Synthesis of the spiroketal system
Tetrahedron printed in
Letters,Vo1.28,No.46,pp Great Britain
APPROACHES
TO AVERMECTIN Anthony
Department
5615-5618,1987
ASSEMBLY:
SYNTHESIS
G.M. Barrett*
of Chemistry,
oo40-4039/87 $3.00 + -00 Perqamon Journals Ltd.
Northwestern
OF THE SPIROKETAL
University,
Evanston,
SUMMARY:
A chiral synthesis of the spiroketal moiety of avermectin in 14 steps from (3S(R),&R(S))-3,5-dimethyl-1-hexen-4-01.
The avermectins interest
and the structurally
in consequence
their complex features:
molecular
the highly
structure.l functionalized
unit and the 16-membered have been
the subject
83, the least complex of the avermectin approaches report
avermectin
macrocyclic
spiroketal
A2b
approach
milbemycins
ectoparasiticidal
A2b (1) exemplifies entity,
product,
ring.
synthetic
milbemycins6
and the milbemycins
Five total syntheses Additionally
hexahydrobenzofuran
and avermectins7y8
to the spiroketal
of milbemycin
several
entity5
in a projected
syntheses
and
have been published.
unit 12 required
and
hexahydrobenzofuran
Both the avermectins
have been reported.2l3
unit 4 and the southern
considerable activities
the key structural
the "southern"
studies.
60208
A2b has been accomplished
have attracted
spiroketal lactone
Illinois
and anthelmintic
Avermectin
of considerable natural
to more complex
a concise
related
of their potent
SYSTEM
and Tony M. Raynham
Herein we
synthesis
of
(1).
1
We considered reaction
that the target
of the 6-lactone
dihydropyrone
8.
spiroketal
7 with dianion
This succinct
12 should be available
3 followed by reduction
methodology
was successfully
5615
via the condensation
of the resultant
employed
Spiro
in our construction
of
5616
milbemycin alcohol
Following
p33.
5 was readily
crotonyl
bromide,
converted dimethyl
the elegant
prepared
lithium
aluminum
into the 6-lactone sulfide
Following reaction
to mention
the reaction
chemistry,
the homoallylic
acetal
by reaction Alcohol
(III) chloride.
413, acidification
that the conversion
The construction
with
5 was
11 ozonolysis
t-butyldimethylsilylation,
diastereoselectivity.
whereas
with a
and t-
of iso-butyraldehyde
of 5 took place with a
of 4 with 6 gave only the depicted
racemic
7.
our milbemycin
with
and chromium
with the ketene
It is germane
with high
diastereoisomer
hydride
condensation
butyldiphenylsilylation.14
97:3 threo selectivity
and HeathcocklO
scale from iso-butyraldehyde
7 via sequential
work up,l*
into 7 proceeded
Hiyama9
on a multigram
lithium
p3 chemistry
di-isopropylamide
the ,9-dione z3 was converted in THF at -78'C (15 min.)
into the dianion
3 by Dianion
and O'C (90 min.).
a,b
94%
5
6
7
OSiPh,t-Bu
OH
f
e,i
g.h
76%
)
Me0
-
75%
Maa
8
69%
9 OSiPh,t&d
OSiPh,t-Bu
OSiPh,t-Eu
10
OSiPh,t-Eu
11
12
Reaeents a) tBuMe2SiC1, 4, BF3.Et20,
imidazole, CH2C12,
dimethylaminopyridine, -23°C; 25'C;
4-dimethylaminopyridine,
-78'C;
DMF, 25'C;
h) H2, Rh/A1203, k) (Ph0)3P+MeI-,
d) nBu4NF,
DMF, 25'C; CH2C12,
f) 3, THF, O'C; AcOH;
EtOH, 25'C; DMF, 25'C;
CF3C02H,
i) LiNPr2iSo, 1) PhS02CH2Li,
b) 03, CH2Cl2,
25'C; e) tBuPh2SiC1. TsOH;
g) HF, pyridine,
THF -78'C; HOAc, THF. HMPT,
-78'C; Me2S; c) imidazole,
25°C.
-78'C;
4-
CH2C12,
j) LiAlH4,
Et20,
5617
3 smoothly
condensed
dihydropyrone hydrolysis
the C-lactone
as a single
effect.15
Although
C-4 diastereoselectivity Diol 9 was readily chromatographic
optically
(19.5:1) resolved
the sulfone
by formation
enolate
controlled
in low yield
transformed
proceeded
diesters
analysis.16
reprotonation.
mandelate
Zemplen
crystallographic
esters16
study.17 sulfone
and
distinguished
methanolysis epimerized
by t-
b3 synthesis, 3 took place via enolate
of this chemistry
require
of the intermediate
Secondly
12 needs
by
gave
This kinetic
Ester 10 was readily homologated
Two aspects and structure
of iodide 11 to produce
and with low
and with excellent
were readily
and reacidification.
in our milbemycin
yield.
adduct 8 of the
into diol 9 by
rapidly
The C-2 side chain of 9 was readily
stereochemistry
by an x-ray
homologation
slowly,
of the bis-(S)-O-methyl
formation
ortho ester
Thus
o C-2 selectivity.
to the Trost-Kosher
12 in good overall
the absolute
confirmed
and exclusive
which has precedent
and steric approach
of 8 proceeded
This reaction
control.
due to the operation
alcohol was readily
pure diol 9 (65% overall).
isomerization,
diastereoisomer
the spiro
acid mediated
of thermodynamic
The two diastereoisomeric
according
butyldiphenylsilylation,l4
Firstly
hydrogenation
on alumina.
separation.
lH NMR spectroscopy
spirane
the derived
over rhodium
on acidification,
the toluene-4-sulfonic
under conditions
(racemic)
C-4 diastereoselectivity, hydrogenation
7 at 0°C to produce,
In this reaction,
and Spiro cyclization
was obtained anomeric
with
8 (76%).
13
to produce
further
comment.
iodide 11 was
the facility
and efficiency
of the
to be underscored.
O.SiPh,t-Bu
I Me
It is thus evident
that the condensation
subsequent
manipulation
avermectin
spiroketal
using
lactonization
ACKNOWLEDGEMENT: (AI20644), spectrometer Instrument
entity.
The conversion
via the Mitsunobu
(RR03245) Facility
a 4OOMHz
(CHE-8211164),
James R. Irving and Nigel
Barnes
a convenient
of 12 into several
Institutes
NMR spectrometer
and the Midwest
of the C-lactone
8 provides
reaction 3,18 is currently
We thank the National
for funding
reaction
of the dihydropyrone
Center
of Health (RRO2314)
avermectins under
for preliminary
including
1
of this program
and a high resolution
mass
an NSF Regional
several mass spectra. studies
3 and
into the
investigation."
for support
for Mass Spectrometry,
for obtaining
7 with dianion entry
Additionally
on the production
of lactone
we thank 7.
5618
References 1. 2.
3.
4.
5.
6.
7. 8. 9.
10. 11.
12. 13. 14. 15. 16.
17. 18. 19.
H.G. Davis and R.H. Green, Nat. Prod. Reoorts. 1986, 2, 87. A.B. Smith III, S.R. Schow, J.D. Bloom, A.S. Thompson, and K.N. Winzenberg, S.R. Schow, J.D. Bloom, A.S. Thompson, J. Am. Chem. Sot., 1982, 104, 4015. D.R. Williams, K.N. Winzenberg and A.B. Smith III, Ibid., 1986, 108, 2662. S.D.A. B.A. Barrier, K. Nishitani and J.G. Phillips, Ibid., 1982, 104, 4708. Street, C. Yeates, P. Kocienski and S.F. Campbell, J. Chem. Sot.. Chem. Commun. 1985, 1386, 1388. R. Baker, M.J. O'Mahony and C.J. Swain, Ibid., -! 1985, 1326. 1986, S.V. Attwood, A.G.M. Barrett, R.A.E. Carr and G. Richardson, -9 Ibid. 479. A.G.M. Barrett, R.A.E. Carr, S.V. Attwood, G. Richardson and N.D.A. Walshe, J. Ore. Chem., 1986, 5l, 4840. S. Hancssian, A. Ugolini and M. Therien, J. Orp. Chem., 1983, 48, 4427. R. Baker, C.J. Swain and J.C. Head, J. Chem. Sot. Chem. Commun., 1985, 309. J. Ardisson, J.P. F&r&zou, M. Julia, L. Lenglet and A. Pancrazi, Tetrahedron Lett. 1986, a, 1987, 28, 1997. M. Hirama, T. Nakamine and S. Ito, -, Ibid. 5281.' M.E. Jung and L.J. Street, J. Am. Chem. Sot., 1984, 106, 8327. R.E. Ireland and D.M. Obrecht, Helv. Chim. Acta., 1986, 69, 1273. M. Prashad and B. Fraser-Reid, J. Ore. Chem., 1985, 50, 1564. M.E. Jung and L.J. Street, Tetrahedron Lett., 1985, 26, 3639. A.P. Kozikowski and K.E. MaloneyHuss, 1986, Ibid. 1985, 26, 5759. S. Hanessian, P. Beaulieu and D. Dub& ,Ibid., -9 Ibid 1987, 21, 5071. J. Ardisson, J.P. Ferezou, M. Julia and A. Pancrazi, -3 1986, 27, 291. A.G.M. 28, 2001. M.T. Crimmins and J.G. Lever, Ibid., Barrett and N.K. Capps, Ibid., 1986, 27, 5571. M.J. Hughes, E.J. Thomas, M.D. Turnbull, R.H. Jones and R.E. Warner ,- J. Chem. Sot. Chem. Cormnun., 1985, 755. I.T. Kay and M.D. Turnbull, "Synthetic Approaches to the Avermectin Toxophore", Recent Advances in the Chemistrv of Insect Control, Ed. N.F. Janes, The Royal Society of Chemistry Special Publication No. 53, London, 1985, p. 229. A.B. Smith III and A.S. Thompson, Tetrahedron Lett., 1985, a, 4283. S. Hanessian. A. Ugolini, D. Dub;, P.J. Hodges and C. Andre, J. Am. Chem. sot 1986, 108, 2776. -' B. Fraser-Reid, H. Wolleb, R. Faghih and J. Barchi Jr., J. Am. Chem. Sot., 1987, 109, 933. T. Hiyama, K. Kimura and H. Nozaki, Tetrahedron Lett., 1981, 22, 1037. T. Hiyama, Y. Okude, K. Kimura and H. Nozaki, Bull. Chem. Sot. JDn., 1982, 55, 581. C.T. Buse and C.H. Heathcock, Tetrahedron Lett., 1978, 1685. E.J. Corey and A. Venkateswarlu, J.. Chem. Sot., 1972, 94, 6190. J.P. Pappas, W.P. Keaveney, E. Gancher and M. Berger, Tetrahedron Lett., 1966, 4273. C. Heathcock and L.A. Flippin, J. Am. Chem. 1983, 105, 1667. -> Sot. S. Hanessian and P. Lavallee, Can. J. Chem., 1975, 53, 2975. P. Deslongchamps, D.D. Rowan, N. Pothier, T. Sauve and J.K. Saunders, Can. J. (zz, 1981, 59, 1105. B.M. Trost, J.L. Belletire, S. Godleski, P.G. McDougal, J.M. Balkovec, J.J. Baldwin, M.E. Christy, G.S. Ponticello, S.L. Varga and J.P. Springer, J. Org. Chem., 1986, 5l, 2370. We thank Dr. M. Sabat, Northwestern University, for obtaining the structure of 11. 0. Mits,mobu, Synthesis, 1981, 1. We plan to invert the C-23 stereochemistry subsequent to macrocyclization. (Received
in
USA
17 Auqust
1987)
Letters,Vo1.28,No.46,pp Great Britain
APPROACHES
TO AVERMECTIN Anthony
Department
5615-5618,1987
ASSEMBLY:
SYNTHESIS
G.M. Barrett*
of Chemistry,
oo40-4039/87 $3.00 + -00 Perqamon Journals Ltd.
Northwestern
OF THE SPIROKETAL
University,
Evanston,
SUMMARY:
A chiral synthesis of the spiroketal moiety of avermectin in 14 steps from (3S(R),&R(S))-3,5-dimethyl-1-hexen-4-01.
The avermectins interest
and the structurally
in consequence
their complex features:
molecular
the highly
structure.l functionalized
unit and the 16-membered have been
the subject
83, the least complex of the avermectin approaches report
avermectin
macrocyclic
spiroketal
A2b
approach
milbemycins
ectoparasiticidal
A2b (1) exemplifies entity,
product,
ring.
synthetic
milbemycins6
and the milbemycins
Five total syntheses Additionally
hexahydrobenzofuran
and avermectins7y8
to the spiroketal
of milbemycin
several
entity5
in a projected
syntheses
and
have been published.
unit 12 required
and
hexahydrobenzofuran
Both the avermectins
have been reported.2l3
unit 4 and the southern
considerable activities
the key structural
the "southern"
studies.
60208
A2b has been accomplished
have attracted
spiroketal lactone
Illinois
and anthelmintic
Avermectin
of considerable natural
to more complex
a concise
related
of their potent
SYSTEM
and Tony M. Raynham
Herein we
synthesis
of
(1).
1
We considered reaction
that the target
of the 6-lactone
dihydropyrone
8.
spiroketal
7 with dianion
This succinct
12 should be available
3 followed by reduction
methodology
was successfully
5615
via the condensation
of the resultant
employed
Spiro
in our construction
of
5616
milbemycin alcohol
Following
p33.
5 was readily
crotonyl
bromide,
converted dimethyl
the elegant
prepared
lithium
aluminum
into the 6-lactone sulfide
Following reaction
to mention
the reaction
chemistry,
the homoallylic
acetal
by reaction Alcohol
(III) chloride.
413, acidification
that the conversion
The construction
with
5 was
11 ozonolysis
t-butyldimethylsilylation,
diastereoselectivity.
whereas
with a
and t-
of iso-butyraldehyde
of 5 took place with a
of 4 with 6 gave only the depicted
racemic
7.
our milbemycin
with
and chromium
with the ketene
It is germane
with high
diastereoisomer
hydride
condensation
butyldiphenylsilylation.14
97:3 threo selectivity
and HeathcocklO
scale from iso-butyraldehyde
7 via sequential
work up,l*
into 7 proceeded
Hiyama9
on a multigram
lithium
p3 chemistry
di-isopropylamide
the ,9-dione z3 was converted in THF at -78'C (15 min.)
into the dianion
3 by Dianion
and O'C (90 min.).
a,b
94%
5
6
7
OSiPh,t-Bu
OH
f
e,i
g.h
76%
)
Me0
-
75%
Maa
8
69%
9 OSiPh,t&d
OSiPh,t-Bu
OSiPh,t-Eu
10
OSiPh,t-Eu
11
12
Reaeents a) tBuMe2SiC1, 4, BF3.Et20,
imidazole, CH2C12,
dimethylaminopyridine, -23°C; 25'C;
4-dimethylaminopyridine,
-78'C;
DMF, 25'C;
h) H2, Rh/A1203, k) (Ph0)3P+MeI-,
d) nBu4NF,
DMF, 25'C; CH2C12,
f) 3, THF, O'C; AcOH;
EtOH, 25'C; DMF, 25'C;
CF3C02H,
i) LiNPr2iSo, 1) PhS02CH2Li,
b) 03, CH2Cl2,
25'C; e) tBuPh2SiC1. TsOH;
g) HF, pyridine,
THF -78'C; HOAc, THF. HMPT,
-78'C; Me2S; c) imidazole,
25°C.
-78'C;
4-
CH2C12,
j) LiAlH4,
Et20,
5617
3 smoothly
condensed
dihydropyrone hydrolysis
the C-lactone
as a single
effect.15
Although
C-4 diastereoselectivity Diol 9 was readily chromatographic
optically
(19.5:1) resolved
the sulfone
by formation
enolate
controlled
in low yield
transformed
proceeded
diesters
analysis.16
reprotonation.
mandelate
Zemplen
crystallographic
esters16
study.17 sulfone
and
distinguished
methanolysis epimerized
by t-
b3 synthesis, 3 took place via enolate
of this chemistry
require
of the intermediate
Secondly
12 needs
by
gave
This kinetic
Ester 10 was readily homologated
Two aspects and structure
of iodide 11 to produce
and with low
and with excellent
were readily
and reacidification.
in our milbemycin
yield.
adduct 8 of the
into diol 9 by
rapidly
The C-2 side chain of 9 was readily
stereochemistry
by an x-ray
homologation
slowly,
of the bis-(S)-O-methyl
formation
ortho ester
Thus
o C-2 selectivity.
to the Trost-Kosher
12 in good overall
the absolute
confirmed
and exclusive
which has precedent
and steric approach
of 8 proceeded
This reaction
control.
due to the operation
alcohol was readily
pure diol 9 (65% overall).
isomerization,
diastereoisomer
the spiro
acid mediated
of thermodynamic
The two diastereoisomeric
according
butyldiphenylsilylation,l4
Firstly
hydrogenation
on alumina.
separation.
lH NMR spectroscopy
spirane
the derived
over rhodium
on acidification,
the toluene-4-sulfonic
under conditions
(racemic)
C-4 diastereoselectivity, hydrogenation
7 at 0°C to produce,
In this reaction,
and Spiro cyclization
was obtained anomeric
with
8 (76%).
13
to produce
further
comment.
iodide 11 was
the facility
and efficiency
of the
to be underscored.
O.SiPh,t-Bu
I Me
It is thus evident
that the condensation
subsequent
manipulation
avermectin
spiroketal
using
lactonization
ACKNOWLEDGEMENT: (AI20644), spectrometer Instrument
entity.
The conversion
via the Mitsunobu
(RR03245) Facility
a 4OOMHz
(CHE-8211164),
James R. Irving and Nigel
Barnes
a convenient
of 12 into several
Institutes
NMR spectrometer
and the Midwest
of the C-lactone
8 provides
reaction 3,18 is currently
We thank the National
for funding
reaction
of the dihydropyrone
Center
of Health (RRO2314)
avermectins under
for preliminary
including
1
of this program
and a high resolution
mass
an NSF Regional
several mass spectra. studies
3 and
into the
investigation."
for support
for Mass Spectrometry,
for obtaining
7 with dianion entry
Additionally
on the production
of lactone
we thank 7.
5618
References 1. 2.
3.
4.
5.
6.
7. 8. 9.
10. 11.
12. 13. 14. 15. 16.
17. 18. 19.
H.G. Davis and R.H. Green, Nat. Prod. Reoorts. 1986, 2, 87. A.B. Smith III, S.R. Schow, J.D. Bloom, A.S. Thompson, and K.N. Winzenberg, S.R. Schow, J.D. Bloom, A.S. Thompson, J. Am. Chem. Sot., 1982, 104, 4015. D.R. Williams, K.N. Winzenberg and A.B. Smith III, Ibid., 1986, 108, 2662. S.D.A. B.A. Barrier, K. Nishitani and J.G. Phillips, Ibid., 1982, 104, 4708. Street, C. Yeates, P. Kocienski and S.F. Campbell, J. Chem. Sot.. Chem. Commun. 1985, 1386, 1388. R. Baker, M.J. O'Mahony and C.J. Swain, Ibid., -! 1985, 1326. 1986, S.V. Attwood, A.G.M. Barrett, R.A.E. Carr and G. Richardson, -9 Ibid. 479. A.G.M. Barrett, R.A.E. Carr, S.V. Attwood, G. Richardson and N.D.A. Walshe, J. Ore. Chem., 1986, 5l, 4840. S. Hancssian, A. Ugolini and M. Therien, J. Orp. Chem., 1983, 48, 4427. R. Baker, C.J. Swain and J.C. Head, J. Chem. Sot. Chem. Commun., 1985, 309. J. Ardisson, J.P. F&r&zou, M. Julia, L. Lenglet and A. Pancrazi, Tetrahedron Lett. 1986, a, 1987, 28, 1997. M. Hirama, T. Nakamine and S. Ito, -, Ibid. 5281.' M.E. Jung and L.J. Street, J. Am. Chem. Sot., 1984, 106, 8327. R.E. Ireland and D.M. Obrecht, Helv. Chim. Acta., 1986, 69, 1273. M. Prashad and B. Fraser-Reid, J. Ore. Chem., 1985, 50, 1564. M.E. Jung and L.J. Street, Tetrahedron Lett., 1985, 26, 3639. A.P. Kozikowski and K.E. MaloneyHuss, 1986, Ibid. 1985, 26, 5759. S. Hanessian, P. Beaulieu and D. Dub& ,Ibid., -9 Ibid 1987, 21, 5071. J. Ardisson, J.P. Ferezou, M. Julia and A. Pancrazi, -3 1986, 27, 291. A.G.M. 28, 2001. M.T. Crimmins and J.G. Lever, Ibid., Barrett and N.K. Capps, Ibid., 1986, 27, 5571. M.J. Hughes, E.J. Thomas, M.D. Turnbull, R.H. Jones and R.E. Warner ,- J. Chem. Sot. Chem. Cormnun., 1985, 755. I.T. Kay and M.D. Turnbull, "Synthetic Approaches to the Avermectin Toxophore", Recent Advances in the Chemistrv of Insect Control, Ed. N.F. Janes, The Royal Society of Chemistry Special Publication No. 53, London, 1985, p. 229. A.B. Smith III and A.S. Thompson, Tetrahedron Lett., 1985, a, 4283. S. Hanessian. A. Ugolini, D. Dub;, P.J. Hodges and C. Andre, J. Am. Chem. sot 1986, 108, 2776. -' B. Fraser-Reid, H. Wolleb, R. Faghih and J. Barchi Jr., J. Am. Chem. Sot., 1987, 109, 933. T. Hiyama, K. Kimura and H. Nozaki, Tetrahedron Lett., 1981, 22, 1037. T. Hiyama, Y. Okude, K. Kimura and H. Nozaki, Bull. Chem. Sot. JDn., 1982, 55, 581. C.T. Buse and C.H. Heathcock, Tetrahedron Lett., 1978, 1685. E.J. Corey and A. Venkateswarlu, J.. Chem. Sot., 1972, 94, 6190. J.P. Pappas, W.P. Keaveney, E. Gancher and M. Berger, Tetrahedron Lett., 1966, 4273. C. Heathcock and L.A. Flippin, J. Am. Chem. 1983, 105, 1667. -> Sot. S. Hanessian and P. Lavallee, Can. J. Chem., 1975, 53, 2975. P. Deslongchamps, D.D. Rowan, N. Pothier, T. Sauve and J.K. Saunders, Can. J. (zz, 1981, 59, 1105. B.M. Trost, J.L. Belletire, S. Godleski, P.G. McDougal, J.M. Balkovec, J.J. Baldwin, M.E. Christy, G.S. Ponticello, S.L. Varga and J.P. Springer, J. Org. Chem., 1986, 5l, 2370. We thank Dr. M. Sabat, Northwestern University, for obtaining the structure of 11. 0. Mits,mobu, Synthesis, 1981, 1. We plan to invert the C-23 stereochemistry subsequent to macrocyclization. (Received
in
USA
17 Auqust
1987)