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The synthesis of substituted pyrrolidines by a samarium (II) iodide mediated ring closure.
OtMO-4039,92 S3.00 + .OO Pcrgmon Press plc
The Synthesis
Of Substituted Pyrrolidines By A Samarium Iodide Mediated Ring Closure.
Jack E. Baldwin*, Sean C. MacKenzie
(II)
Turner, and Mark G. Moloney
The Dyson Pen-ins Laboratory, University of Oxford, South Parks Road, Oxford. OX1 3QY
Abstract: Samarium (II) iodide mediated ring closures series of 2,3,4-trisubstituted pyrrolidine derivatives.
have been used to generate
a
The usefulness of samarium iodide as a versatile reagent in organic synthesis has been demonstrated widespread
application1
unusual reductive
for reduction
cyclisatior&
of a variety of functional
and intramolecular
groups2, as well as its mediation
coupling reactinns4.
potent reducing agent, induces reaction via two sequential one-electron so fotmed
are capable of undergoing
a range of carbon-carbon
The oxophilic reductions,
bond forming
samarium(I1)
species, a
and the intermediate
reactions.
by its
of a range of radicals
Using this approach,
samarium iodide mediated reactions have been used to generate a wide range of carbocycles5
and heterocyclese.
We report the extension of this reaction to the construction
(Scheme 1). These
of 2,3,4-trisubstituted
pyrrolidines
are potential precursors for the neurotoxic kainoid group of amino acids7.
0
OR Scheme 1
The required starting materials were prepared in a manner analogous to reported proceduresg39. Ester (l), prepared
from L-serine
converted
to unsaturated
appropriate
unsaturated
by esterification
(MeOH/HCl)
amine derivatives
(2) (Scheme 2 and Table 1) either by reductive
aldehyde (NaBH.&IeOH)
(in Et3N, toluene solution), chloroformate,
and protection
(TBDMSCl/EtlN,
or by alkylation with the corresponding
to give the products in yields of 16-54%. Protection
these compounds
amination propargylic
butanol in a THF/HMPA
Reaction of
in the presence of 2 equivalents
solvent mixture at OOC,gave the products (4a-g) as a mixture of diastereomers.
1.517
with the bromide
-78nC) cleanly gave
@a-g) in good yields, which were generally used without further purification.
with an excess of samarium iodide (3-4 e.quivalents)lO,
was
of the amine function (phenyl
NaFIC03, EtOAc. H20 ) followed by reduction of the ester (Dibal, toluene,
the desired aldehydes
cat. DMAP)
oft-
1518
Table 1: Reaction of Aldehydes (3) with Samarium (II) Iodide
Substrate
Approximate Reaction Time (mins)
Product, (Yield1
(3a) R=Me,C-CHCIl,-
30
(3b) R= P-M~OC~H&H.=CIICH,-
30
(4b)
R = p-MeO-
[430/o]
(3~) R= p-CF,C,H,,CII=CHCH,-
60
i&c)
R = pm CF,m
[44%]
(4d)
R = p- NOL-
[ O%]
(3d) R= p~NOzChII,CH=CHCHz~
(3e) R-
(30 R=
H-CsCCH,-
Me-CECmCH2-
(3g) R= Me$iCEC-CHZ-
15
15
7
151Y
Ml2
NHCHzR
i
RCH,
. .
‘NC(O)OPh
11,111
MeOOC
MeOOC 5
H 5
OTBDMS
OTBDMS
t
A 0
(1)
OTBDMS
(2) (3)
Reagents:
(i) RCH$r,
EtsN, toluene; or RCH(O), NaBH4, MeOH;
(ii) PhC(O)Cl, Et3N
(iii) Dihal, -78’C Scheme 2 Thus, allylic amine (3a) gave isopropyl derivative (4a) in 25% yield, as a mixture of diastereomers two new chiral centres. corresponding compound
The pmmethoxycinnamyl
products (4b) and (4d) in 43% and 44% yields respectively,
was longer. Ilowever,
simple reduction
the p-nitro-
derivative
of the nitro group. The propargyl
closures, to give the corresponding
by direct
homologation
triphenylphosphorane,
derivatives
although the reaction time for the latter
(3~) gave not the expected
derivatives
at the
(3b) and (3~) gave the cyclised
(3e-g) gave especially
product (4c), but
rapid and efficient
ring
alkenes (4e-g) in high yields.
The reaction is also applicable to vinylogous prepared
and trifluoromethyl
of aldehydes
aldehydes. The required starting aldehydes (3a) and (3g) using the Wittig
reagent,
and then treated under the standard samarium iodide conditions
(5a and 5b) were formylmethylene
(Table 2). Substrate (5a)
gave product (6a), although only in relatively low yield. However, the prenyl derivative (5b) did not undergo the desired
ring closure,
corresponding
giving
only products
(hb) arising
from
samarium
iodide-induced
ester (7), prepared in an analogous manner using carbomethoxymethylene
reduction.
The
triphenylphosphorane,
did not undergo any reaction under these conditions.
OPh OSiMe2t-Bu
Thus, samarium irxiide mediated cyclisations ring systems, and a detailed examination progress.
provide a convenient entry to highly substituted pyrrolidine
of the application of this approach to a range of natural products is in
Table 2: Reaction of Vinylogous
Substrate
Aldehydes with Samarium (II) Iodide
Reaction Time (mins)
Product, IYield]
30 GdOSiMe+Bu HG&OSiMe$-Bu
(5b)
Acknowledgements:
We thank SERC for a studentship
(6b)
(to S. C.
[27’%]
M. T.)
References, For reviews see Soderquist, J.A., Aldrichimica Acru, 1991, 24, 15-23; Kagan, H.B., New J. Chem., 1. 1990, 14, 453-460. 2. Girard, P.; Namy, J.L.; Kagan, H.B., jr. Am. Chcm. Sot., 1980, 102, 2693-2698. Molander, G.A.; Etter, J.B., J. Org. Chem., 1986, 51, 17781786; Fevig, T.L.; Elliott, R.L,; Curran, 3. D.P., J. Am. Chem. Sot., 1988, 110, 5064-5067; Martin, S.F.; Yang, C-P.; Laswell, W.L.; Rueger, H., Tetrahedron. L,ett., 1988, 27, 66856688; Enholm, E.E.; Trivellas, A., ./. Am. Chem. Sot., 1989, 111, 6463. 6465; Curran, D. P. ; Wolin, R. L.,Syn. Lett., 1991, 317-318; 4. Enholm, E.E. ; Forbes; D.C.; Holub, D.P., Syn. Cnmmun., 1990, 20, 981-987; Inanaga, J.; Katsuki, J. ; Ujikawa, 0.; Yamaguchi, M., Tetrahedrtm. Letr., 1991, 32, 4921-4924. Molander, G. A.; Kenny, C., J. Am. Chem. Sot., 1989, 111, X236-8246. 5. Shim, S. C. ; Hwang, J.-T. ; Kang, H.-Y.; Chang, M. H., Tetrahedron Lerr., 1990, 32, 4765-4768. 6. E.G.; Olney, J.W. ; McGeer, P.L. , Raven “Kainic Acid as a Tool in Neurobiology” , EdsMcGeer, 7. Press, New York, 1978, and references therein; for a review of the synthesis of kainoids, see “Synthesis of Optically Active a-Amino Acids”, Williams, R.M. , Pergamon Press, 1989, pp306-320. Baldwin, J.E.; Maloney, M.G.; Parsons, A.F., Tetrahedron, 1990,46, 7263-7282; Baldwin; J.E., 8. Maloney, M.G.; Parsons, A.F., Terrahedmn, 1991,47, 155-172. All new compounds gave satisfactory spectral and mass spectroscopic or elemental analysis data. Y. Prepared by reacting samarium metal with diiodoethane in THF solution, as described in Reference 2. 10.
(Received
in UK 7 January 1992)
The Synthesis
Of Substituted Pyrrolidines By A Samarium Iodide Mediated Ring Closure.
Jack E. Baldwin*, Sean C. MacKenzie
(II)
Turner, and Mark G. Moloney
The Dyson Pen-ins Laboratory, University of Oxford, South Parks Road, Oxford. OX1 3QY
Abstract: Samarium (II) iodide mediated ring closures series of 2,3,4-trisubstituted pyrrolidine derivatives.
have been used to generate
a
The usefulness of samarium iodide as a versatile reagent in organic synthesis has been demonstrated widespread
application1
unusual reductive
for reduction
cyclisatior&
of a variety of functional
and intramolecular
groups2, as well as its mediation
coupling reactinns4.
potent reducing agent, induces reaction via two sequential one-electron so fotmed
are capable of undergoing
a range of carbon-carbon
The oxophilic reductions,
bond forming
samarium(I1)
species, a
and the intermediate
reactions.
by its
of a range of radicals
Using this approach,
samarium iodide mediated reactions have been used to generate a wide range of carbocycles5
and heterocyclese.
We report the extension of this reaction to the construction
(Scheme 1). These
of 2,3,4-trisubstituted
pyrrolidines
are potential precursors for the neurotoxic kainoid group of amino acids7.
0
OR Scheme 1
The required starting materials were prepared in a manner analogous to reported proceduresg39. Ester (l), prepared
from L-serine
converted
to unsaturated
appropriate
unsaturated
by esterification
(MeOH/HCl)
amine derivatives
(2) (Scheme 2 and Table 1) either by reductive
aldehyde (NaBH.&IeOH)
(in Et3N, toluene solution), chloroformate,
and protection
(TBDMSCl/EtlN,
or by alkylation with the corresponding
to give the products in yields of 16-54%. Protection
these compounds
amination propargylic
butanol in a THF/HMPA
Reaction of
in the presence of 2 equivalents
solvent mixture at OOC,gave the products (4a-g) as a mixture of diastereomers.
1.517
with the bromide
-78nC) cleanly gave
@a-g) in good yields, which were generally used without further purification.
with an excess of samarium iodide (3-4 e.quivalents)lO,
was
of the amine function (phenyl
NaFIC03, EtOAc. H20 ) followed by reduction of the ester (Dibal, toluene,
the desired aldehydes
cat. DMAP)
oft-
1518
Table 1: Reaction of Aldehydes (3) with Samarium (II) Iodide
Substrate
Approximate Reaction Time (mins)
Product, (Yield1
(3a) R=Me,C-CHCIl,-
30
(3b) R= P-M~OC~H&H.=CIICH,-
30
(4b)
R = p-MeO-
[430/o]
(3~) R= p-CF,C,H,,CII=CHCH,-
60
i&c)
R = pm CF,m
[44%]
(4d)
R = p- NOL-
[ O%]
(3d) R= p~NOzChII,CH=CHCHz~
(3e) R-
(30 R=
H-CsCCH,-
Me-CECmCH2-
(3g) R= Me$iCEC-CHZ-
15
15
7
151Y
Ml2
NHCHzR
i
RCH,
. .
‘NC(O)OPh
11,111
MeOOC
MeOOC 5
H 5
OTBDMS
OTBDMS
t
A 0
(1)
OTBDMS
(2) (3)
Reagents:
(i) RCH$r,
EtsN, toluene; or RCH(O), NaBH4, MeOH;
(ii) PhC(O)Cl, Et3N
(iii) Dihal, -78’C Scheme 2 Thus, allylic amine (3a) gave isopropyl derivative (4a) in 25% yield, as a mixture of diastereomers two new chiral centres. corresponding compound
The pmmethoxycinnamyl
products (4b) and (4d) in 43% and 44% yields respectively,
was longer. Ilowever,
simple reduction
the p-nitro-
derivative
of the nitro group. The propargyl
closures, to give the corresponding
by direct
homologation
triphenylphosphorane,
derivatives
although the reaction time for the latter
(3~) gave not the expected
derivatives
at the
(3b) and (3~) gave the cyclised
(3e-g) gave especially
product (4c), but
rapid and efficient
ring
alkenes (4e-g) in high yields.
The reaction is also applicable to vinylogous prepared
and trifluoromethyl
of aldehydes
aldehydes. The required starting aldehydes (3a) and (3g) using the Wittig
reagent,
and then treated under the standard samarium iodide conditions
(5a and 5b) were formylmethylene
(Table 2). Substrate (5a)
gave product (6a), although only in relatively low yield. However, the prenyl derivative (5b) did not undergo the desired
ring closure,
corresponding
giving
only products
(hb) arising
from
samarium
iodide-induced
ester (7), prepared in an analogous manner using carbomethoxymethylene
reduction.
The
triphenylphosphorane,
did not undergo any reaction under these conditions.
OPh OSiMe2t-Bu
Thus, samarium irxiide mediated cyclisations ring systems, and a detailed examination progress.
provide a convenient entry to highly substituted pyrrolidine
of the application of this approach to a range of natural products is in
Table 2: Reaction of Vinylogous
Substrate
Aldehydes with Samarium (II) Iodide
Reaction Time (mins)
Product, IYield]
30 GdOSiMe+Bu HG&OSiMe$-Bu
(5b)
Acknowledgements:
We thank SERC for a studentship
(6b)
(to S. C.
[27’%]
M. T.)
References, For reviews see Soderquist, J.A., Aldrichimica Acru, 1991, 24, 15-23; Kagan, H.B., New J. Chem., 1. 1990, 14, 453-460. 2. Girard, P.; Namy, J.L.; Kagan, H.B., jr. Am. Chcm. Sot., 1980, 102, 2693-2698. Molander, G.A.; Etter, J.B., J. Org. Chem., 1986, 51, 17781786; Fevig, T.L.; Elliott, R.L,; Curran, 3. D.P., J. Am. Chem. Sot., 1988, 110, 5064-5067; Martin, S.F.; Yang, C-P.; Laswell, W.L.; Rueger, H., Tetrahedron. L,ett., 1988, 27, 66856688; Enholm, E.E.; Trivellas, A., ./. Am. Chem. Sot., 1989, 111, 6463. 6465; Curran, D. P. ; Wolin, R. L.,Syn. Lett., 1991, 317-318; 4. Enholm, E.E. ; Forbes; D.C.; Holub, D.P., Syn. Cnmmun., 1990, 20, 981-987; Inanaga, J.; Katsuki, J. ; Ujikawa, 0.; Yamaguchi, M., Tetrahedrtm. Letr., 1991, 32, 4921-4924. Molander, G. A.; Kenny, C., J. Am. Chem. Sot., 1989, 111, X236-8246. 5. Shim, S. C. ; Hwang, J.-T. ; Kang, H.-Y.; Chang, M. H., Tetrahedron Lerr., 1990, 32, 4765-4768. 6. E.G.; Olney, J.W. ; McGeer, P.L. , Raven “Kainic Acid as a Tool in Neurobiology” , EdsMcGeer, 7. Press, New York, 1978, and references therein; for a review of the synthesis of kainoids, see “Synthesis of Optically Active a-Amino Acids”, Williams, R.M. , Pergamon Press, 1989, pp306-320. Baldwin, J.E.; Maloney, M.G.; Parsons, A.F., Tetrahedron, 1990,46, 7263-7282; Baldwin; J.E., 8. Maloney, M.G.; Parsons, A.F., Terrahedmn, 1991,47, 155-172. All new compounds gave satisfactory spectral and mass spectroscopic or elemental analysis data. Y. Prepared by reacting samarium metal with diiodoethane in THF solution, as described in Reference 2. 10.
(Received
in UK 7 January 1992)