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Asymmetric aldol and alkylation reactions mediated by the “quat” chiral auxiliary (R)-(−)-5-methyl-3,3-dimethyl-2-pyrrolidinone
oo40_4039(94)EO250-2
Asymmetric Aldd
and Alkyldion
Medlated by the “Quat” Chid Auxiliary
React&u
(RH-)-5-Metb~-3~~e~yl-2-Pgrrolidin
Absrcl
:
Bnolates derived from the N-propionoyl derivative of the “quat” chiral auxihary (RI-
(-)-S-methyl-3.3~dimethyl-2-pyrrolidinone undergo highly stereoselective aldol and alkylation reactions. Removal of the auxiliary has been demonstrated with LiOH, PhCH2OLi. MeOMgBr and LiAlH4 to generate respectively
(~,3~)-3-hyd~xy-2-me~yl-3-p~nylp~pio~c
homochiral form, and with 96% e-e. (~-2-~~yl-~p~ylp~pionic
acid in
acid and derived methyl
and benzyl esters and with >94% e.e. (s)_2-methyl-3-pbenylpropanoL In a pteceeding communication1 we have reported a synthetic route to the homochiml S-substituted3,34imethyl-2-pyrrolidinones,
“quat” chiml auxiliarks, and demonstrated that the steric effect of the gem-
dimethyl group is beneficial for increasing selectivity LiOH as the nucleop~e.
in the cleavage of their IV-acyl derivatives using
We demonstrate here examples of the synthetic utility of these quat chii
auxiliaries by reporting highly stereoselective aldol and alkylation reactions of enolates derived from the Npropionoyl derivative of (RH-)-s-methyl-3,3~yl-2-p~~0~ Treatment of the “quat” chiral auxiliary
1.
(R)-(-)-S-methyl-3.3~dimethyl-2-pyrrolidinone
1 with
butyllithium followed by propionoyl chloride generated tbe N-propionoyl derivative 2 in 90% yield. Using the dibutylboron methodology developed by Evans2, the syn aldol product 3 was obtained as a single diastereoisomer (~47% d.e.) by 3OOMHz NMR spectroscopy (Scheme I). 0
%b/ NH
*., ‘..
i) BuLi
ii) BtCOCl
0
0
%5 N A/
\,
+
i) BuaBOTf (1.1 eq.)
OH Ph
iii) PhCHO (1.2 eq.) 4!$Y iv) H202
1
0
ii) ‘PraNB4(1.2 eq.)
2
S,,
3 yield St%; de. ~97%
sebclnel In a representative procedure, a methylene chloride solution of the ZV-propionoyl pyrrolidinoae 3 at O’C uuder an argon atmosphere, was treated s uccessively (l.lcq.)
in methykne chloride, and then dikpropylethylamine
with a l.OM solution of dibutylboron t&late (1.2eq.). To the resulting solution cooled to
-78% was added benxaldehyde (1.2eq.) and this mixture was stirred for 1 h at -78% and 1.5 h at O’C. The
2373
2374
reaction was then quenched by addition of pH 7 phosphate buffer solution and methanol, and treated with methanolic hydrogen peroxide at o’C for 1 h spectroscopy
indicated
crystalline
adduct
stereochemistry
the presence
Analysis of the crude product mixture by 300 MHz 1H NMR
of only one diastereoisomeric
3 was purified
by flash column
product 3 (d.e. > 97%).
chromatogmphy
on silica
gel. The syn relative
of the aldol product was assigned ou the basis of 1H NMR coupling
coupling constant Hz-H3 measutud for the product 3 was 3.OHz. consistent stemocbemistry.
The absolute
con~g~tions
of the new stereogenic
coustants3.
Comparison
3-hydroxy-Z-methyl-3-phenylpmpionic
of the specific rotation
([a]D 2* = +X.8
The
with the expected syn relative
centms in 3 were assigned
removal of the chiral auxihary. Hydrolysis of 3 using LiOH in a 3:l mixture of ~~y~~ O‘C generated
The non
after
and water at
acid 4 as a single diastemoisomer
in 94% yield.
(c 0.5, CHzC12)) of the crystallii
3-hydroxy-2-
acid 4 thus obtained, with the literatute value2 for (2&3S)-4 ([CZ@ = -26.4 (c
methyl-3-phenylpropionic 1.04. CHzClz)} established
its absolute configuration
was tucovered nearly quantitatively
as (2R,3R), (Scheme 2). The quat chiml auxiliary
in this hydrolysis
with no products from endocyclic
1
cleavage being
observed. 0
OH
%I!$~
LiOH (2.3eq.f
Ph
*
HOvPh
derivative
to enolate alkylation
reactions.495
The lithium
enolate of the N-
2 was formed in ‘IHF by addition at O’C of lithium diisopropylamide
After 1 h at O’C an excess (3eq.) of benxyl bromide was added.
LDA (1.0&q.
The reaction
by addition of pH 7 phosphate buffer solution and the crude product 5 extracted
ether. The diastereomeric NMR spectroscopic removal
1
(WW
We next turned our attention solution in THF).
94% yieG
84% yield
O°C 3
quenched
>e:
THF/H*O (3: 1)
%‘,
propionoyl
+
excess of the
analysis
of the auxiliary,
corresponding
cnrdc
al@lated product was determined
(Scheme 3) with the relative configurations as described
3-phenylpropionoyl
below.
derivative
a diastereoisomeric
Quenching
6 with methyl
diastereoisomer
7 with
diastereoisomers
5 and 7 were 82% and 62% respectively.
excess
as 96% by 300 MHz *H
being assigned after hydrolytic
the lithium iodide
was
with diethyl
enolate
generated
of 89% (Scheme
derived
from the
the complementary
3). The
yields
of purified
The yields and diastereoselectivities
for these
alkylation reactions am comparable with those reported by Evans et al using lithium enolates derived from 4-substituted
oxaxolidin-2-ones.4~5
The non crystalline U~o~~a~ly,
the separation
observed for the formation instabiity
products
were purified
of the diastereoisomers
of 7 can be expiained
by flash column
chromatography
formed could not be achieved.
by a slower
alkylation
with methyl
of the lithium enolate at WC, which decomposes via a ketene pathway.
the absolute configuration
on silica
gel.
The lower yield iodide and the
As for the aldol produtxs,
of the new stereogenic cenuus in 5 and 6 could be assigned by comparison
of the
2375
specific rotation of the products obtained after hydrolytic or teductive removal of the auxiliary with literature values.
i) LDA (1.85 eq.) 82% yield 96% d.e.
ii) PbCHaBr (3 eq.)
i) IXiA (1.85 eq.) 62% yield 89% d.e.
ii) Me1 (3 eq.) 7
6 fWeme3
Treatment of diastereoisomer 5 (96% d.e.)with LiOH, MeOMgBr, and PhCHzOLi gave rise to CD 2~me~yI-3-p~ylp~pio~c acid 8 and thecorresponding metbyl ester 9 and benxyl ester 10mspedively. 0
d* X, *
ROPh
5
* LiOH MeOMgBr PhCHaOLi
ROY
+*; +
Ph 8-10
1
%% d-e. Product
R
Yii
e.e
Wn2’
8
H
83%
95%
+28.6 (c 1.O,CHCIS)
95%
9
Me
82%
%%
+34.5 (c 0.8, CHCl$
92%
PhCHs
94%
%%
+25.7 (c 1.15, CHCl,)
97%
10
Yiid of I
Scheme 4 1H NMR spectroscopic analysis of each of the crude products g-10 from these different react&us indicated in each case the total absence of endocyciic cleavage. The absolute ~o~~atio~ (s) and enantiomeric purity of products S-10 were determined by comparison of their specific rotations with the Iiteratutt values and/or by 1H NMR spectroscopic analysis using cbiral shift reagents 6. No si@ficant mcemisation occurred during these cleavage reactions. Pinally treatment of 5 (96% d-e.) with an excess of LiAlH.4 in THP at 0°C fumisbed in 84% yieId the alcohol (s)_ll+94% e.e.>[aba = -10.3 (c 0.9, benzene),lit_?[abw = -11 (c 4.6, benzene) and the auxiliary 1 in practicaIly quantitative yield.
2376
1
81% yield O-11
5 SeIteme5
In conclusion the results presented in this communication show the “quat” chiral auxibary (Z+o)-5methyl-3.3~dlmethyl-2-pyrrolldlnone 1 to he.a very effective chiral auxiliary in asymmetric alkylations and aldol reactions. In particular the reactions to remove the chlral auxiliary from the elaborated substrate occur very efficiently allowing effective recovery of the “quat” chlral auxiliary. We thank the SERC, the CNRS and the Royal society for support and Oxford Asymmetry Limited for the generous gift of materials. Refe-
1
ad
notes
See pmceedlng communication.
2
Gage, JR.; Evans, D.A. Org. Syn., 1990.68,83.
3
Heathcock, C.H.; Plrrun8, M.C.; Sohn, JE. J. Org. Chem, IWS, 44.4294.
4
For review see Evans, D.A. Asymmetric Jynthcsis , ed. Morrison. Academic Press. 1964. ~013. p. 1.
5
Evans, D-A_; AZdrichimica AC&, 1982,Z5,23 ; Evans. D.A.; Ennis, MD.; Mathre, D-J. Z. Am
6
Chem sot.. 1992, Z14.5971. Terashlma, S.; Yamada, S.-I. Chem fhurm
Bull., 1968,26, 1816, (Q-(+)-S [a]$
benzene) ; Margolln. AL_; Del&k. D.L. Tetrahedron Letr.. WJO. 31,6797,
= +30 (c 4.9,
(S)-(+)-9 [aJ#
=
+35.9 (c 1.0, CHC13) ; Evans, D.A.; Ennls, M.D.; Mathre. D.J. Z.Am Chem Sot., 1982,104, 1737, (R>(->lO [a]# = -26.9 (c 6.12. CH$ld ; The enantiomuic excesses. have been determined by lH NMR spectroscopic analysis in the presence of (R, R)- diphenyldlaminoethane for 8, Parker, D.; Fulwood. R. Tetrahedron Asymmetry, 1992,3.25
and trls[3-(‘heptafluoropropylhydroxy-methylene)-(+)-camphoratol europium (III) for
10, Goeting, H.L.; Elkenberry, J.N.; Koermer, G.S. J. Am. Chem Sot., 1971.93.5913. 7
Terashlla, S.; Yamada, S.-I. Chcm Pharm BuZL, l!X&Z6,1953.
(Received in UK 17 November 1993; revised 3 February 1994, accepted 4 February 1994)
Asymmetric Aldd
and Alkyldion
Medlated by the “Quat” Chid Auxiliary
React&u
(RH-)-5-Metb~-3~~e~yl-2-Pgrrolidin
Absrcl
:
Bnolates derived from the N-propionoyl derivative of the “quat” chiral auxihary (RI-
(-)-S-methyl-3.3~dimethyl-2-pyrrolidinone undergo highly stereoselective aldol and alkylation reactions. Removal of the auxiliary has been demonstrated with LiOH, PhCH2OLi. MeOMgBr and LiAlH4 to generate respectively
(~,3~)-3-hyd~xy-2-me~yl-3-p~nylp~pio~c
homochiral form, and with 96% e-e. (~-2-~~yl-~p~ylp~pionic
acid in
acid and derived methyl
and benzyl esters and with >94% e.e. (s)_2-methyl-3-pbenylpropanoL In a pteceeding communication1 we have reported a synthetic route to the homochiml S-substituted3,34imethyl-2-pyrrolidinones,
“quat” chiml auxiliarks, and demonstrated that the steric effect of the gem-
dimethyl group is beneficial for increasing selectivity LiOH as the nucleop~e.
in the cleavage of their IV-acyl derivatives using
We demonstrate here examples of the synthetic utility of these quat chii
auxiliaries by reporting highly stereoselective aldol and alkylation reactions of enolates derived from the Npropionoyl derivative of (RH-)-s-methyl-3,3~yl-2-p~~0~ Treatment of the “quat” chiral auxiliary
1.
(R)-(-)-S-methyl-3.3~dimethyl-2-pyrrolidinone
1 with
butyllithium followed by propionoyl chloride generated tbe N-propionoyl derivative 2 in 90% yield. Using the dibutylboron methodology developed by Evans2, the syn aldol product 3 was obtained as a single diastereoisomer (~47% d.e.) by 3OOMHz NMR spectroscopy (Scheme I). 0
%b/ NH
*., ‘..
i) BuLi
ii) BtCOCl
0
0
%5 N A/
\,
+
i) BuaBOTf (1.1 eq.)
OH Ph
iii) PhCHO (1.2 eq.) 4!$Y iv) H202
1
0
ii) ‘PraNB4(1.2 eq.)
2
S,,
3 yield St%; de. ~97%
sebclnel In a representative procedure, a methylene chloride solution of the ZV-propionoyl pyrrolidinoae 3 at O’C uuder an argon atmosphere, was treated s uccessively (l.lcq.)
in methykne chloride, and then dikpropylethylamine
with a l.OM solution of dibutylboron t&late (1.2eq.). To the resulting solution cooled to
-78% was added benxaldehyde (1.2eq.) and this mixture was stirred for 1 h at -78% and 1.5 h at O’C. The
2373
2374
reaction was then quenched by addition of pH 7 phosphate buffer solution and methanol, and treated with methanolic hydrogen peroxide at o’C for 1 h spectroscopy
indicated
crystalline
adduct
stereochemistry
the presence
Analysis of the crude product mixture by 300 MHz 1H NMR
of only one diastereoisomeric
3 was purified
by flash column
product 3 (d.e. > 97%).
chromatogmphy
on silica
gel. The syn relative
of the aldol product was assigned ou the basis of 1H NMR coupling
coupling constant Hz-H3 measutud for the product 3 was 3.OHz. consistent stemocbemistry.
The absolute
con~g~tions
of the new stereogenic
coustants3.
Comparison
3-hydroxy-Z-methyl-3-phenylpmpionic
of the specific rotation
([a]D 2* = +X.8
The
with the expected syn relative
centms in 3 were assigned
removal of the chiral auxihary. Hydrolysis of 3 using LiOH in a 3:l mixture of ~~y~~ O‘C generated
The non
after
and water at
acid 4 as a single diastemoisomer
in 94% yield.
(c 0.5, CHzC12)) of the crystallii
3-hydroxy-2-
acid 4 thus obtained, with the literatute value2 for (2&3S)-4 ([CZ@ = -26.4 (c
methyl-3-phenylpropionic 1.04. CHzClz)} established
its absolute configuration
was tucovered nearly quantitatively
as (2R,3R), (Scheme 2). The quat chiml auxiliary
in this hydrolysis
with no products from endocyclic
1
cleavage being
observed. 0
OH
%I!$~
LiOH (2.3eq.f
Ph
*
HOvPh
derivative
to enolate alkylation
reactions.495
The lithium
enolate of the N-
2 was formed in ‘IHF by addition at O’C of lithium diisopropylamide
After 1 h at O’C an excess (3eq.) of benxyl bromide was added.
LDA (1.0&q.
The reaction
by addition of pH 7 phosphate buffer solution and the crude product 5 extracted
ether. The diastereomeric NMR spectroscopic removal
1
(WW
We next turned our attention solution in THF).
94% yieG
84% yield
O°C 3
quenched
>e:
THF/H*O (3: 1)
%‘,
propionoyl
+
excess of the
analysis
of the auxiliary,
corresponding
cnrdc
al@lated product was determined
(Scheme 3) with the relative configurations as described
3-phenylpropionoyl
below.
derivative
a diastereoisomeric
Quenching
6 with methyl
diastereoisomer
7 with
diastereoisomers
5 and 7 were 82% and 62% respectively.
excess
as 96% by 300 MHz *H
being assigned after hydrolytic
the lithium iodide
was
with diethyl
enolate
generated
of 89% (Scheme
derived
from the
the complementary
3). The
yields
of purified
The yields and diastereoselectivities
for these
alkylation reactions am comparable with those reported by Evans et al using lithium enolates derived from 4-substituted
oxaxolidin-2-ones.4~5
The non crystalline U~o~~a~ly,
the separation
observed for the formation instabiity
products
were purified
of the diastereoisomers
of 7 can be expiained
by flash column
chromatography
formed could not be achieved.
by a slower
alkylation
with methyl
of the lithium enolate at WC, which decomposes via a ketene pathway.
the absolute configuration
on silica
gel.
The lower yield iodide and the
As for the aldol produtxs,
of the new stereogenic cenuus in 5 and 6 could be assigned by comparison
of the
2375
specific rotation of the products obtained after hydrolytic or teductive removal of the auxiliary with literature values.
i) LDA (1.85 eq.) 82% yield 96% d.e.
ii) PbCHaBr (3 eq.)
i) IXiA (1.85 eq.) 62% yield 89% d.e.
ii) Me1 (3 eq.) 7
6 fWeme3
Treatment of diastereoisomer 5 (96% d.e.)with LiOH, MeOMgBr, and PhCHzOLi gave rise to CD 2~me~yI-3-p~ylp~pio~c acid 8 and thecorresponding metbyl ester 9 and benxyl ester 10mspedively. 0
d* X, *
ROPh
5
* LiOH MeOMgBr PhCHaOLi
ROY
+*; +
Ph 8-10
1
%% d-e. Product
R
Yii
e.e
Wn2’
8
H
83%
95%
+28.6 (c 1.O,CHCIS)
95%
9
Me
82%
%%
+34.5 (c 0.8, CHCl$
92%
PhCHs
94%
%%
+25.7 (c 1.15, CHCl,)
97%
10
Yiid of I
Scheme 4 1H NMR spectroscopic analysis of each of the crude products g-10 from these different react&us indicated in each case the total absence of endocyciic cleavage. The absolute ~o~~atio~ (s) and enantiomeric purity of products S-10 were determined by comparison of their specific rotations with the Iiteratutt values and/or by 1H NMR spectroscopic analysis using cbiral shift reagents 6. No si@ficant mcemisation occurred during these cleavage reactions. Pinally treatment of 5 (96% d-e.) with an excess of LiAlH.4 in THP at 0°C fumisbed in 84% yieId the alcohol (s)_ll+94% e.e.>[aba = -10.3 (c 0.9, benzene),lit_?[abw = -11 (c 4.6, benzene) and the auxiliary 1 in practicaIly quantitative yield.
2376
1
81% yield O-11
5 SeIteme5
In conclusion the results presented in this communication show the “quat” chiral auxibary (Z+o)-5methyl-3.3~dlmethyl-2-pyrrolldlnone 1 to he.a very effective chiral auxiliary in asymmetric alkylations and aldol reactions. In particular the reactions to remove the chlral auxiliary from the elaborated substrate occur very efficiently allowing effective recovery of the “quat” chlral auxiliary. We thank the SERC, the CNRS and the Royal society for support and Oxford Asymmetry Limited for the generous gift of materials. Refe-
1
ad
notes
See pmceedlng communication.
2
Gage, JR.; Evans, D.A. Org. Syn., 1990.68,83.
3
Heathcock, C.H.; Plrrun8, M.C.; Sohn, JE. J. Org. Chem, IWS, 44.4294.
4
For review see Evans, D.A. Asymmetric Jynthcsis , ed. Morrison. Academic Press. 1964. ~013. p. 1.
5
Evans, D-A_; AZdrichimica AC&, 1982,Z5,23 ; Evans. D.A.; Ennis, MD.; Mathre, D-J. Z. Am
6
Chem sot.. 1992, Z14.5971. Terashlma, S.; Yamada, S.-I. Chem fhurm
Bull., 1968,26, 1816, (Q-(+)-S [a]$
benzene) ; Margolln. AL_; Del&k. D.L. Tetrahedron Letr.. WJO. 31,6797,
= +30 (c 4.9,
(S)-(+)-9 [aJ#
=
+35.9 (c 1.0, CHC13) ; Evans, D.A.; Ennls, M.D.; Mathre. D.J. Z.Am Chem Sot., 1982,104, 1737, (R>(->lO [a]# = -26.9 (c 6.12. CH$ld ; The enantiomuic excesses. have been determined by lH NMR spectroscopic analysis in the presence of (R, R)- diphenyldlaminoethane for 8, Parker, D.; Fulwood. R. Tetrahedron Asymmetry, 1992,3.25
and trls[3-(‘heptafluoropropylhydroxy-methylene)-(+)-camphoratol europium (III) for
10, Goeting, H.L.; Elkenberry, J.N.; Koermer, G.S. J. Am. Chem Sot., 1971.93.5913. 7
Terashlla, S.; Yamada, S.-I. Chcm Pharm BuZL, l!X&Z6,1953.
(Received in UK 17 November 1993; revised 3 February 1994, accepted 4 February 1994)