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Tandem zinc mediated reductive cleavage-reductive amination as a new approach to substituted pyrrolidines from homoallylic amines
Tetrahedron Letters, Vol. 36, No. 17, pp. 2971-2974, 1995
Pergamon
Elsevier Science Ltd Printed in Great Britain 0040-4039/95 $9.50+0.00
0040-4039(95)00354-1
Tandem Zinc Mediated Reductive Cleavage-Reductive Amination as a New Approach to Substituted Pyrrolidines from Homoallylic Amines
Corinne Vanucci, Xavier Brusson, Val~rie Verdel, Fr~d~rique Zana, Hamid Dhimane and G~rard Lhommet* Universit6P. et M. Curie, Laboratoirede Chimie des Hrt6rocycles,associ6au CNRS, 4 Place Jussieu, F75252 Paris cedex 05.
A b s t r a c t : N-Boc or N-Cbz homoallylic amines are convened in four steps into pyrrolidines through a
sequence involving as a key-step a tandem zinc mediated reductive cleavage-reductiveamination from an intermediate 1,3-oxazin-2-one During the course of a program directed toward the synthesis of the 1,2-cyclopentanoindolizidine 5a, a representative fragment of the steroidal alkaloid solanidine1, we observed, in line with some unexpected results recently reported 2, that, under acidic catalysis, epoxide 2a 3 was very prone to an intramolecular attack by the carbamate moiety to afford 1,3-oxazin-2-one 3a, in high yield. At this point, we envisionned that oxidation of the hydroxyl group followed by a zinc mediated cleavage of the carbamate substituant, according to a known methodology for a-oxygenated ketones4, would afford a y-amino ketone. Hopefully, this intermediate would undergo a reductive amination to afford directly the expected heterocycle. Much to our delight, oxazinone 4a, upon treatment with zinc in refuxing acetic acid, led to compound 5a, as a (6:4) mixture of diastereoisomers (Scheme 1).
I
o
IH+l
tOI
. 2a
. OH
o..Zo o
3a
4a
Zn,H + b
5a
Scheme I
Considering that cyclic amines has long attracted considerable synthetic efforts owing to their ubiquity in • .
5
a wide range of natural products, such as 2,5-dialkyl pyrrohdmes as well as in other molecules of biological importance, we decided to investigate the scope and limitations of a similar methodology, starting from various homoallylic amines, as a new way to synthesize substituted pyrrolidines.
2971
2972
Hereafter, we report the results of this study that demonstrates that pyrrolidines 5 can indeed be prepared from homoallylic amines 1, through a five step sequence which is formally equivalent to a disfavored direct 5endo-trig ring closure from 1. R4 32~H~
1
Rs
R •
Rz
R1
~
R4 N
I
Rs
RI
1
5
Amines lb-i were first converted into methyl, benzyl or t-butyl carbamates and these compounds were, in turn, epoxidized by treatment with m-CPBA in a buffered two-phase system 6, to afford epoxides 2 quantitatively (Table 1) . Noteworthy was a sharp decrease of isolated yield for some of these compounds (Entries d-f) after column chromatography. Due to their acid sensitiveness, these compounds were indeed partially converted into oxazinones 3 on silica gel. Fortunately, crude epoxides were generally pure enough to be used in the next step without any purification. Subsequent treatment of 2 in the presence of p-TSA or TFA in anhydrous methanol, at room temperature,
led to the regioselective intramolecular epoxide opening to
afford cyclic carbamates 3 in good yields. Whereas catalytic amounts (0.1-0.2 molar equiv) of acid were generally sufficient to complete the reaction in about 1 hour, the reactions with compounds 2d and 2h required l molar equivalent to proceed efficiently in the same lenght of time. Moreover, t-butyl carbamates usually reacted faster than their benzyl analogues, whereas methyl carbamate 2c in the presence of 1 equivalent of acid was found to lead to a complex mixture from which oxazinone 3c could be isolated only in modest yield (Entry c). Finally, when applied to 2i, our procedure did not deliver 3i but rather a complex mixture owing to the position of the phenyl group that probably disfavored the expected cyclisation and hence, allowed the occurrence of side reactions.
--
OH
OH
--
R.I R~
Rs
R~',,,,~
O
i
ii
jCO2-R' R2
N
J
R~
Reagents
•
I
I 2
m
R!
_
R~
3
i) R'OCOCI, K_,CO3,acetone (R' = Me or Bn) or Boc,O, CHCIs-H:O, NaHCOs-NaCI (R' = tBu); ii)
m-CPBA, CH2Cl2-phosphate buffer; iii) p-TSA or TFA, MeOH Scheme 2
2973
1 ' Synthesis of Cyclic Carbamates 3
Table
Yield (%)b Entry
R1
R2
R3
R4
R5
R'
Epoxide 2
Carbamate 3 e
aa
-(CH2)4-
ctCH3
-(CH2)r
Bn
80 d
95
ba
-(CH2)4-
I3CH3
-(CH2)3-
Bn
69 d
95
c
H
H
H
-
(CH2)4 -
Me
60 c
10
d
H
H
H
-
(CH2)4 -
Bn
88 c (48 d)
68
e
H
H
H
-
(CH2)4 -
tBu
86 c (48 d)
92
f
H
H
H
H
C~Hu
tBu
90 c (40 d)
8l
g
H
H
H
CH3
tBu
74 d
88
H
H
H
Bn
75 d
73
H
H
C6H5
tBu
93 c
<5
h i
C6H5
-(CH2)3H
H
b
.
•
a See ref. 3 for the synthesis of the starting material, all compounds gave satisfactory spectroscopic data, c yield of crude epoxide, d isolated yield after column chromatography on silica gel, e 0.2 molar equiv, of acid was used except for 2e, 2d and 2h for which 1 molar equiv, was required. The intermediate oxazinones 3a-g were then oxidized without event to the corresponding ketones 4 in satisfactory yields using PDC in CH2C12, in the presence of 4,g, molecular sieves and a catalytic amount of AcOH 7. On the other hand, attempted isolation of aldehyde 4h invariably resulted in extensive degradation of the reaction mixture • neither the previous conditions nor other oxidation methods (Swern, Dess-Martin ...) could deliver a trace of the expected compound. Finally, the obtained ct-oxygenated ketones 4 were treated with zinc in refuxing acetic acid for 24 hours. Under these conditions, the non-isolated intermediate amino ketone underwent an m-situ reductive amination leading directly, as previously observed for 4a, to the expected substituted pyrrolidines 5 in good yields (Table 2). Whereas 5b and 5e were obtained stereoselectively as a single isomer,
compounds
5a and fig were both shown to be a
mixture of
diastereoisomers (respectively 60:40 and 85:15 ratios). The different stereochemical outcomes for compounds 5a and 5b were ascribed to a probable consequence of the different steric environments in the two transition states of the reductive amination step. O
s.,}-.,, I R,
s,]
4
Reagems " i) PDC, 4A molecular sieves, CH2C12, AcOH; ii) Zn, AcOH. Scheme 3
2974
T a b l e 2 : Synthesis ofPyrrolidines 5
Entry
a
b
e
f
g
h
Ketone 4a Yield (%)
72
81
70
68
66
b
79
75
56c
63 c
57c
H
II
Pyrrolidine 5a Yield (%)
C,Hs H
1t
H
a all compounds gave satisfactor spectroscopic data; degradation upon isolation; c isolated yield as the corresponding Boc or Cbz carbamate; d (6:4) mixture of diastereoisomers according to capillary GC; NMR f experiments did not allow their identification; e stereochemistry assigned thanks to NOE experiments; stereochemistry assigned by comparaison of the L3CNMR spectrum with the published dataS; g cis-trans (85:15) diastereoisomeric mixture determined by capillary GC and stereochemistry determined by RX crystallography of the major isomer. We have developed a new approach to pyrrolidines from homoallylic amines featuring an intramolecular epoxide opening by a carbamate group and a final zinc mediated reductive cleavage-reductive amination from an intermediate 1,3-oxazin-2-one. Further applications of this new methodology to the synthesis of natural products are under way in our laboratory.
Acknowledgements : We are grateful to Dr O. Convert for NMR experiments and to Dr E. Bacque for fruitful discussions. R e f e r e n c e s a n d notes
I.
Schreiber, K ; R6nsch, H Te/rahedron 1965, 21, 645-650.
2.
Urabe, H.; Aoyama, Y.; Sato, F Tetrahedron 1992, 48, 5639-5646. Romeo, S.; Rich, D H Tetrahedron
Lett. 1993, 34, 7187-7190. 3.
The two stereoisomers 2a and 2b were obtained according to the following sequence :
, ~
2) l~:o •
/" " "'~ ~
2)anococl,KzcO3 /" " II
~
+
3) 112-5% Rh/C
w
0
3) SOC|2, Pyridine 4) m-CPBA 33 : 67
" n
I
0
I
+ 2a
2b
4.
Rosenfeld, R.S.; Gallagher, T.F.J. Am. Chem. Soc. 1955, 77, 4367-4370.
5.
Bacos, D.; Basselier, J.J.; Cd6rier, J.P.; Lange, C.; Marx, E.; Lhommet, G.; Escoubas, P.; Lemaire, M.; Clement, J.L Tetrahedron Lett. 1988, 29, 3061-3064.
6.
Imuta, M.; Ziffer, H. J. Org. Chem. 1979, 44, 1351-1352.
7.
Czernecki, S.; Georgoulis, C ; Stevens, C.L TetrahedronLett. 1985, 26, 1699-1702.
8.
Mokotoff, H.; Scott, T.H.J. Heterocyclic Chem. 1988, 25, 65-71;
(Received in France 5 February 1995; accepted 20 February 1995)
Pergamon
Elsevier Science Ltd Printed in Great Britain 0040-4039/95 $9.50+0.00
0040-4039(95)00354-1
Tandem Zinc Mediated Reductive Cleavage-Reductive Amination as a New Approach to Substituted Pyrrolidines from Homoallylic Amines
Corinne Vanucci, Xavier Brusson, Val~rie Verdel, Fr~d~rique Zana, Hamid Dhimane and G~rard Lhommet* Universit6P. et M. Curie, Laboratoirede Chimie des Hrt6rocycles,associ6au CNRS, 4 Place Jussieu, F75252 Paris cedex 05.
A b s t r a c t : N-Boc or N-Cbz homoallylic amines are convened in four steps into pyrrolidines through a
sequence involving as a key-step a tandem zinc mediated reductive cleavage-reductiveamination from an intermediate 1,3-oxazin-2-one During the course of a program directed toward the synthesis of the 1,2-cyclopentanoindolizidine 5a, a representative fragment of the steroidal alkaloid solanidine1, we observed, in line with some unexpected results recently reported 2, that, under acidic catalysis, epoxide 2a 3 was very prone to an intramolecular attack by the carbamate moiety to afford 1,3-oxazin-2-one 3a, in high yield. At this point, we envisionned that oxidation of the hydroxyl group followed by a zinc mediated cleavage of the carbamate substituant, according to a known methodology for a-oxygenated ketones4, would afford a y-amino ketone. Hopefully, this intermediate would undergo a reductive amination to afford directly the expected heterocycle. Much to our delight, oxazinone 4a, upon treatment with zinc in refuxing acetic acid, led to compound 5a, as a (6:4) mixture of diastereoisomers (Scheme 1).
I
o
IH+l
tOI
. 2a
. OH
o..Zo o
3a
4a
Zn,H + b
5a
Scheme I
Considering that cyclic amines has long attracted considerable synthetic efforts owing to their ubiquity in • .
5
a wide range of natural products, such as 2,5-dialkyl pyrrohdmes as well as in other molecules of biological importance, we decided to investigate the scope and limitations of a similar methodology, starting from various homoallylic amines, as a new way to synthesize substituted pyrrolidines.
2971
2972
Hereafter, we report the results of this study that demonstrates that pyrrolidines 5 can indeed be prepared from homoallylic amines 1, through a five step sequence which is formally equivalent to a disfavored direct 5endo-trig ring closure from 1. R4 32~H~
1
Rs
R •
Rz
R1
~
R4 N
I
Rs
RI
1
5
Amines lb-i were first converted into methyl, benzyl or t-butyl carbamates and these compounds were, in turn, epoxidized by treatment with m-CPBA in a buffered two-phase system 6, to afford epoxides 2 quantitatively (Table 1) . Noteworthy was a sharp decrease of isolated yield for some of these compounds (Entries d-f) after column chromatography. Due to their acid sensitiveness, these compounds were indeed partially converted into oxazinones 3 on silica gel. Fortunately, crude epoxides were generally pure enough to be used in the next step without any purification. Subsequent treatment of 2 in the presence of p-TSA or TFA in anhydrous methanol, at room temperature,
led to the regioselective intramolecular epoxide opening to
afford cyclic carbamates 3 in good yields. Whereas catalytic amounts (0.1-0.2 molar equiv) of acid were generally sufficient to complete the reaction in about 1 hour, the reactions with compounds 2d and 2h required l molar equivalent to proceed efficiently in the same lenght of time. Moreover, t-butyl carbamates usually reacted faster than their benzyl analogues, whereas methyl carbamate 2c in the presence of 1 equivalent of acid was found to lead to a complex mixture from which oxazinone 3c could be isolated only in modest yield (Entry c). Finally, when applied to 2i, our procedure did not deliver 3i but rather a complex mixture owing to the position of the phenyl group that probably disfavored the expected cyclisation and hence, allowed the occurrence of side reactions.
--
OH
OH
--
R.I R~
Rs
R~',,,,~
O
i
ii
jCO2-R' R2
N
J
R~
Reagents
•
I
I 2
m
R!
_
R~
3
i) R'OCOCI, K_,CO3,acetone (R' = Me or Bn) or Boc,O, CHCIs-H:O, NaHCOs-NaCI (R' = tBu); ii)
m-CPBA, CH2Cl2-phosphate buffer; iii) p-TSA or TFA, MeOH Scheme 2
2973
1 ' Synthesis of Cyclic Carbamates 3
Table
Yield (%)b Entry
R1
R2
R3
R4
R5
R'
Epoxide 2
Carbamate 3 e
aa
-(CH2)4-
ctCH3
-(CH2)r
Bn
80 d
95
ba
-(CH2)4-
I3CH3
-(CH2)3-
Bn
69 d
95
c
H
H
H
-
(CH2)4 -
Me
60 c
10
d
H
H
H
-
(CH2)4 -
Bn
88 c (48 d)
68
e
H
H
H
-
(CH2)4 -
tBu
86 c (48 d)
92
f
H
H
H
H
C~Hu
tBu
90 c (40 d)
8l
g
H
H
H
CH3
tBu
74 d
88
H
H
H
Bn
75 d
73
H
H
C6H5
tBu
93 c
<5
h i
C6H5
-(CH2)3H
H
b
.
•
a See ref. 3 for the synthesis of the starting material, all compounds gave satisfactory spectroscopic data, c yield of crude epoxide, d isolated yield after column chromatography on silica gel, e 0.2 molar equiv, of acid was used except for 2e, 2d and 2h for which 1 molar equiv, was required. The intermediate oxazinones 3a-g were then oxidized without event to the corresponding ketones 4 in satisfactory yields using PDC in CH2C12, in the presence of 4,g, molecular sieves and a catalytic amount of AcOH 7. On the other hand, attempted isolation of aldehyde 4h invariably resulted in extensive degradation of the reaction mixture • neither the previous conditions nor other oxidation methods (Swern, Dess-Martin ...) could deliver a trace of the expected compound. Finally, the obtained ct-oxygenated ketones 4 were treated with zinc in refuxing acetic acid for 24 hours. Under these conditions, the non-isolated intermediate amino ketone underwent an m-situ reductive amination leading directly, as previously observed for 4a, to the expected substituted pyrrolidines 5 in good yields (Table 2). Whereas 5b and 5e were obtained stereoselectively as a single isomer,
compounds
5a and fig were both shown to be a
mixture of
diastereoisomers (respectively 60:40 and 85:15 ratios). The different stereochemical outcomes for compounds 5a and 5b were ascribed to a probable consequence of the different steric environments in the two transition states of the reductive amination step. O
s.,}-.,, I R,
s,]
4
Reagems " i) PDC, 4A molecular sieves, CH2C12, AcOH; ii) Zn, AcOH. Scheme 3
2974
T a b l e 2 : Synthesis ofPyrrolidines 5
Entry
a
b
e
f
g
h
Ketone 4a Yield (%)
72
81
70
68
66
b
79
75
56c
63 c
57c
H
II
Pyrrolidine 5a Yield (%)
C,Hs H
1t
H
a all compounds gave satisfactor spectroscopic data; degradation upon isolation; c isolated yield as the corresponding Boc or Cbz carbamate; d (6:4) mixture of diastereoisomers according to capillary GC; NMR f experiments did not allow their identification; e stereochemistry assigned thanks to NOE experiments; stereochemistry assigned by comparaison of the L3CNMR spectrum with the published dataS; g cis-trans (85:15) diastereoisomeric mixture determined by capillary GC and stereochemistry determined by RX crystallography of the major isomer. We have developed a new approach to pyrrolidines from homoallylic amines featuring an intramolecular epoxide opening by a carbamate group and a final zinc mediated reductive cleavage-reductive amination from an intermediate 1,3-oxazin-2-one. Further applications of this new methodology to the synthesis of natural products are under way in our laboratory.
Acknowledgements : We are grateful to Dr O. Convert for NMR experiments and to Dr E. Bacque for fruitful discussions. R e f e r e n c e s a n d notes
I.
Schreiber, K ; R6nsch, H Te/rahedron 1965, 21, 645-650.
2.
Urabe, H.; Aoyama, Y.; Sato, F Tetrahedron 1992, 48, 5639-5646. Romeo, S.; Rich, D H Tetrahedron
Lett. 1993, 34, 7187-7190. 3.
The two stereoisomers 2a and 2b were obtained according to the following sequence :
, ~
2) l~:o •
/" " "'~ ~
2)anococl,KzcO3 /" " II
~
+
3) 112-5% Rh/C
w
0
3) SOC|2, Pyridine 4) m-CPBA 33 : 67
" n
I
0
I
+ 2a
2b
4.
Rosenfeld, R.S.; Gallagher, T.F.J. Am. Chem. Soc. 1955, 77, 4367-4370.
5.
Bacos, D.; Basselier, J.J.; Cd6rier, J.P.; Lange, C.; Marx, E.; Lhommet, G.; Escoubas, P.; Lemaire, M.; Clement, J.L Tetrahedron Lett. 1988, 29, 3061-3064.
6.
Imuta, M.; Ziffer, H. J. Org. Chem. 1979, 44, 1351-1352.
7.
Czernecki, S.; Georgoulis, C ; Stevens, C.L TetrahedronLett. 1985, 26, 1699-1702.
8.
Mokotoff, H.; Scott, T.H.J. Heterocyclic Chem. 1988, 25, 65-71;
(Received in France 5 February 1995; accepted 20 February 1995)