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Asymmetric conjugate additions to chiral bicyclic lactams. A stereoselective, concise synthesis of chiral 2-alkyl-3,4-aziridinopyrrolidines
Tetrahedron Letters, Vol. 36, No. 20, pp. 3491-3494, 1995
Pergamon
Elsevier Science Ltd Printed in Great Britain 0040-4039/95 $9.50+0.00
0040-4039(95)00573-0
Asymmetric Conjugate Additions to Chiral Bicyclic Lactams. A Stereoselective, Concise Synthesis of Chiral 2-Alkyl3,4-Aziridinopyrrolidines C. J. Andres and A. I. Meyers* Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523 U. S. A.
Summary: Stereoselective, conjugate additions of primary amines to chiral a-iodo (~, ,6unsaturated bicyclic lactams are described. Typical yields of the resulting aziridinolactams ranged from 60-90% with facial diastereoselectivities of >98:2 in all cases. Selected optically pure aziridinobicyclic lactams were transformed, by reductive cleavage, into chiral 2-alkyl, 3, 4aziridinopyrrolidines. The synthesis of non-racemic aziridines continues to be a major area of interest in organic chemistry 1 because of the following: a) the utility of aziridines as intermediates in the synthesis of complex molecular moieties; 2 b) the ability of the aziridine to act as a chiral directing group in asymmetric transformations; 3 and c) the presence of the aziridine ring system in biologically important natural products. 4
Recently, we developed an efficient route to chiral 2-alkyl-3-
aminopyrrolidines 5 based on a highly stereoselective conjugate amine addition to chiral bicyclic lactams.
As an extension of this methodology, we envisioned that amine addition to bicyclic
lactam 16 would result in the attainment of aziridinolactams 2 based upon earlier studies by Cromwell. 7 Reductive cleavage of the latter5 would yield chiral 2-alkyl-3, 4-aziridinopyrrolidines 3, moieties related to the core structural unit of the mitomycin class of natural products. 4
O
O
1
2
0 3
Reaction of lactam 1 with a variety of primary amines (Table 1) yielded aziridinolactams 2a-i. The stereochemistry of the major diastereomer resulting from amine addition to 1 was found to be endo
by nuclear Overhauser effect (nOe) correlation of aziridinolactam 2e with the
previously described cyclopropyl lactam 4. 8 Cyclopropyl lactam 4 exhibited a 3.6% C-7 methine
3491
3492
signal enhancement upon irradiation of the angular methyl group whereas 2e similarly showed a 3.3% signal enhancement of the C-7 methine hydrogen resonance upon irradiation of the lactam angular methyl group. Additionally, the aziridine nitrogen was found to be asymmetric with the lone pair of electrons pointing into the tricyclic lactam framework. Irradiation of the C-7 methine hydrogen gave an average 19.0% enhancement of signal from the substituents (e.g., phenyl, methyl, hydrogen) on the aziridine side chain.
This assignment is in accord with molecular
modeling 9 which predicts 2e to be 13 kcal/mol more stable than its nitrogen epimer. 3.6 %
Me,
3.3 %
/H
Me
Ph~x~N~
19.0 %
/H
Ph" /O ~ ' ~
i~hH H 0N/J~"Me
O
O
4
2e
It was necessary to demonstrate that the aziridinolactams could be transformed into more general useful compounds. Thus, treatment of lactam 2a after chromatography, with LiAIH4-AICI3 yielded 5 a 20:1 (NMR) mixture of epimeric N-substituted pyrrolidines 5a and 5b (77%). Contrary to previous lactam reductions, 5 the major diastereomer 5a was found to have undergone facial inversion (95:5) of the angular methyl group. This was confirmed by comparison of first order 1H NMR splitting patterns and nOe's for pyrrolidines 5a and 5b. In compound 5a, proton Ha was a doublet of quartets and proton Hb a doublet of doublets. Conversely, in compound 5b, proton Ha was a qua.rtet and Hb a doublet. Additionally, irradiation of the angular methyl group in pyrrolidine 5a gave a 3.1% enhancement of signal for proton Ha and a 1.0% enhancement of signal for Hb. In comparison, angular methyl irradiation of 5b resulted in a 3.3% enhancement of signal for Ha and a 2.5% enhancement of signal for Hb.
AIH3 2a
HO "
Me Ha Hb :~,' •~,"NtBu ph-~N 5a
Me_H a H b HO + ph--~ NX..,~,,,~',NtBu 5b
3493
Table 1. Conjugate Addition of Amines to Unsaturated Iodo Bicyclic Lactam 1. Entry
R1
Amine
1
Me
tBuNH2
2a
60
2
Me
H2N-<~]
2b
61
2c
92
2d
75
~
3
Me
4
Me
l
Product
Yield (%)
U
~
H2N..,~ "OMe
5
Me
H 2 N - , ~~ l Me
2e
74
6
Me
H2N v ~ = Me
2f
70
7
Me
H 2 N ~
2g
72
2h
70
21
78
M_?H 8
Me
9
Me
H2N
Ph
H2N',I,"',J Me
Typical experimental conditions: Lactam 1 (1.0 equiv) was placed in a round bottom flask equipped with a magnetic stirringbar. The primaryamine (15.0 equiv)was syringedinto the flask, stirringwas initiated, and the lactam dissolved. After stirring 12 h at rl, the resulting solutionwas placedon a silicagel column and elutedwithetherto yieldthe pureaziridinolactam.
3494
Treatment of lactams 2d and 2g with alane gave, after chromatography, diastereomerically pure (NMR) N-substituted pyrrolidines 5d (78%) and 5i (70%). Subjecting compounds 5d and
51
to palladium hydroxide on carbon and hydrogen provided, after purification, aziddinopyrrolidines 7d (53%) and 71 (53%).
Aziridinopyrrolidine 7a exhibited high volatility and therefore, was
difficult to isolate in good yields.
2a 2d 21
AIH3 THF -78 °C
Me HO~ r - - N / ~ ,':N-R phg 'X,....J"
Pd(OH)2/C EtOH H2 ~
Me HN
"~N-R ,,,
5a R=:BL . ~ O M e 5d R="~L~,~j~v~
7a R=tBu • .~..Ar-p-OMe 7d R = ~
51 R=
71 R=
"r v Me
Me
In conclusion, a concise route to chiral 2-alkyl-3, 4-aziridinopyrrolidines has been realized. The wide variety of tolerated primary amines, availability of both iodo unsaturated lactam antipodes, and previously demonstrated ability to vary the lactam angular substituent10 make this an attractive method for reaching a wide variety of these chiral systems. Work on ring opening of the aziridinolactams is in progress and will be reported in due course.
Acknowledgement: Financial support of the acknowledged.
National Institutes of Health is gratefully
Furthermore, we thank Dr. Chris Rithner and Tamera Joice for the nOe
determinations.
References
(1) For a recent review see: Tanner, D. Angew. Chem. Int. Ed. Engl. 1994, 35, 599. (2) See for example: a)Hudlicky, T.; Luna, H.; Price, J. D.; Rulin, F. J. Org. Chem. 1990, 55, 4683; b) Williams, D. R.; Brown, D. L.; Benbow, J. J. Am. Chem. Soc. 1989, 111, 1923; c) Harding, K. E.; Burks, S. R. J. Org. Chem. 1984, 49, 40; d) Garner, P.; Dogan, O. J. Org. Chem. 1994, 59, 4; e) Benbow, J. W.; McClure, K. F.; Danishefsky, S. J. J. Am. Chem. Soc. 1993, 115, 12035. (3) Tanner, D.; Birgersson, C. Tetrahedron Lett. 1991, 32, 2533. (4) See: a) Ziegler, F. E.; Belema, M. J. Org. Chem. 1994, 59, 7962; b) Fukuyama, T.; Nakatsubo, F.; Cocuzza, A. J.; Kishi, Y. Tetrahedron Lett. 1977, 4295; c) Coleman, R. S.; Carpenter, A. J. J. Org. Chem. 1992, 57, 5813. (5) Andres, C. J.; Lee, P. H.; Nguyen, T. H.; Meyers, A. I. J. Org. Chem., 1995, in press. (6) Newhouse, B. J.; Meyers, A. I.; Sirisoma, N. S.; Braun, M.; Johnson, C. R. Synlett, 1994, 573. (7) Cromwell, N. H.; McMaster, M. C. J. Org. Chem. 1967, 32, 2145. (8) Romo D. Ph.D. Dissertation 1991, Colorado State University. (9) Molecular modeling utilized BiografTM software. (10) Burgess, L. E.; Meyers, A. I. J. Org. Chem. 1993, 58, 36.
(Received in USA 16 February 1995; revised 17 March 1995; accepted 21 March 1995)
Pergamon
Elsevier Science Ltd Printed in Great Britain 0040-4039/95 $9.50+0.00
0040-4039(95)00573-0
Asymmetric Conjugate Additions to Chiral Bicyclic Lactams. A Stereoselective, Concise Synthesis of Chiral 2-Alkyl3,4-Aziridinopyrrolidines C. J. Andres and A. I. Meyers* Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523 U. S. A.
Summary: Stereoselective, conjugate additions of primary amines to chiral a-iodo (~, ,6unsaturated bicyclic lactams are described. Typical yields of the resulting aziridinolactams ranged from 60-90% with facial diastereoselectivities of >98:2 in all cases. Selected optically pure aziridinobicyclic lactams were transformed, by reductive cleavage, into chiral 2-alkyl, 3, 4aziridinopyrrolidines. The synthesis of non-racemic aziridines continues to be a major area of interest in organic chemistry 1 because of the following: a) the utility of aziridines as intermediates in the synthesis of complex molecular moieties; 2 b) the ability of the aziridine to act as a chiral directing group in asymmetric transformations; 3 and c) the presence of the aziridine ring system in biologically important natural products. 4
Recently, we developed an efficient route to chiral 2-alkyl-3-
aminopyrrolidines 5 based on a highly stereoselective conjugate amine addition to chiral bicyclic lactams.
As an extension of this methodology, we envisioned that amine addition to bicyclic
lactam 16 would result in the attainment of aziridinolactams 2 based upon earlier studies by Cromwell. 7 Reductive cleavage of the latter5 would yield chiral 2-alkyl-3, 4-aziridinopyrrolidines 3, moieties related to the core structural unit of the mitomycin class of natural products. 4
O
O
1
2
0 3
Reaction of lactam 1 with a variety of primary amines (Table 1) yielded aziridinolactams 2a-i. The stereochemistry of the major diastereomer resulting from amine addition to 1 was found to be endo
by nuclear Overhauser effect (nOe) correlation of aziridinolactam 2e with the
previously described cyclopropyl lactam 4. 8 Cyclopropyl lactam 4 exhibited a 3.6% C-7 methine
3491
3492
signal enhancement upon irradiation of the angular methyl group whereas 2e similarly showed a 3.3% signal enhancement of the C-7 methine hydrogen resonance upon irradiation of the lactam angular methyl group. Additionally, the aziridine nitrogen was found to be asymmetric with the lone pair of electrons pointing into the tricyclic lactam framework. Irradiation of the C-7 methine hydrogen gave an average 19.0% enhancement of signal from the substituents (e.g., phenyl, methyl, hydrogen) on the aziridine side chain.
This assignment is in accord with molecular
modeling 9 which predicts 2e to be 13 kcal/mol more stable than its nitrogen epimer. 3.6 %
Me,
3.3 %
/H
Me
Ph~x~N~
19.0 %
/H
Ph" /O ~ ' ~
i~hH H 0N/J~"Me
O
O
4
2e
It was necessary to demonstrate that the aziridinolactams could be transformed into more general useful compounds. Thus, treatment of lactam 2a after chromatography, with LiAIH4-AICI3 yielded 5 a 20:1 (NMR) mixture of epimeric N-substituted pyrrolidines 5a and 5b (77%). Contrary to previous lactam reductions, 5 the major diastereomer 5a was found to have undergone facial inversion (95:5) of the angular methyl group. This was confirmed by comparison of first order 1H NMR splitting patterns and nOe's for pyrrolidines 5a and 5b. In compound 5a, proton Ha was a doublet of quartets and proton Hb a doublet of doublets. Conversely, in compound 5b, proton Ha was a qua.rtet and Hb a doublet. Additionally, irradiation of the angular methyl group in pyrrolidine 5a gave a 3.1% enhancement of signal for proton Ha and a 1.0% enhancement of signal for Hb. In comparison, angular methyl irradiation of 5b resulted in a 3.3% enhancement of signal for Ha and a 2.5% enhancement of signal for Hb.
AIH3 2a
HO "
Me Ha Hb :~,' •~,"NtBu ph-~N 5a
Me_H a H b HO + ph--~ NX..,~,,,~',NtBu 5b
3493
Table 1. Conjugate Addition of Amines to Unsaturated Iodo Bicyclic Lactam 1. Entry
R1
Amine
1
Me
tBuNH2
2a
60
2
Me
H2N-<~]
2b
61
2c
92
2d
75
~
3
Me
4
Me
l
Product
Yield (%)
U
~
H2N..,~ "OMe
5
Me
H 2 N - , ~~ l Me
2e
74
6
Me
H2N v ~ = Me
2f
70
7
Me
H 2 N ~
2g
72
2h
70
21
78
M_?H 8
Me
9
Me
H2N
Ph
H2N',I,"',J Me
Typical experimental conditions: Lactam 1 (1.0 equiv) was placed in a round bottom flask equipped with a magnetic stirringbar. The primaryamine (15.0 equiv)was syringedinto the flask, stirringwas initiated, and the lactam dissolved. After stirring 12 h at rl, the resulting solutionwas placedon a silicagel column and elutedwithetherto yieldthe pureaziridinolactam.
3494
Treatment of lactams 2d and 2g with alane gave, after chromatography, diastereomerically pure (NMR) N-substituted pyrrolidines 5d (78%) and 5i (70%). Subjecting compounds 5d and
51
to palladium hydroxide on carbon and hydrogen provided, after purification, aziddinopyrrolidines 7d (53%) and 71 (53%).
Aziridinopyrrolidine 7a exhibited high volatility and therefore, was
difficult to isolate in good yields.
2a 2d 21
AIH3 THF -78 °C
Me HO~ r - - N / ~ ,':N-R phg 'X,....J"
Pd(OH)2/C EtOH H2 ~
Me HN
"~N-R ,,,
5a R=:BL . ~ O M e 5d R="~L~,~j~v~
7a R=tBu • .~..Ar-p-OMe 7d R = ~
51 R=
71 R=
"r v Me
Me
In conclusion, a concise route to chiral 2-alkyl-3, 4-aziridinopyrrolidines has been realized. The wide variety of tolerated primary amines, availability of both iodo unsaturated lactam antipodes, and previously demonstrated ability to vary the lactam angular substituent10 make this an attractive method for reaching a wide variety of these chiral systems. Work on ring opening of the aziridinolactams is in progress and will be reported in due course.
Acknowledgement: Financial support of the acknowledged.
National Institutes of Health is gratefully
Furthermore, we thank Dr. Chris Rithner and Tamera Joice for the nOe
determinations.
References
(1) For a recent review see: Tanner, D. Angew. Chem. Int. Ed. Engl. 1994, 35, 599. (2) See for example: a)Hudlicky, T.; Luna, H.; Price, J. D.; Rulin, F. J. Org. Chem. 1990, 55, 4683; b) Williams, D. R.; Brown, D. L.; Benbow, J. J. Am. Chem. Soc. 1989, 111, 1923; c) Harding, K. E.; Burks, S. R. J. Org. Chem. 1984, 49, 40; d) Garner, P.; Dogan, O. J. Org. Chem. 1994, 59, 4; e) Benbow, J. W.; McClure, K. F.; Danishefsky, S. J. J. Am. Chem. Soc. 1993, 115, 12035. (3) Tanner, D.; Birgersson, C. Tetrahedron Lett. 1991, 32, 2533. (4) See: a) Ziegler, F. E.; Belema, M. J. Org. Chem. 1994, 59, 7962; b) Fukuyama, T.; Nakatsubo, F.; Cocuzza, A. J.; Kishi, Y. Tetrahedron Lett. 1977, 4295; c) Coleman, R. S.; Carpenter, A. J. J. Org. Chem. 1992, 57, 5813. (5) Andres, C. J.; Lee, P. H.; Nguyen, T. H.; Meyers, A. I. J. Org. Chem., 1995, in press. (6) Newhouse, B. J.; Meyers, A. I.; Sirisoma, N. S.; Braun, M.; Johnson, C. R. Synlett, 1994, 573. (7) Cromwell, N. H.; McMaster, M. C. J. Org. Chem. 1967, 32, 2145. (8) Romo D. Ph.D. Dissertation 1991, Colorado State University. (9) Molecular modeling utilized BiografTM software. (10) Burgess, L. E.; Meyers, A. I. J. Org. Chem. 1993, 58, 36.
(Received in USA 16 February 1995; revised 17 March 1995; accepted 21 March 1995)