J. Org. Chem. 1996, 61, 7959-7962
Intermolecular Addition of Amines to an N-Tosyloxy β-Lactam1
7959 Scheme 1
John R. Bellettini and Marvin J. Miller* Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556 Received June 24, 1996
The emergence of resistance by bacteria to many of the currently used β-lactam antibiotics has led to the search for new and improved antibiotics.2 One area of interest in our research group is the development of new methods to selectively functionalize the β-lactam ring. We have recently reported the discovery of a remarkable reaction for the addition of nucleophiles to the C-3 position of N-tosyloxy β-lactams (Scheme 1).3 Treatment of a variety of N-tosyloxy β-lactams with a tertiary amine base in the presence of various nucleophiles including azide, chloride, bromide, iodide, acetate, and others afforded products in which the nucleophile had added to the C-3 position of the β-lactam and the N-O bond had been cleaved. The addition proceeded with predominately trans stereochemistry relative to the substituent at C-4. Presumably, this transformation occurred by a base-catalyzed enolization followed by an SN2′ displacement of the tosylate during attack of the nucleophile on the enol intermediate. Hoffman and co-workers have recently described a similar transformation on acyclic hydroxamate systems.4 One class of nucleophiles which we had not yet fully explored was amine nucleophiles. The addition of amines to the C-3 position of N-tosyloxy β-lactams would allow for the facile introduction of the R-amino substituent on the β-lactam ring and therefore provide a useful route to important R-amino β-lactam derivatives. In some of our previous work we showed that tertiary amines such as triethylamine and diisopropylethylamine (Hu¨nig’s base) added competitively with some of the nucleophiles used in the nucleophilic addition reaction.3 By using primary and secondary amines, we anticipated that the amine would serve as both the catalyst and the nucleophile to provide precursors to biologically interesting R-amino β-lactams. For this study we chose β-lactam 1 as our substrate. The synthesis of β-lactam 1 from the corresponding commercially available β-hydroxy ester by our hydroxamate-mediated approach5 was straightforward and has been reported.3b To avoid competitive attack of the nucleophilic amines at the β-lactam carbonyl, we first studied reactions with sterically hindered amines. Thus, treatment of β-lactam 1 with 2 equiv of diisopropylamine afforded addition to the C-3 position of β-lactam 1 in excellent overall yield (Table 1). The addition of another relatively hindered amine, tert-butylamine, also afforded mostly the anticipated C-3 addition products 2b (major) and 3b (minor) as well as small amounts of amide 4b. (1) Results presented, in part, at the 29th Great Lakes Meeting of the American Chemical Society, Normal, IL, May 1996, Program and Abstracts, 131, and at the 210th National Meeting of the American Chemical Society, Chicago, IL, August 1995, Program and Abstracts, 358. (2) Davies, J. Science 1994, 264, 375. (3) (a) Guzzo, P. R.; Teng, M.; Miller, M. J. Tetrahedron 1994, 50, 8275. (b) Teng, M.; Miller, M. J. J. Am. Chem. Soc. 1993, 115, 548. (4) (a) Hoffman, R. V.; Nayyar, N. K. J. Org. Chem. 1995, 60, 7043 and references therein. (b) Hoffman, R. V.; Nayyar, N. K. J. Org. Chem. 1995, 60, 5992 and references therein. (5) Miller, M. J. Acc. Chem. Res. 1986, 19, 49.
S0022-3263(96)01184-X CCC: $12.00
The proposed mechanism for the formation of amide 4b is shown in Scheme 2 (R1 ) t-Bu, R2 ) H). First the amine apparently attacked the β-lactam carbonyl opening the ring to afford hydroxylamine 5. Elimination of a molecule of p-toluenesulfonic acid from 5 afforded imine 6 which then hydrolyzed to give the observed product 4. Interestingly, substitution of isopropylamine for diisopropylamine or tert-butylamine completely altered the course of the reaction. Thus, treatment of β-lactam 1 with 2 equiv of isopropylamine followed by 1H NMR analysis of the crude reaction mixture showed that no addition of isopropylamine to the C-3 position had occurred. Instead, after purification, amide 4c was isolated in good yield (82-89%), indicating that isopropylamine attacked β-lactam 1 only at the carbonyl carbon as shown in Scheme 2 (R1 ) i-Pr, R2 ) H). The addition of diethylamine also was tried since it is more hindered than isopropylamine but less hindered than diisopropylamine and tert-butylamine. Treatment of β-lactam 1 with 2 equiv of diethylamine afforded a 32% yield of addition to C-3. Nucleophilic addition of ammonia or an ammonia equivalent at the C-3 position of various C-4-substituted N-tosyloxy β-lactams would provide a direct route to monobactam6 precursors (Scheme 3). Subsequent acylation of the C-3 amine with physiologically appropriate side chains and standard introduction of the ring N-SO3H linkage would allow production of a tremendous variety of monobactams and analogs. Current variation of substituents at the C-4 position of monobactams most often requires access to the corresponding β-hydroxy amino acid precursors 7. While some naturally-occuring β-hydroxy amino acids, such as serine (7, R ) H) and threonine (7, R ) Me), are readily available, others are much less common or require total syntheses themselves.7 Alternatively, optically pure β-hydroxy acids 10 are readily available by asymmetric enzymatic8 and chemical9 reductions. Their conversion to 4-substitutedN-hydroxy β-lactams 11 by standard protocol5 followed by tosylation and subsequent reaction with an ammonia equivalent (12 f 9) may provide an effective route to an increased variety of monobactams 8. We previously demonstrated that azide is very effective in the C-3 nucleophile transfer reaction.3b While azides are readily reduced to amines, we also thought that it would be interesting to determine the compatibility of the C-3 nucleophile transfer process with other ammonia equivalents to avoid the generation and use of intermediate azides. One of our first considerations was that removal of the tert-butyl group from 2b should afford the (6) Slusarchyk, W. A.; Dejneka, T.; Gordon, E. M.; Weaver, E. R.; Koster, W. H. Heterocycles 1984, 21, 191. (7) For an enzyme-mediated synthesis of novel β-hydroxy amino acids, see: Lotz, B. T.; Gasparski, C. M.; Peterson, K.; Miller, M. J. J. Chem. Soc., Chem. Commun. 1990, 1107. (8) (a) Christen, M; Crout, D. H. G.; Holt, R. A.; Morris, J. G.; Simon, H. J. Chem. Soc., Perkin Trans. 1 1992, 491. (b) Servi, S. Synthesis 1990, 1. (c) Sih, C. J.; Chen, C.-S. Angew. Chem., Int. Ed. Engl. 1984, 23, 570. (9) Guzzo, P. R.; Miller, M. J. J. Org. Chem. 1994, 59, 4862.
© 1996 American Chemical Society
7960 J. Org. Chem., Vol. 61, No. 22, 1996
Notes
Table 1. Reactions of 1 with Amine Nucleophiles
entry
R1
R2
2 (%)a
3 (%)a
4 (%)a
pKa
i-Pr2NEtd
1 2 3 4 5 6 7
i-Pr t-Bu i-Pr Et Ph3C Ph2CH allyl
i-Pr H H Et H H allyl
2a (86-88) 2b (80-89) 2c (0) 2d (29-32) 2e (21-22) 2f (37-44) 2g (45-49)
3a (5) 3b (6-7) 3c (0) 3d (0) 3e (0) 3f (0) 3g (0)
4a (0) 4b (3-10) 4c (82-89) 4d (0) 4e (0) 4f (0) 4g (0)
11.1b 10.5b 10.6b 11.0b 6.1c 7.2c 9.3b
no no no no yes yes yes
a Isolated yields after purification. b See ref 13. c Determined in methylcellosolve/water, see ref 11. to catalyze the enolization.
Scheme 2
Scheme 3
free amine. However, our attempts to remove the tertbutyl group from 2b have so far been unsuccessful. Since the trityl group can be deprotected under relatively mild conditions,10 we attempted to add tritylamine to the C-3 position of β-lactam 1. Treatment of β-lactam 1 with 2 equiv of tritylamine afforded only recovery of starting material. Apparently, tritylamine (pKa ) 6.1)11 is not basic enough to catalyze the proposed enolization. It appears as though the pKa of the amine needs to be approximately 11 to efficiently catalyze the enolization. (10) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 2nd ed.; John Wiley & Sons: New York, 1991; pp 366-367. (11) Dahn, H.; Farine, J.-C; Nguyeˆn, T. T. T. Helv. Chim. Acta 1980, 63, 780.
d
In some cases, i-Pr2NEt was added
Scheme 4
Treatment of β-lactam 1 with 2 equiv of tritylamine along with the addition of 2 equiv of diisopropylethylamine, to catalyze the apparently required enolization, led to addition of tritylamine to the C-3 position in 21-22% yield. Treatment of β-lactam 1 with 2 equiv of aminodiphenylmethane (pKa ) 7.2)11 also afforded no addition to C-3; however, when diisopropylethylamine was added to the reaction the C-3 addition product 2f was obtained in 37-44% yield. The addition of diallylamine was attempted since rhodium-catalyzed isomerization of the allyl groups to imines followed by hydrolysis of the imines should afford the free amine.12 Interestingly, treatment of β-lactam 1 with 2 equiv of diallylamine afforded urea 13 in 24% yield. Only a small amount (
