Figure 2. Mechanism of intramolecular ester enolateꢀimine
cyclization reaction of (S)-1a.
Figure 1. NH-β-lactams 5bꢀd,5gꢀi and β-amino-esters 7 and 8.
In conclusion, we have shown that enolates of N-
(R-methyl-p-methoxybenzyl)imino esters can undergo intra-
molecular cyclization reactions to afford (syn)-aza-anions
that undergo 4-exo-trig cyclization reactions onto their ester
carbonyl groups to afford cyclic β-lactams in high dr. These
cyclic β-lactams may then be oxidatively deprotected to
afford their corresponding NH-β-lactams, β-amino esters,
or β-amino acids as required.20 To the best of our knowledge,
this report represents the first example of an intramolecular
version of the ester enolateꢀimine condensation reaction, the
first intermolecular variant of which was reported for the
preparation of monocyclic β-lactams over 60 years ago.21
which in turn could be isomerized into trans-pentacin ethyl
ester (1R,2R)-8 via treatment with sodium ethoxide in
refluxing tert-BuOH.7
The stereoselective outcome of these intramolecular ester
enolateꢀimine cyclization reactions has been rationalized as
follows. Literature precedent indicates that deprotonation
of ester 1a with NaHMDS in THF should afford a config-
urationally stable (E)-enolate 9 (Figure 2).16 Since cycliza-
tion of the sodium enolate of ω-imino ester 1a in the
absence/presence of 15-crown-5 affords the same β-
lactam 2a, it is likely that its initial 5-exo-trig cycliza-
tion reaction proceeds via a nonchelated ‘open’ transi-
tion state.17 As we have shown in our base catalyzed
epimerization studies, (anti)-cyclic β-amino esters are
thermodynamically more stable than their correspond-
ing (syn)-diastereomers.7 Therefore, it is proposed that
an intramolecular cyclization reaction of (E)-9 occurs
under kinetic control to afford the aza-anion of (syn)-β-
amino ester (S,RR,βR)-10 (Figure 2).18 This aza-anion
10 then undergoes rapid 4-exo-trig cyclization reaction
onto the carbonyl of its ester group to give the observed
β-lactam (S,RR,βR)-2a (Figure 2).19
Acknowledgment. We would like to thank the EPSRC,
ARC, and the Foldamer COST Network for funding and
AstraZeneca for a CASE award to C.D.E.
Supporting Information Available. Experimental de-
tails, spectroscopic data, details of mechanistic experi-
ments, and crystal data. This material is available free of
(17) For selected reports where ester enolates undergo intermolecular
cyclization reactions onto imines to afford (syn)-β-lactams, see: (a) Ha,
D. C.; Hart, D. J.; Yang, T. K. J. Am. Chem. Soc. 1984, 106, 4819–4825.
(b) Hart, D. J.; Lee, C. S.; Pirkle, W. H.; Hyon, M. H.; Tsipouras, A. J.
Am. Chem. Soc. 1986, 108, 6054–6056. (c) Braun, M.; Sacha, H.; Galle,
D.; El-Alali, A. Tetrahedron Lett. 1995, 36, 4213–4216. (d) Ojima, I.;
Habus, I. Tetrahedron Lett. 1990, 31, 4289–4292.
(18) We cannot discount the possibility that a reversible enola-
teꢀimine cyclization reaction is occurring to generate a diastereomeric
mixture of (anti)-/(syn)-aza-anions under thermodynamic control. The
equilibria of this reversible cyclization reaction could then be driven by
the lowest energy (syn)-aza-anion (S,RR,βR)-10 undergoing subsequent
4-exo-trig cyclization to afford (S,RR,βR)-β-lactam 2a.
(15) Attempts to oxidatively deprotect lactams 2eꢀf using CAN
afforded crude reaction products containing more than one product,
the major components of which were the respective keto-β-lactams 11
and 12. For a previous report of CAN mediated benzylic oxidation of
Indane systems, see: Syper, L. Tetrahedron Lett. 1966, 37, 4493–4498.
(19) Del Rio, E.; Lopez, R.; Menendez, M. I.; Sordo, T. L.; Ruiz-
Lopez, M. F. J. Comput. Chem. 1998, 19, 1826–1833.
(20) Cyclic β-amino esters are useful chiral monomers for the synth-
esis of bioactive peptides and the construction of novel foldamer
structures; see: (a) Reference 11. (b) Satyanarayanajois, S.; Villalba,
S.; Liu, J. C.; Lin, G. M. Chem. Biol. Drug Des. 2009, 74, 246–257. (c)
Kneissl, B.; Leonhardt, B.; Hildebrandt, A.; Tautermann, C. S. J. Med.
Chem. 2009, 52, 3166–3173. (d) Vieth, M.; Cummins, D. J. J. Med.
Chem. 2000, 43, 3020–3032.
(16) See: (a) Ireland, R. E.; Mueller, R. H.; Willard, A. K. J. Am.
Chem. Soc. 1976, 98, 2868–2877. (b) Heathcock, C. H.; Buse, C. T.;
Kleschick, W. A.; Pirrung, M. A.; Sohn, J. E.; Lampe, J. J. Org. Chem.
1980, 45, 1066–1081.
(21) Gilman, H.; Speeter, H. J. Am. Chem. Soc. 1943, 65, 2255–2256.
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