Intramolecular ester enolate-imine cyclization reactions for the asymmetric synthesis of polycyclic β-lactams and cyclic β-amino acid derivatives

Article abstract of DOI:10.1021/ol202750u

Enolates of chiral N-(α-methyl-p-methoxybenzyl)-ω-imino-esters undergo intramolecular cyclization reactions to afford (syn)-aza-anions of β-amino esters in high dr that cyclize to afford N-(α-methyl-p- methoxybenzyl)-β-lactams that can be readily deprotec

Full text of DOI:10.1021/ol202750u

ORGANIC
LETTERS
2011
Vol. 13, No. 23
6276–6279
Intramolecular Ester EnolateꢀImine
Cyclization Reactions for the Asymmetric
Synthesis of Polycyclic β-Lactams and
Cyclic β-Amino Acid Derivatives
Caroline D. Evans,† Mary F. Mahon,‡ Philip C. Andrews,§ James Muir, and
Steven D. Bull*,†
Department of Chemistry, University of Bath, Claverton Down, Bath, BA2 7AY, U.K.,
Department of Chemical Crystallography, University of Bath, BA2 7AY, U.K., School of
Chemistry, Monash University, Victoria 3800, Australia, and Astra-Zeneca PR&D,
Macclesfield, SK10 2NA, U.K.
s.d.bull@bath.ac.uk
Received October 13, 2011
ABSTRACT
Enolates of chiral N-(R-methyl-p-methoxybenzyl)-ω-imino-esters undergo intramolecular cyclization reactions to afford (syn)-aza-anions of β-
amino esters in high dr that cyclize to afford N-(R-methyl-p-methoxybenzyl)-β-lactams that can be readily deprotected to afford their
corresponding cyclic NH-β-lactams, β-amino esters, or β-amino acids.
Chiral β-lactams exhibit a wide range of biological
properties, including antibiotic, cholesterol absorption
inhibition, antiviral, and protease inhibitor activities.1
Theyare alsoused widely asversatile chiral building blocks
for the synthesis of bioactive peptides, natural products,
and heterocyclic drug molecules.2 Popular methodologies
for their asymmetric synthesis include Staudinger keteneꢀ
imine [2 þ 2] cycloadditions, Kinugasa alkyneꢀnitrone
cycloadditions, and intramolecular cyclization reactions of
β-amino acid derivatives.3 Stereoselective variants of ester
enolateꢀimine condensation reactions have also been
reported,4 which rely on the addition of chiral ester enolate
equivalents to achiral imines or addition of achiral ester
enolate equivalents to chiral imines.5 These intermolecular
reactions arise from stereoselective addition of a metal
enolate equivalent to an imine to afford the aza-anion of a
chiral β-amino ester that then undergoes intramolecular
ring closure onto its ester carbonyl to afford a monocyclic
β-lactam. However, an intramolecular version of this type
† Department of Chemistry, University of Bath.
‡ Department of Chemical Crystallography, University of Bath.
§ Monash University.
Astra-Zeneca PR&D.
(1) (a) von Nussbaum, F.; Brands, M.; Hinzen, B.; Weigand, S.;
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(2) Alcaide, B.; Almendros, P.; Aragoncillo, C. Chem. Rev. 2007, 107,
4437–4492.
(4) For reports of enantioselective ester enolateꢀimine cyclization
reactions, see: (a) Tomioka, K.; Fujieda, H.; Hayashi, S.; Hussein,
M. A.; Kambara, T.; Nomura, Y.; Kanai, M.; Koga, K. Chem. Commun.
1999, 715–716. (b) Hussein, M. A.; Iida, A.; Tomioka, K. Tetrahedron
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r
10.1021/ol202750u
Published on Web 11/03/2011
2011 American Chemical Society

It was found that lithium or potassium enolates of (S)-1a
in THF at room temperature underwent cyclization reac-
tions to afford a mixture of β-lactam (S,RR,βR)-2a,7,8
β-lactam (S,RS,βS)-3a, and (anti)-β-amino ester (S,RR,βS)-49
in moderate yields (Table 1, entries 1,2). The use of NaHMDS
or KOtBu as bases in THF resulted in more selective
reactions, affording a mixture of β-lactams 2a/3a in 65:35
and 77:23 diastereoisomeric ratios (drs) respectively
(Table 1, entries 3,4). Use of the noncoordinating solvent
toluene did not result in any improvement in either the dr or
yield of the reaction (Table 1, entry 5). However, the use of
1.1 equiv of NaHMDS and 15-crown-5 in THF gave
β-lactam 2a in a much improved 94:6 dr (Table 1, entry 6).
Finally, it was found that using NaHMDS in THF
at ꢀ40 °C, in the presence of 1.1 equiv of 15-crown-5,
resulted in clean formation of tricyclic β-lactam 2a in 99:1
dr in an isolated 82% yield (Table 1, entry 7).
Scheme 1. Syntheses of ω-imino esters (S)-1aꢀi
Table 1. Optimization of Ester EnolateꢀImine Cyclization Re-
actions of ω-Imino Ester (S)-1a
ratio of productsb
entry
conditionsa
LiHMDS, THF, rt
2a:3a:4
1
2
3
4
5
6
7
2a (49):3a (18):4 (33)
2a (30):3a (31):4 (39)
2a (65):3a (35)
KHMDs, THF, rt
KOtBu, THF, rt
NaHMDS, THF, rt
2a (77):3a (23)
NaHMDS, Toluene, rt
NaHMDS, THF, rt, 15-crown-5
2a (74):3a (26)
2a (94):3a (6)
NaHMDS, THF, ꢀ40 °C, 15-crown-5 2a (99):3a (1)
a Use of sodium ethoxide, triethylamine, sodium hydride, or phos-
phazene as bases to generate enolates of (S)-1a did not afford any
cyclization products. b Ratio of products determined from integration of
respective peaks in the 1H NMR spectra of crude reaction products.
of ester enolateꢀimine cyclization reaction has not been
reported to date, and we now report herein that enolates of
chiral ω-imino esters can also undergo intramolecular
cyclization reactions to afford polycyclic β-lactams with
excellent levels of stereocontrol.
A series of cyclic and acyclic N-(R-methyl-p-metho-
xybenzyl)-ω-imino esters (S)-1aꢀi were prepared as poten-
tial cyclization substrates employing the range of synthetic
protocols shown in Scheme 1. ω-Imino ester (S)-1a was
chosen as a representative substrate for cyclization studies,
and its enolate generated under a range of conditions.6
The absolute configuration of tricyclic β-lactam 2a was
confirmed as (S,RR,βR) via oxidative deprotection using
ceric ammonium nitrate (CAN) to afford NH-β-lactam
(R,R)-5a,10 which was then hydrolyzed under acidic con-
ditions to give the known β-amino acid (R,R)-6
(Scheme 2).11
(7) For previous asymmetric syntheses of benzocispentacin analo-
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ꢀ
ꢀ
ꢀ
ꢀ ꢀ
€€
€ €
gues see: (a) Fulop, F.; Palko, M.; Kaman, J.; Lazar, L.; Sillanpaa, R.
ꢀ
Tetrahedron: Asymmetry 2000, 11, 4179–4187. (b) Forro, E.; Fulop, F.
Chem.;Eur. J. 2006, 12, 2587–2592. (c) Price, D. A. Synlett 1999
1919–1920. (d) Voigt, K.; Lansky, A.; Noltemeyer, M.; de Meijere, A.
Liebigs Ann. 1996, 899–911.
(6) For a previous report where 6-endo-trig cyclization of an ester
enolate onto an imine was observed as the last step of a cascade reaction
that gave a cyclic β-amino ester containing six vicinal stereocenters, see:
Koutsaplis, M.; Andrews, P. C.; Bull, S. D.; Duggan, P. J.; Fraser, B. H.;
Jensen, P. Chem. Commun. 2007, 3580–3582.
(8) For previous examples where intramolecular cyclization reactions
of ester enolates onto imidoyl chlorides gave cyclic enamino esters that
were stereoselectively hydrogenated to afford cyclic β-amino esters, see:
ꢀ
ꢀ
~
ꢀ
Fustero, S.; Sanchez-Rosello, M.; Acena, J. L.; Fernandez, B.; Asensio,
A.; Sanz-Cervera, J. F.; del Pozo, C. J. Org. Chem. 2009, 74, 3414–3423.
Org. Lett., Vol. 13, No. 23, 2011
6277

Table 2. Asymmetric Synthesis of (R,R)-β-Lactams 2bꢀi
Scheme 2. Protocol Used To Assign the Configuration of β-
Lactam (S,RR,βR)-2a
The five substituted ω-imino aryl esters (S)-1bꢀf were
then treated with 1.1 equiv of NaHMDS in THF atꢀ40 °C
in the presence of 1.1 equiv of 15-crown-5 to give a range of
tricyclic β-lactams (S,RR,βR)-2bꢀf in g95:5 dr in accep-
table 59ꢀ79% isolated yields (Table 2, entries 1ꢀ5).12
Reaction of the enolate of ω-imino ester (S)-1g, which
contains an extra methylene unit in its ester side chain,
under the same conditions, gave its corresponding tricyclic
β-lactam (S,RR,βR)-2g, albeit in a reduced 92:8 dr
(Table 2, entry 6). Cyclization of the acyclic enolates of
ω-imino esters(S)-1hꢀi atroomtemperaturealsooccurred
in a highly stereoselective manner to give their correspond-
ing bicyclic β-lactams (S,RR,βR)-2hꢀi in g96:4 dr
(Table 2, entries 7ꢀ8).13 The improved yield obtained for
the formation of β-lactam 2i over 2h is likely to be due to
the ThorpeꢀIngold effect,14 whereby the geminal dimethyl
group of (S)-1i predisposes the conformation of its enolate
toward intramolecular cyclization. Six of these β-lactams
2bꢀd and 2gꢀi were then oxidatively cleaved via treatment
with CAN in CH3CN/H2O to afford their corresponding
NH-β-lactams (R,R)-5bꢀd,g and (1S,2R)-5hꢀi (Figure 1).15
β-Lactam (1S,2R)-5h could be converted into cis-pentacin
ethyl ester (1S,2R)-7 via treatment with acidic ethanol,
(9) The absolute configuration of the minor anti-β-amino-ester
(S,RR,βS)-4 was assigned via comparison of its spectroscopic data with
an authentic sample prepared via sequential treatment of (S,RS,βS)-3a
with HCl/EtOH and NaOEt in EtOH.
(10) Bull, S. D.; Davies, S. G.; Kelly, P. M.; Gianotti, M.; Smith,
A. D. J. Chem. Soc., Perkin Trans. 1 2001, 3106–3111.
(11) (a) Schmitt, M. A.; Weisblum, B.; Gellman, S. H. J. Am. Chem.
Soc. 2004, 126, 6848–6849. (b) Martinek, T. A.; Toth, G. K.; Vass, E.;
€ €
Hollosi, M.; Fulop, F. Angew. Chem., Int. Ed. 2002, 41, 1718–1721. (c)
€ €
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Fulop, F.; Forro, E.; Toth, G. K. Org. Lett. 2004, 6, 4239–4241. (d)
Lengyel, G. A.; Frank, R. C.; Horne, W. S. J. Am. Chem. Soc. 2011, 133,
4246–4249.
(12) The absolute configuration of trifluoro-aryl-β-lactam (RR,βR)-
2c was confirmed by X-ray crystallographic analysis (see Supporting
Information).
(13) Importantly, no cyclization products arising from competing
formation of metalated enamine equivalents were observed in these
reactions.
(14) For an excellent review on the factors affecting the steric
promotion of ring formation, see: Sammes, P. G.; Weller, D. J. Synthesis
1995, 1205–1222.
a Enolates of (S)-1bꢀg generated at ꢀ40 °C, while enolates of (S)-
1hꢀi were generated at room temperature. b Drs determined from
integration of respective peaks for 2bꢀi in the 1H NMR spectra of their
crude reaction products.
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Org. Lett., Vol. 13, No. 23, 2011

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
charge via the Internet at http://pubs.acs.org.
(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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