Diastereoselective Baylis-Hillman reaction of 4-oxoazetidine-2-carbaldehydes: Rapid, stereocontrolled and divergent radical synthesis of highly functionalised β-lactams fused to medium rings

Article abstract of DOI:10.1039/a905017e

Baylis-Hillman adducts derived from enantiopure 1-alkenyl- or alkynyl-4-oxoazetidine-2-carbaldehydes are used for the stereoselective and divergent preparation of highly functionalised β-lactams fused to medium rings through novel, chemocontrolled tandem radical addition-cyclization sequences.

Full text of DOI:10.1039/a905017e

Diastereoselective Baylis–Hillman reaction of 4-oxoazetidine-2-carbaldehydes:
rapid, stereocontrolled and divergent radical synthesis of highly functionalised
b-lactams fused to medium rings
Benito Alcaide,* Pedro Almendros and Cristina Aragoncillo
Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense, 28040-Madrid,
Spain. E-mail: alcaideb@eucmax.sim.ucm.es
Received (in Liverpool, UK) 21st June 1999, Accepted 30th July 1999
Baylis–Hillman adducts derived from enantiopure 1-alk-
enyl- or alkynyl-4-oxoazetidine-2-carbaldehydes are used
for the stereoselective and divergent preparation of highly
functionalised b-lactams fused to medium rings through
novel, chemocontrolled tandem radical addition–cyclization
sequences.
25 °C, k7-exo < 7 3 1021 s21). Nevertheless, several authors
were able to prepare seven-membered rings by radical cycliza-
tion on substrates bearing only a limited degree of freedom,
including b-lactam-tethered haloalkenes or alkynes6,7 and aryl-
bridged compounds.8
Baylis–Hillman adducts 3 were easily prepared by DABCO-
mediated reaction of enantiopure 4-oxoazetidine-2-carbalde-
hydes 4 with methyl vinyl ketone in excellent yields and
stereoselectivities (Scheme 2). Alkenyl or alkynyl aldehydes 4
were easily prepared as single cis-enantiomers from imines of
(R)-2,3-O-isopropylidenepropanal, through Staüdinger reac-
tions with the corresponding acid chlorides in the presence of
Et3N,9 followed by standard transformations of the acetal
moiety.5 The Baylis–Hillman reaction using protected a-amino
aldehydes has been attempted with limited success, due to
partial racemisation of the chiral aldehyde by DABCO after
prolongate exposure times.10 We were pleased to find that the
Baylis–Hillman reaction proceeds faster than racemization (our
typical reaction time ranging from 18 h for 4a to 72 h for 4b)
using an equimolar amount of DABCO and 10 equiv. of methyl
vinyl ketone and performing the experiment in MeCN at low
temperature (220 °C).†
The Baylis–Hillman reaction is an emerging carbon–carbon
bond forming reaction for the preparation of densely functiona-
lysed products involving an activated alkene, a carbon electro-
phile and a suitable catalyst (particularly a tertiary amine).1 On
the other hand, synthetic methodologies based on free radical
cyclization reactions have experienced an impressive growth
and are the focus of extensive studies. This wide research has
been fostered by its operational simplicity, its tolerance to
substrate functionalization, and the fact that it proceeds usually
with high degrees of regio- and stereo-control.2
The increased resistance of bacteria to the commonly used b-
lactam antibiotics3 and the ever-growing new applications of
these products in fields ranging from enzyme inhibition to the
use of azetidin-2-ones as starting materials to develop new
synthetic methodologies, has triggered a renewed interest in the
construction of new systems having the azetidin-2-one ring as a
common feature.4 Our interest in the use of 4-oxoazetidine-
2-carbaldehydes as substrates for intramolecular cyclization
processes5 prompted us to evaluate the combination of the
Baylis–Hillman reaction with free-radical methodology as a
route to unusual, chiral non-racemic bicyclic b-lactams. We
report here novel, simple strategies for the stereoselective and
divergent preparation of medium sized ring-fused highly
functionalized bicyclic b-lactams 1 and 2 based on chemocon-
trolled tandem radical addition–cyclization sequences (Scheme
1). The useful and expedient approach described herein presents
the opportunity to merge the rapidly expanding fields of Baylis–
Hillman reaction and radical chemistry. The problems asso-
ciated with the formation of medium sized rings are widely
appreciated. Even the formation of seven-membered rings in the
7-exo-trig mode is likely to be unsuccessful in most cases (at
Subjection of any organic molecule to a high enough
temperature in the gas phase results in the formation of free
radicals. When the molecule contains bonds with dissociation
energies from 20 to 40 kcal mol21, cleavage can be caused in
the liquid phase. The dissociation energy of the PhCH2–H bond
is 88 kcal mol21, so the generation of the benzylic radical is an
unexpected process via heating at usual temperatures.11 To our
Scheme 1
Scheme 2
Chem. Commun., 1999, 1913–1914
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Scheme 3
surprise, Baylis–Hillman adduct (+)-3a, on heating in toluene or
p-xylene in a sealed tube at 210 °C, formed the bicyclic products
1a, b, which were isolated in modest yields (37–45%).‡ Use of
chlorobenzene or anisole as solvents gave unaltered starting
material (+)-3a. When enyne (+)-3b was used instead of diene
(+)-3a the reaction proceeded in the same manner, giving
product (+)-1c in good yield (60%). Furthermore, thermal
treatment of enyne (+)-3c with p-xylene gave the bicycle (+)-1e
in reasonable yield (Scheme 2). Interestingly, the use of benzyl
alcohol allowed us to obtain the hemiacetal derivative of
compound 1d. Although this latter compound was isolated in
low yield (20%) this is an interesting case because three new
chiral centers are generated in a highly stereoselective manner.§
All compounds 1 were obtained as single diastereomers. When
a catalytic amount of hydroquinone was added, the reaction rate
was considerably reduced and the product yield fell dramat-
ically. This fact confirms that a radical reaction is involved.
Also, together with compounds 1, 1,2-diarylethanes were
isolated as byproducts in all cases. These products may be
formed by recombination of the initially generated benzylic
radicals.
In view of the particular disposition of the 1,5- and 1,6-enyne
azetidin-2-ones to undergo 5-exo and 6-exo tin promoted radical
cyclization,12 we examined the applicability of this method-
ology to our novel Baylis–Hillman 1,w-enyne substrates 3b–3d
for the synthesis of less common bicyclic b-lactams. This
approach in the synthesis of seven-membered or higher sized
rings has not been hitherto applied.13 A dramatic change in the
chemoselectivity was observed when the bicyclic b-lactam
(+)-2a was formed as the exclusive product from (+)-3b, in
nearly quantitative yield as crude product. The tin-promoted
radical reaction was also useful in the conversion of the
homologous 1,4-tethered enynes (+)-3c and (+)-3d into the
corresponding bicyclic systems with similar efficiency and
selectivity. Compounds 2 were exclusively obtained as Z-
isomers. In addition, PhSH reacted smoothly with b-lactams
(+)-3b and (+)-3c in the presence of AIBN, in boiling benzene,
to give in good yields the corresponding phenylthiovinyl
derivatives as mixtures of easily separable Z and E isomers
(Scheme 3). The bicyclic structure (by DEPT, HETCOR, and
COSY) and the stereochemistry (by vicinal proton couplings
and NOE experiments) of compounds 1 and 2 were established
by NMR one- and two-dimensional techniques.
Scheme 4
Notes and references
† When the reaction was performed at room temperature maintaining the
molar ratio of reagents (aldehyde:DABCO:methyl vinyl ketone = 1+1+10),
partial epimerisation together with some unreacted aldehyde were ob-
served.
‡ Representative experimental procedure for thermal promoted tandem
radical reaction: A solution of Baylis–Hillman adduct 3 (0.2 mmol) in the
corresponding benzylic solvent (10 ml) was heated in a sealed tube at
210 °C for 3 h. The reaction mixture was allowed to cool to room
temperature, the solvent was removed under reduced pressure and, after
purification by flash chromatography, bicycles 1 were obtained in
analytically pure form.
§ All new compounds were fully characterised by spectroscopic methods
and microanalysis and/or HRMS.
1 Reviews: E. Ciganek, Org. React., 1997, 51, 201; D. Basavaiah, P. D.
Rao and R. S. Hyma, Tetrahedron, 1996, 52, 8001.
2 For leading references, see: D. P. Curran, N. A. Porter and B. Giese, in
Stereochemistry of Radical Reactions, VCH Publishers, New York,
1996; D. P. Curran, in Comprehensive Organic Synthesis, ed. B. M.
Trost, Pergamon, Oxford, 1992, vol 4, ch. 4.2.
3 See, for example: D. Niccolai, L. Tarsi and R. J. Thomas, Chem.
Commun., 1997, 2333; V. Hook, Chem. Br., 1997, 33, 34; J. Davies,
Science, 1994, 264, 375.
4 See for example: Symposia-in-Print Number 8, Recent Advances in the
Chemistry and Biology of b-Lactams and b-Lactam antibiotics, ed. G. I.
Georg, Bioorg. Med. Chem. Lett., 1993, 3, 2159.
5 B. Alcaide and P. Almendros, Tetrahedron Lett., 1999, 40, 1015.
6 J. Knight, P. J. Parsons and R. Southgate, J. Chem. Soc., Chem.
Commun. 1986, 78; J. Knight and P. J. Parsons, J. Chem. Soc., Perkin
Trans. 1 1987, 1237.
7 M. D. Bachi, F. Frolow and C. Hoornaert, J. Org. Chem., 1983, 48,
1841.
8 D. L. Boger and R. Mathvink, J. Org. Chem., 1988, 53, 3377.
9 G. I. Georg and V. T. Ravikumar, in The Organic Chemistry of b-
Lactams, ed. G. I. Georg, VCH, Weinheim, 1993, ch. 3, p. 295.
10 S. E. Drewes, A. A. Khan and K. Rowland, Synth. Commun., 1993, 23,
183.
11 W. B. Motherwell and D. Crich, in Free Radical Chain Reactions in
Organic Synthesis, Academic Press, London, 1991, ch. 6, pp. 183–185
and references cited therein.
Formation of bicyclic b-lactams 1 and 2 can be explained in
terms of a competition between a tandem radical Michael
addition–endo-cyclization and a tandem radical addition–
Michael addition, depending on the electronic nature of the
radical promoter (Scheme 4). The more nucleophilic benzylic
radical would favour formation of compounds 1, while the more
electrophilic radicals, such as PhS. and Ph3Sn., should promote
formation of compounds 2. The high stereoselectivity of the
processes can be tentatively interpreted in terms of the allylic
strain model of Giese, showing for planar substituents such as
Ac good levels of 1,2-stereoinduction on a-substituted b-oxy
radicals (types 5 and 6 in Scheme 4).14
12 B. Alcaide, I. M. Rodr´ıguez-Campos, J. Rodr´ıguez-Lopez and A.
Rodr´ıguez-Vincente, J. Org. Chem., 1999, 64, 5377.
13 The only related example is by Parsons et al. and refers to the cyclization
of N-(2-bromoprop-2-en-1-yl)-4-allylazetidin-2-one to yield a homo-
carbacephem derivative. See ref. 6.
We would like to thank the DGES (MEC-Spain, grant PB96-
0565) for financial support. P. A. thanks the DGES (MEC,
Spain) for a ‘Contrato de Incorporación’. C. A. thanks the DGI
(CEC-Comunidad de Madrid-Spain) for a fellowship.
14 B. Giese, M. Bulliard, J. Dickhaut, R. Halbach, C. Hassler, U.
Hoffmann, B. Hinzen and M. Senn, Synlett, 1995, 116.
Communication 9/05017E
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Chem. Commun., 1999, 1913–1914