Rapid entry to enantiopure carbacepham derivatives via Lewis acid promoted carbonyl-ene cyclization of 2-azetidinone-tethered alkenylaldehydes

Article abstract of DOI:10.1021/ol016871a

(Matrix Presented) Lewis acid promoted types I and II carbonyl-ene cyclizations of 2-azetidinone-tethered alkenylaldehydes are used for the rapid, highly diastereoselective synthesis of polyfunctionalized, enantiomerically pure carbacepham derivatives.

Full text of DOI:10.1021/ol016871a

ORGANIC
LETTERS
2001
Vol. 3, No. 26
4205-4208
Rapid Entry to Enantiopure
Carbacepham Derivatives via Lewis Acid
Promoted Carbonyl-Ene Cyclization of
2-Azetidinone-Tethered
Alkenylaldehydes
Benito Alcaide,* Carmen Pardo, Carolina Rodr´ıguez-Ranera, and
Alberto Rodr´ıguez-Vicente
Departamento de Qu´ımica Orga´nica I, Facultad de Ciencias Qu´ımicas,
UniVersidad Complutense de Madrid, 28040-Madrid, Spain
alcaideb@quim.ucm.es
Received October 8, 2001
ABSTRACT
Lewis acid promoted types I and II carbonyl-ene cyclizations of 2-azetidinone-tethered alkenylaldehydes are used for the rapid, highly
diastereoselective synthesis of polyfunctionalized, enantiomerically pure carbacepham derivatives.
The Lewis acid promoted ene cyclizations of unsaturated
carbonyl compound represent a valuable method for the
stereoselective synthesis of functionalized cyclic compounds.1
Similarly to other intramolecular cycloadditions, ene cycli-
zation profits from entropic advantage, operational simplicity,
and the fact that it proceeds usually with high degrees of
regio- and stereocontrol. In addition, the development of new
approaches to the stereocontrolled synthesis of â-lactam
systems is a subject of interest in the context of their possible
use as biologically active compounds2 or as versatile chiral
building blocks.3 Our interest in the use of 4-oxoazetidine-
2-carbaldehydes 1 as substrates for addition reactions and
cyclization processes4 prompted us to evaluate their ene
reactions as a straighforward route to functionalized fused
bicyclic 2-azetidinones. We reasoned that the presence of
activated alkenyl groups attached to position N1 of the
â-lactam ring might provide an opportunity to use such
carbonyl-ene cyclization for the synthesis of bicyclic â-lac-
tams of the carbapenam and carbacepham series, through
both type I and type II cyclization modes (Scheme 1). Despite
the great number of reported methodologies that have been
developed for the synthesis of bicyclic â-lactams from a
(1) For reviews, see: (a) Mikami, K.; Shimizu, M. Chem. ReV. 1992,
92, 1021. (b) Snider, B. B. ComprehensiVe Organic Synthesis; Trost, B.
M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 2, p 527. (c) Snieckus,
V.; Oppolzer, W. Angew. Chem., Int. Ed. Engl. 1978, 17, 476.
(2) See, for example: (a) Niccolai, D.; Tarsi, L.; Thomas, R. J. Chem.
Commun. 1997, 2333. (b) Southgate, R. Contemp. Org. Synth. 1994, 1,
417. (c) Southgate, R.; Branch, C.; Coulton, S.; Hunt, E. In Recent Progress
in the Chemical Synthesis of Antibiotics and Related Microbial Products;
Lukacs, G., Ed.; Springer: Berlin, 1993; Vol. 2, p 621. (d) The Chemistry
of â-Lactams; Page, M. I., Ed.; Chapman and Hall: London, 1992A.
(3) See, for instance: (a) Palomo, C.; Aizpurua, J. M.; Ganboa, I.;
Oiarbide, M. Amino Acids 1999, 16, 321. (b) Ojima, I.; Delaloge, F. Chem.
Soc. ReV. 1997, 26, 377. (c) Manhas, M. S.; Wagle, D. R.; Chiang, J.; Bose,
A. K. Heterocycles 1988, 27, 1755.
(4) Alcaide, B.; Almendros, P. Chem. Soc. ReV. 2001, 30, 226 and
references therein.
10.1021/ol016871a CCC: $20.00 © 2001 American Chemical Society
Published on Web 11/22/2001

Scheme 1. Types I and II Carbonyl-Ene Cyclization Modes of
2-Azetidinone-Tethered Alkenyldehydes to Carbapenam and
Carbacepham
Scheme 2. Intramolecular Carbonyl-Ene Cyclization of
2-Azetidinone-Tethered Alkenylaldehydes 1
preformed functionalized 2-azetidinone,5 no reports refer to
the carbonyl-ene cyclization.6 We wish to report here the
use of Lewis acid promoted carbonyl-ene cyclizations of
2-azetidinone-tethered alkenylaldehydes for the rapid syn-
thesis of functionalized, enantiomerically pure carbacepham
systems with extremely high diastereofacial selectivity.7
To evaluate the potential of intramolecular carbonyl-ene
reaction for the synthesis of bicyclic â-lactams of the
carbapenam and carbacepham series, we prepared several
2-azetidinone-tethered alkenylaldehydes 1 having variable
length of the linking chain, different connectivity pattern of
the reactive sites, and different substituted terminal or internal
alkene moieties. Cyclization precursors, aldehydes 1, were
easily prepared as single cis-enantiomers from imines of (R)-
2,3-O-isopropylidene-propanal, through Stau¨dinger reactions
with the corresponding acid chlorides in the presence of
Et3N,8 followed by standard transformation of the acetal
moiety.9 Scheme 2 summarizes our results for the different
enals 1 tested.10 Reaction of 1a with both SnCl4 and BF3‚
Et2O failed to give the corresponding carbapenam system
under different experimental conditions. However, homolo-
gous substrate 1b proceeded smoothly to stereoselectively
provide carbacepham 2a in good yield as pure product both
with SnCl4 and BF3‚Et2O.11 Other tested Lewis acids such
as Me2AlCl, TiCl4, and ZnBr2 were less effective for the
cyclization process. Apparently, because of the rigid angular
disposition imparted by the planar lactam group, geometric
constraints in reactive conformation arising from 1a preclude
an ene reaction to the 1,4-fused [4,5]-system. It is known
that in type I ene cyclizations formation of cyclohexanols is
(5) Kant, J.; Walker, D. G. In The Organic Chemistry of â-Lactams;
Georg, G. I., Ed.; VCH: Weinheim, 1993; Chapter 3, p 121.
(6) To the best of our knowledge there is only one example of ene
reaction for the synthesis of a cepham derivative via a transient sulfinyl
cation: Kokulja, S.; Lammert, S. R.; Gleissner, M. R. B.; Ellis, A. I. J.
Am. Chem. Soc. 1976, 98, 5040.
(7) Carbacephems are a promising new family of â-lactam antibiotics
closely related to the widely used cephalosporins, with similar antibacterial
profiles but with greater chemical stability and enhanced pharmacokinetic
properties. See, for example: (a) Cooper, R. D. G. In The Chemistry of
â-Lactams; Page, M. I., Ed.; Chapman and Hall: London, 1992; Chapter
8, p 272. See, also: (b) Folmer, J. J.; Acero, C.; Thai, D. L.; Rapoport, H.
J. Org. Chem. 1998, 63, 8170. (c) Palomo, C.; Ganboa, I.; Kot, A.;
Dembkowski, L. J. Org. Chem. 1998, 63, 6398. (d) Ciufulini, M. A. Chem.
Commun. 1996, 881. (e) Lotz, B. T.; Miller, M. J. J. Org. Chem. 1993, 58,
618.
(8) (a) Wagle, D. R.; Garai, C.; Chiang, J.; Monteleone, M. G.; Kurys,
B. E.; Strohmeyer, T. W.; Hedge, V. R.; Manhas, M. S.; Bose, A. K. J.
Org. Chem. 1988, 53, 4227. (b) Georg, G. I.; Ravikumar, V. T. In The
Organic Chemistry of â-Lactams; Georg, G. I., Ed.; VCH: Weinheim, 1993;
Chapter 3, p 295.
(9) See, for example: (a) Alcaide, B.; Almendros, P.; R.-Salgado, N. J.
Org. Chem. 2000, 65, 3310. (b) Alcaide, B.; Almendros, P.; Aragoncillo,
C. J. Org. Chem. 2001, 66, 1612.
The reaction was allowed to reach room temperature and quenched with
NaHCO3 (sat.). After extraction of the mixture with CH2Cl2 the organic
layer was dried over MgSO4, and the solvent was removed under reduced
pressure. After purification by flash chromatography, carbacepham 2a was
obtained in analytically pure form.
(11) All new compounds described herein were fully characterised by
spectroscopic methods and microanalysis and/or HRMS. All yields refer
to chromatographed, pure (NMR, TLC) compounds. Representative data
are given for compound 2a: mp 90-92 °C; [R]D ) +58.5 (c 1, CHCl3);
1H NMR (CDCl3) δ 1.70 (m, 2H), 1.73 (s, 3H), 1.94 (s, 1H), 2.24 (dt, J )
6.0, 10.0 Hz, 1H), 2.78 (m, J ) 1.0, 6.0, 10.0, 13.7 Hz, 1H), 3.64 (dd, J )
3.9, 8.3 Hz, 1H), 3.77 (dd, J ) 8.3, 10.0 Hz, 1H), 3.90 (ddd, J ) 2.9, 3.9,
13.7 Hz, 1H), 4.91 (br s, 1H), 4.97 (t, J ) 1.5 Hz, 1H), 5.33 (dd, 1H, J )
1.0, 3.9 Hz), 7.01-7.11 (m, 3H), 7.31 (m, 2H); 13C NMR (CDCl3) δ 164.9,
157.2, 143.8, 129.4, 122.3, 115.7, 114.2, 81.6, 66.5, 59.1, 49.6, 37.8, 29.3,
19.2; IR (KBr, cm-1) ν 3440, 1741; MS (EI) m/z 274 (M++ 1, 2), 149
(100), 131 (47). Anal. Calcd for C16H19NO3: C, 70.31; H, 7.01; N, 5.12.
Found: C, 70.50; H, 7.21; N, 5.08.
(10) Representative experimental procedure for the synthesis of
carbacepham 2a. To a solution of the starting â-lactam 1b (1 mmol) in dry
CH2Cl2 (10 mL) under argon at 0 °C was added BF3‚OEt2 (1.2 mmol)
dropwise, and the reaction mixture was stirred at this temperature for 2 h.
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Org. Lett., Vol. 3, No. 26, 2001

faster than formation of cyclopentanols as a result of the
greater ring strain of cyclopentanols (n ) 6 > 5 . 7).
Alkenylaldehydes 1c and 1d afforded compounds 2b and
2c, respectively, in good yields in their corresponding
reactions with BF3‚Et2O. When alkene substituent was moved
from position N1 to C3, as in 3,4-tethered enal 1e, it also
furnished the corresponding 3,4-fused [4,6]-system 3 in good
yield and as only one isomer in its reaction with SnCl4.
However, use of BF3‚Et2O yielded a complex mixture of
products with complete disappearance of the starting material.
Reaction of enal 1f proceeded both with SnCl4 and BF3‚
Et2O albeit in moderate to low yields of carbacepham 4.
Interestingly, along with compound 4, chlorocarbacepham
derivative 5 was also obtained as byproduct in the SnCl4-
promoted reaction. Formation of compound 5 with a cis
disposition between chloro and hydroxyl groups suggests a
stepwise mechanism and can be rationalized through initial
participation of an aldehyde-SnCl4 complex and further
evolution to zwitterion 6 followed by intramolecular [1,5]
chloride shift to chloro-alkoxide 7, which finally gives
chlorocarbacepham 5 after hydrolysis (Scheme 3). As far as
Scheme 4. Synthesis of Epimeric Carbacepham 2d and 2ea
a (a) (i) LDA, THF, -78 °C, (ii) Me2CHdCHCH2Br, -78 °C
to room temperature, 65%. (b) (i) PPTS‚H2O, (ii) NaIO4. (c) (i)
BF3‚OEt2, CH2Cl2, 0 °C, (ii) SiO2 separation, 42% from 9.
Scheme 3. Proposed Reaction Course for the Formation of
Chlorocarbacepham 5
and NOE experiments allowed assignment of 2d and 2e as
the (4R)- and (4S)-diastereomers, respectively.
The stereochemical outcome in the present carbonyl-ene
cyclizations leading to carbacephams 2 and 4 can be
explained in terms of the six-membered, cyclic chairlike
transition state models depicted in Scheme 5.15
Scheme 5. Proposed Models for Ene-Cyclization of Alkenyl
Aldehydes 1d, 1f, and 1g Leading to Carbacephams 2c-e and 4
we know this behavior known for Lewis acid catalyst such
as Me2AlCl or TiCl4 is unprecedented for tin(IV) chloride.12
Because a carboxy group contiguous to the lactam nitrogen
is a prerequisite for biological activity, we also prepared the
carbacepham precursor 1g as 1:1 mixture of isomers (Scheme
4). Sequential reaction of â-lactam 813 with LDA and
methallyl bromide furnished an inseparable mixture (1:1) of
epimers 9.14 After acetal deprotection and oxidative cleavage
aldehyde 1g was obtained as an inseparable mixture of
isomers, which was used directly for carbonyl-ene experi-
ments. Reaction of 1g in the presence of BF3‚Et2O afforded
an easily separable 1:1 mixture of epimeric carbacephams
2d and 2e, which were obtained in 20% and 22% yield,
respectively, as pure products after chromatography (42%
overall yield from compound 9). Vicinal coupling constants
In conclusion, we have demonstrated the utility of the
reported methodology for the facile and diastereoselective
elaboration of enantiopure bicyclic â-lactam systems relevant
(12) Andersen, N. H.; Hadley, S. W.; Kelly, J. D.; Bacon, E. R. J. Org.
Chem. 1985, 50, 4144.
(13) Alcaide, B.; Almendros, P.; R.-Salgado, N.; Mart´ınez-Alca´zar, M.
P.; Herna´ndez-Cano, F. Eur. J. Org. Chem. 2001, 2001.
(14) The poor selectivity obtained in allylation of compound 8 is in clear
contrast with the excellent stereoselectivity observed by Ojima for related
type 2 alkylations in chiral 4-phenyl-â-lactam acetates. See, for example:
Ojima, I.; Komata, T.; Qiu, X. J. Am. Chem. Soc. 1990, 112, 770.
(15) For models on the carbonyl-ene cyclization reaction, see: (a)
Braddock, D. Ch.; Hii, K. K.; Brown, J. M. Angew. Chem., Int. Ed. Engl.
1998, 37, 1720. (b) Mikami, K.; Sawa, E.; Terada, M. Tetrahedron:
Asymmetry 1991, 2, 1403. (c) Maruoka, K.; Ooi, T.; Yamamoto, H. J. Am.
Chem. Soc. 1990, 112, 9011. (d) Johnston, M.; Kwass, J. A.; Beal, R. B.;
Snider, B. B. J. Org. Chem. 1987, 52, 5419.
Org. Lett., Vol. 3, No. 26, 2001
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to the synthesis of carbacephem antibiotics. The synthetic
potential of these intramolecular processes as well as related
intermolecular carbonyl-ene reactions are currently under
investigation, and further aspects of this chemistry will be
reported in due course.
Comunidad de Madrid-Spain) for a predoctoral and post-
doctoral fellowship, respectively.
Supporting Information Available: Compound charac-
terization data and experimental procedures for products 1a,
1c-g, 2a-e, and 3-5. This material is available free of
charge via the Internet at http://pubs.acs.org.
Acknowledgment. We are grateful to the DGI (MCYT-
Spain) for financial support of this research (project BQU2000-
0645). C. Rodr´ıguez and A. Rodr´ıguez thank the DGI (CEC-
OL016871A
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