Novel N1-C4 β-lactam bond breakage. Synthesis of enantiopure γ-alkoxy-γ-keto acid derivatives

Article abstract of DOI:10.1021/ol049549j

Matrix presented. Addition reaction of 2-(trimethylsilyl)thiazole (TMST) to cis- or trans-4-formyl-β-lactams gave enantiopure α-alkoxy-γ- keto acid derivatives via a novel N1-C4 bond breakage of the β-lactam nucleus. This is the first time that the cleava

Full text of DOI:10.1021/ol049549j

ORGANIC
LETTERS
2004
Vol. 6, No. 11
1765-1767
Novel N1−C4 â-Lactam Bond Breakage.
Synthesis of Enantiopure
r-Alkoxy-γ-keto Acid Derivatives†
,‡
,§
Benito Alcaide,* Pedro Almendros,* and Mar´ıa C. Redondo‡
Departamento de Qu´ımica Orga´nica, Facultad de Qu´ımica,
UniVersidad Complutense de Madrid, 28040-Madrid, Spain, and Instituto de Qu´ımica
Orga´nica General, CSIC, Juan de la CierVa 3, 28006-Madrid, Spain
alcaideb@quim.ucm.es; iqoa392@iqog.csic.es
Received March 10, 2004
ABSTRACT
Addition reaction of 2-(trimethylsilyl)thiazole (TMST) to cis- or trans-4-formyl-â-lactams gave enantiopure r-alkoxy-γ-keto acid derivatives via
a novel N1−C4 bond breakage of the â-lactam nucleus. This is the first time that the cleavage of the N1−C4 bond on the â-lactam nucleus
has been shown to occur in 2-azetidinones lacking an aryl moiety at C4.
In addition to the key role that â-lactams have played in the
fight against pathogenic bacteria, the use of 2-azetidinones
as chiral building blocks in organic synthesis is now well
established.1 Opening of the â-lactam ring can occur through
cleavage of any of the single bonds of the four-membered
ring.2 Cleavage of the amide bond (a in Figure 1) has been
peridines, cyclic enaminones, pyridones, oxazinones, and
complex natural products. N-Carboxy anhydrides, R-amino
acids, peptides, and haloalkyl isocyanates have been obtained
by breakage of the C2-C3 bond (b in Figure 1). Pyrazine-
2,3-diones, substituted amides, and eight-membered lactams
can be prepared through cleavage of the C3-C4 bond on
the â-lactam nucleus (c in Figure 1). However, little was
known about the application in synthesis of the N1-C4 bond
breakage of the â-lactam system (d in Figure 1), until Ojima
and his group entered this field.3 These authors developed a
methodology for the synthesis of R-amino acids and deriva-
tives, based on the hydrogenolytic cleavage of the N1-C4
bond of 4-aryl-â-lactams.4 In continuation of our efforts on
the synthesis and synthetic applications of functionalized
â-lactams,5 herein we report a novel N1-C4 bond breakage
of the â-lactam skeleton to yield enantiopure R-hydroxy acid
derivatives 2, an important class of molecules that are
building blocks for the synthesis of depsides and depsipep-
Figure 1. Various modes of ring opening of the â-lactam nucleus.
the subject of many investigations to give â-amino acids,
bis-γ-lactams, pyrrolizidines, indolizidines, pyrrolidines, pi-
(2) For a review on the selective bond cleavage of the â-lactam nucleus,
see: Alcaide, B.; Almendros, P. Synlett 2002, 381.
(3) For reviews, see: (a) Ojima, I.; Delaloge, F. Chem. Soc. ReV. 1997,
26, 377. (b) Ojima, I. AdV. Asymmetric Synth. 1995, 1, 95. (c) Ojima, I.
Acc. Chem. Res. 1995, 28, 383.
† Dedicated to Prof. Jose´ Luis Soto on the occasion of his retirement.
‡ Universidad Complutense de Madrid.
§ CSIC.
(1) For selected reviews, see: (a) Alcaide, B.; Almendros, P. Chem. Soc.
ReV. 2001, 30, 226. (b) Palomo, C.; Aizpurua, J. M.; Ganboa, I.; Oiarbide,
M. Synlett 2001, 1813. (c) Manhas, M. S.; Wagle, D. R.; Chiang, J.; Bose,
A. K. Heterocycles 1988, 27, 1755.
(4) In addition to Ojima’s work, the only available reports on the N1-
C4 bond cleavage are: (a) Cabell, L. A.; McMurray, J. S. Tetrahedron
Lett. 2002, 43, 2491. (b) Alcaide, B.; Dom´ınguez, G.; Mart´ın-Domenech,
A.; Plumet, J.; Monge, A.; Pe´rez-Garc´ıa, V. Heterocycles 1987, 26, 1461.
10.1021/ol049549j CCC: $27.50 © 2004 American Chemical Society
Published on Web 04/22/2004

tides, natural products than often exhibit significant biological
activity.6
Table 1. Conversion of cis-4-Formyl-â-lactams 1 into
R-Hydroxy Carboxamides 2a
The starting substrates, enantiopure 2-azetidinones 1a-f,
were prepared using standard methodology as single cis
enantiomers from aryl imines of (R)-2,3-O-isopropylidene-
glyceraldehyde, through Staudinger reaction with methoxy-
or benzyloxyacetyl chloride in the presence of Et3N, followed
by sequential acidic acetonide hydrolysis and oxidative
cleavage.7
Thiazole-based organometallics are well documented
reagents for carbonyl addition.8 In this context, we began
this work by investigating the diastereoselectivity of the
addition of cis-4-formyl-â-lactam (+)-1a with 2-(trimeth-
ylsilyl)thiazole (TMST) in dichloromethane. The reaction
provided the enantiomerically pure R-hydroxy acid derivative
(+)-2a in a reasonable 58% isolated yield (Table 1, entry
1). The expected addition product, (+)-3a, was obtained as
a minor component (31%). Polyfunctionalized compound
(+)-2a can be considered both an aldol as well as a Passerini-
type product. Placing a less electron-donating substituent in
the para position of the N-aryl ring decreased the selectivity
of the process (Table 1, entry 2). The NMe2 analogue was a
poor participant (Table 1, entry 3). It was revealed that the
introduction of one halogen atom at the 4-position of the
aromatic ring was slightly effective (Table 1, entry 4). To
further improve the selectivity, we focused on a more
electron-rich aromatic ring. Indeed, placing two electron-
donating substituents in the ortho and para positions of the
aromatic ring at N1 increased the selectivity of the process
(Table 1, entry 5). â-Lactams bearing a benzyl or an allyl
substituent at nitrogen failed to give the R-alkoxy acid
derivative, giving the addition product. No advantage is
gained from changing the methoxy group at C3 to a
benzyloxy (Table 1, entry 6) in the starting (3R,4R)-4-formyl-
â-lactam 1. Switching solvents (acetonitrile, THF, toluene)
had no beneficial effects. In terms of achieving fair yields
with reasonable selectivity of reaction, 0 °C seemed to be
the temperature of choice for running the experiments.
The susceptibility of the reaction to stereochemically
different â-lactam aldehydes was next examined, by explor-
ing the possibility of employing trans-4-formyl-â-lactams
4. Optically pure 2-azetidinones (+)-4a, (-)-4a, and (+)-
4b were prepared adopting literature methodology.9
a TMST ) 2-(trimethylsilyl)thiazole. Thz ) 2-thiazolyl. b Yields are for
pure isolated products with correct analytical and spectroscopic data. In all
cases, compounds 2 and 3 could be easily separated by column chroma-
tography.
Gratifyingly, the corresponding enantiopure R-alkoxy
carboxamides could be obtained (Scheme 1). The (3R,4S)-
4-formyl-â-lactam (-)-4a gave compound (+)-2a, while its
enantiomer (+)-4a gave compound (-)-2a. Addition prod-
ucts 5a-c were obtained as minor components in the
coupling reactions. The higher ratio of R-alkoxy carboxa-
mide/addition product using aldehydes (-)-4a or (+)-4a in
comparison to (+)-1a was mainly due to the inefficiency of
the competitive addition reaction in diastereomeric aldehydes
4, since the opening product accounted as well for a 50%
yield in pure product. In each case, the absolute configuration
of the R-alkoxy acid product matched that of the correspond-
ing â-lactam aldehyde. Therefore, a synthesis of both
enantiomers of R-hydroxy acid derivatives was achieved just
by a subtle variation in the stereochemistry of the aldehyde
component.
(5) See, for instance: (a) Alcaide, B.; Almendros, P.; Alonso, J. M. J.
Org. Chem. 2004, 69, 993. (b) Alcaide, B.; Almendros, P.; Aragoncillo,
C.; Rodr´ıguez-Acebes, R. J. Org. Chem. 2004, 69, 826. (c) Alcaide, B.;
Almendros, P.; Alonso, J. M. Chem. Eur. J. 2003, 9, 5793. (d) Alcaide, B.;
Almendros, P.; Aragoncillo, C. Org. Lett. 2003, 5, 3795. (e) Alcaide, B.;
Almendros, P.; Alonso, J. M.; Aly, M. F. Chem. Eur. J. 2003, 9, 3415.
(6) (a) Nicolaou, K. C.; Boddy, C. N. C.; Bra¨se, S.; Winssinger, N.
Angew. Chem., Int. Ed. 1999, 38, 2096. (b) Ballard, C. E.; Yu, H.; Wang,
B. Curr. Med. Chem. 2002, 9, 471.
(7) (a) Alcaide, B.; Almendros, P.; Aragoncillo, C. Chem. Eur. J. 2002,
8, 1719. (b) Alcaide, B.; Almendros, P.; Salgado, N. R. J. Org. Chem. 2000,
65, 3310.
(8) (a) Dondoni, A.; Marra, A. Tetrahedron Lett. 2003, 44, 13. (b)
Dondoni, A. Synthesis 1998, 1681. (c) Dondoni, A. Pure Appl. Chem. 2000,
72, 1577.
(9) For (-)-4a, see: (a) Alcaide, B.; Aly, M.; Rodr´ıguez, C.; Rodr´ıguez-
Vicente, A. J. Org. Chem. 2000, 65, 3453. For (+)-4a and (+)-4b, see:
(b) 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.
It may be possible that, under the reaction conditions, the
initially formed adducts 3 or 5 evolve to the corresponding
R-hydroxy carboxamides 2. However, compounds (+)-3a or
(+)-3f remained unaltered after several days in the presence
of TMST at the above conditions. At present time, we
propose alkoxide 6 as a common intermediate for the thiazole
adducts formation (Scheme 2). Alkoxide 6 may suffer a 1,2
migration of hydrogen with concomitant N1-C4 â-lactam
1766
Org. Lett., Vol. 6, No. 11, 2004

Scheme 1. Conversion of trans-4-Formyl-â-lactams 4 into
R-Alkoxy Carboxamides 2a
Scheme 2. Proposed Reaction Course for the Formation of
R-Alkoxy Carboxamides 2 and Addition Products 3 or 5 from
4-Formyl-â-lactams 1 and 4
a Key: (i) TMST, DCM, 0 °C. Yields are for pure isolated
products with correct analytical and spectroscopic data. In all cases,
the compounds 2 and 5 could be easily separated by column
chromatography. TMST ) 2-(trimethylsilyl)thiazole. Thz ) 2-thia-
zolyl. Ar1 ) 4-MeOC6H4. Ar2 ) 2,4-di-MeOC6H3.
scope and generality of this methodology are underway in
our laboratory, and further details will be reported in due
course.
Acknowledgment. Support for this work by the DGI-
MCYT (Project BQU2003-07793-C02-01) is gratefully
acknowledged. M.C.R. thanks the MECD for a predoctoral
grant.
bond breakage to afford the R-alkoxy acid derivatives 2 (A
in Scheme 2), or it may accept an electrophile to give the
addition products 3 or 5 (B in Scheme 2).
In conclusion, this is the first report involving the N1-
C4 bond breakage in â-lactams lacking an aryl moiety at
C4. In addition, the resulting products, possessing simulta-
neously a â-alkoxy ketone (aldol-type product) and an
R-alkoxy carboxamide (Passerini-type product), cannot be
easily obtained by alternative means. Studies concerning the
Supporting Information Available: General experimen-
tal procedures as well as spectroscopic and analytical data
for compounds 1a-f, 2a-f, 3a-f, and 5a-c. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL049549J
Org. Lett., Vol. 6, No. 11, 2004
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