of azetidine-2,3-diones has not been reported yet. Further-
more, the information available on the use of â-lactams as
chiral building blocks on the propargylation reaction is still
very scarce; just Cho has recently reported the propargyl-
zincation of 6-oxopenicillanates in anhydrous tetrahydro-
furan.6 On the other hand, the 3-substituted 3-hydroxy-2-
azetidinone moiety, representing an efficient carboxylate
mimic,7 is present in several pharmacologically active
monobactams such as sulphazecin and related products,8 and
in enzyme inhibitors such as tabtoxin and its analogues.9
Moreover, these compounds with correct absolute configura-
tions serve as precursors to the corresponding R-hydroxy-
â-amino acids (isoserines), which are key components of a
large number of therapeutically important compounds.10
However, little attention has been paid to develop methods
for the construction of â-lactams with quaternary stereogenic
centers at the C3 position.11
control of stereochemistry at the C3-substituted C3-hydroxy
quaternary center, we have devised a strategy by placing a
chiral substituent at C-4. To develop full regiocontrol we
have investigated a number of protocols in anhydrous and
aqueous environments, being involved a variety of metal
mediators and different prop-2-ynyl systems. Chemical yields
were generally good, but the regioselectivity of the process
was a function of the nature of both the metal reagent and
the prop-2-ynyl bromide, and in many cases of the solvent
system as well. The diastereoselectivity was complete in all
cases.
Initially the regio- and diastereoselectivity of the carbon-
carbon bond formation were investigated through the indium-
mediated reaction between the 2,3-azetidinedione (+)-1a and
propargyl bromide in aqueous tetrahydrofuran at room
temperature. In the event, the 3-substituted 3-hydroxy-â-
lactam moiety was obtained with total diastereoselection;
however, the observed regioselectivity was very poor (42:
58) in favor of the allenic product. Surprisingly, the regio-
chemical preference was reversed on the indium-promoted
reaction just by changing the system solvent (a saturated
aqueous solution of NH4Cl in THF was used instead of
aqueous tetrahydrofuran), with the expected alcohols (+)-
2a and (+)-3a being obtained as a mixture of regioisomers
in a ratio of 2a:3a ) 71:29. This preliminary result
encouraged us to find a more convenient reagent for this
transformation. To our delight, when the above reaction was
mediated by zinc and was conducted in a saturated aqueous
solution of NH4Cl in THF at 0 °C, it gave rise to the optically
pure homopropargyl alcohol (+)-2a as single regio- and
diastereoisomer in a reasonable 70% yield. However, the
yield fell dramatically when the zinc-mediated coupling of
the 2,3-azetidinedione (+)-1a and propargyl bromide in
anhydrous THF in the presence of solid NH4Cl was
performed. No reaction was observed in anhydrous THF
when the NH4Cl was supressed, and the change of the system
solvent from tetrahydrofuran/NH4Cl (aq. sat.) to methanol/
NH4Cl (aq. sat.) resulted in the absence of regioselection.
When propargylmagnesium bromide was added to the dione
(+)-1a the homopropargylic alcohol was afforded as a major
product, containing 15% of the homoallenic alcohol. The
tin-mediated reaction between ketone (+)-1a and propargyl
bromide in aqueous tetrahydrofuran resulted in the absence
of coupling. By contrast, when the same experiment was
carried out in a saturated aqueous solution of NH4Cl in THF,
the homoallenyl alcohol was formed as major product,
together with 25% of the homopropargylic alcohol. Allenyl-
ation with propargyl bromide in anhydrous THF using the
bimetal system copper(II)/tin(II) as the mediator, further
lowered the regioselectivity (34:66).14 Efforts to promote the
copper(II)/tin(II)-mediated propargylation in DMF were
proven to be unsuccessful. Similar results were obtained in
the metal-mediated Barbier-type reactions of different N-
substituted azetidine-2,3-diones 1b-d with propargyl bro-
mide (Table 1).
In our ongoing project directed toward the asymmetric
synthesis and synthetic applications of functionalized 2-azet-
idinones,12 in a previous paper we reported a detailed study
of both the allylation and the stereoselective Baylis-Hillman
reaction of azetidine-2,3-diones.13 In connection with this
work we report here the manner in which enantiomerically
pure azetidine-2,3-diones and a variety of allenyl organo-
metallics or propargylmetal reagents undergo coupling. The
starting azetidine-2,3-diones 1 were available in high yield
by Swern oxidation of 3-hydroxy-â-lactams, by following a
previously reported procedure.13
Our aim was to evaluate the feasibility of the metal-
mediated Barbier-type reactions in enantiomerically pure
azetidine-2,3-diones, studying the regiochemistry of the
connection (e.g., allenylation vs propargylation) and the
diastereochemistry (syn vs anti). To achieve the goal of full
(6) Cho, Y. S.; Lee, J. E.; Pae, N.; Choi, K. I.; Koh, H. Y. Tetrahedron
Lett. 1999, 40, 1725.
(7) (a) Unkefer, C. J.; London, R. E.; Durbin, R. D.; Uchytil, T. F.;
Langston-Unkefer, P. J. J. Biol. Chem. 1987, 262, 4993. (b) Meek, T. D.;
Villafranca, J. V. Biochemistry 1980, 19, 5513. (c) Sinden, S. L.; Durbin,
R. D. Nature 1968, 219, 379.
(8) Imada, A.; Kitano, K.; Kintana, K.; Muroi, M.; Asai, M. Nature 1981,
289, 590.
(9) (a) Dolle, R. E.; Hughes, M. J.; Li, C.-S.; Kruse, L. I. J. Chem. Soc.,
Chem. Commun. 1989, 1448. (b) Greenlee, W. J.; Springer, J. P.; Patchett,
A. A. J. Med. Chem. 1989, 32, 165. (c) Baldwin, J. E.; Otsuka, M.; Wallace,
P. M. Tetrahedron 1986, 42, 3097. (d) Stewart, W. W. Nature 1971, 229,
174.
(10) (a) Thaisrivongs, S.; Pals, D. T.; Kroll, L. T.; Turner, S. R.; Han,
F.-S. J. Med. Chem. 1987, 30, 976. (b) Huff, J. R. J. Med. Chem. 1991, 34,
2305. (c) Ojima, I.; Wang, T.; Delagoge, F. Tetrahedron Lett. 1998, 39,
3663. (d) Ojima, I.; Kuduk, S. D.; Pera, P.; Veith, J. M.; Bernacki, R. J. J.
Med. Chem. 1997, 40, 267. (e) Denis, J.-N.; Fkyerat, A.; Gimbert, Y.;
Coutterez, C.; Mantellier, P.; Jost, S.; Greene, A. E. J. Chem. Soc., Perkin
Trans. 1 1995, 1811.
(11) For different enantioselective approaches to 3-alkyl 3-hydroxy-â-
lactams, see: (a) Barbaro, G.; Battaglia, A.; Guerrini, A. J. Org. Chem.
1999, 64, 4643. (b) Paquette, L. A.; Rothhaar, R. R.; Isaac, M.; Rogers, L.
M.; Rogers R. D. J. Org. Chem. 1998, 63, 5463. (c) Basak, A.; Bdour, H.
M. M.; Bhattacharya, G. Tetrahedron Lett. 1997, 38, 2535.
(12) (a) Alcaide, B.; Almendros, P.; Aragoncillo, C.; Salgado, N. R. J.
Org. Chem. 1999, 64, 9596. (b) Alcaide, B.; Almendros, P.; Aragoncillo,
C. Chem. Commun. 1999, 1913. (c) Alcaide, B.; Rodr´ıguez-Campos, I. M.;
Rodr´ıguez-Lo´pez, J.; Rodr´ıguez-Vicente, A. J. Org. Chem. 1999, 64, 5377.
(d) Alcaide, B.; Alonso, J. M.; Aly, M. F.; Sa´ez, E.; Mart´ınez-Alca´zar, M.
P.; Herna´ndez-Cano, F. Tetrahedron Lett. 1999, 40, 5391. (e) Alcaide, B.;
Almendros, P. Tetrahedron Lett. 1999, 40, 1015.
(14) For a reversal of the regiochemistry on the reaction of propargyl
bromide with simple aldehydes using the systemt copper(II)/tin(II) as the
mediator, see ref 3b.
(13) Alcaide, B.; Almendros, P.; Aragoncillo, C. Tetrahedron Lett. 1999,
40, 7537.
1412
Org. Lett., Vol. 2, No. 10, 2000
Alcaide, Benito
