Metal-promoted allylation, propargylation, or allenylation of azetidine-2,3-diones in aqueous and anhydrous media. Application to the asymmetric synthesis of densely functionalized 3-substituted 3-hydroxy-β-lactams

Article abstract of DOI:10.1021/jo015704l

Metal-mediated carbonyl allylation, allenylation, and propargylation of optically pure azetidine-2,3-diones were investigated in both anhydrous and aqueous environments. Different metals promoters showed varied regioselectivities on product formation duri

Full text of DOI:10.1021/jo015704l

5208
J . Org. Chem. 2001, 66, 5208-5216
Meta l-P r om oted Allyla tion , P r op a r gyla tion , or Allen yla tion of
Azetid in e-2,3-d ion es in Aqu eou s a n d An h yd r ou s Med ia .
Ap p lica tion to th e Asym m etr ic Syn th esis of Den sely
F u n ction a lized 3-Su bstitu ted 3-Hyd r oxy-â-la cta m s
Benito Alcaide,* Pedro Almendros, Cristina Aragoncillo, and Raquel Rodr´ıguez-Acebes
Departamento de Quı´mica Orga´nica I, Facultad de Quı´mica, Universidad Complutense,
28040-Madrid, Spain
alcaideb@eucmax.sim.ucm.es
Received April 24, 2001
Metal-mediated carbonyl allylation, allenylation, and propargylation of optically pure azetidine-
2,3-diones were investigated in both anhydrous and aqueous environments. Different metals
promoters showed varied regioselectivities on product formation during allenylation/propargylation
reactions of the keto-â-lactams. The stereochemistry of the new C3-substituted C3-hydroxy
quaternary center was controlled by placing a chiral auxiliary at C4. In this way, the coupling of
azetidine-2,3-diones with a variety of propenyl-, propynyl-, and allenylmetal reagents offers a
convenient asymmetric entry to potentially bioactive 3-substituted 3-hydroxy-â-lactams.
In tr od u ction
important compounds. As an example, (2R,3S)-3-amino-
2-hydroxy-5-methylhexanoic acid (norstatine) and (3R,4S)-
4-amino-3-hydroxy-5-methylheptanoic acid (statine) are
residues for peptide inhibitors of enzymes, such as renin6
and HIV-1 protease.7 In addition, phenylisoserine ana-
logues are used to synthesize new taxoids.8 However,
little attention has been paid to develop methods for the
preparation of trisubstituted â-lactams bearing hetero-
substituents at a C3 quaternary stereogenic center,9
despite its importance both as synthons and substrates
for studies of biological activity.
On the other hand, the development of new carbon-
carbon bond-forming reactions is of particular interest
in organic synthesis, especially in the context of creating
quaternary chiral centers involving a stereoselective
reaction.10 Among the most fundamental and important
reactions for constructing carbon-carbon bonds are the
allylation and the propargylation/allenylation of alde-
hydes and ketones (carbonyls) with organometallic re-
agents. For example, Sakurai-, Grignard-, and Barbier-
type reactions have been widely utilized for the allylation11
or propargylation/allenylation12 of carbonyls, in which
chemo-, regio-, and stereoselectivities of the desired
alcohols are highly dependent on the nature of the metals
employed. Although many efforts have been made in
The presence of the 2-azetidinone ring in several widely
used families of antibiotics has stimulated considerable
activity directed at the stereocontrolled synthesis of
â-lactams.1 In recent years, various natural monocyclic
â-lactams were shown to exhibit high anti-bacterial
activity, suggesting that a suitably substituted monocy-
clic 2-azetidinone ring might perhaps be the minimum
requirement for biological activity. Besides, the ever-
growing new applications of azetidine-2-ones in fields
ranging from enzyme inhibition,2 to the use of these
products as starting materials to develop new synthetic
methodologies, justify a renewed interest in these com-
pounds. In particular, the 3-substituted 3-hydroxy-2-
azetidinone moiety, representing an efficient carboxylate
mimic,3 is present in several pharmacologically active
monobactams such as sulfazecin and related products4
and in enzyme inhibitors such as tabtoxin and its
analogues.5 Moreover, these compounds with correct
absolute configurations serve as precursors to the corre-
sponding R-hydroxy-â-amino acids (isoserines), which are
key components of a large number of therapeutically
(1) For reviews on this subject, see: (a) 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. (b) Ojima, I. The Organic
Chemistry of â-lactams; Georg, G. I., Ed.; VCH: New York, 1993; p
197. (c) The Chemistry of â-Lactams; Page, M. I., Ed.; Chapman and
Hall: London, 1992.
(2) For reviews, see: (a) Mascaretti, O. A.; Boschetti, C. E.; Danelon,
G. O.; Mata, E. G.; Roveri, O. A. Current Med. Chem. 1995, 1, 441. (b)
Edwards, P. D.; Bernstein, P. R. Med. Res. Rev. 1994, 14, 127.
(3) (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.
(4) Imada, A.; Kitano, K.; Kintana, K.; Muroi, M.; Asai, M. Nature
1981, 289, 590.
(5) (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.
(6) Thaisrivongs, S.; Pals, D. T.; Kroll, L. T.; Turner, S. R.; Han,
F.-S. J . Med. Chem. 1987, 30, 976.
(7) Huff, J . R. J . Med. Chem. 1991, 34, 2305.
(8) (a) Ojima, I.; Wang, T.; Delaloge, F. Tetrahedron Lett. 1998, 39,
3663. (b) Ojima, I.; Kuduk, S. D.; Pera, P.; Veith, J . M.; Bernacki, R.
J . J . Med. Chem. 1997, 40, 267. (c) Denis, J .-N.; Fkyerat, A.; Gimbert,
Y.; Coutterez, C.; Mantellier, P.; J ost, S.; Greene, A. E. J . Chem. Soc.,
Perkin Trans. 1 1995, 1811.
(9) 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) Basak, A.; Bdour, H. M. M.; Bhattacharya,
G. Tetrahedron Lett. 1997, 38, 2535. (c) Paquette, L. A.; Behrens, C.
Heterocycles 1997, 46, 31. (d) Palomo, C.; Aizpurua, J . M.; Garc´ıa, J .
M.; Lo´pez, M. C.; Aurrekoetxea, N.; Oiarbide, M. Tetrahedron Lett.
1990, 31, 6425.
(10) For reviews, see: (a) Corey, E. J .; Guzma´n-Pe´rez, A. Angew.
Chem., Int. Ed. Engl. 1996, 35, 388. (b) Fuji, K. Chem. Rev. 1993, 93,
2037.
10.1021/jo015704l CCC: $20.00 © 2001 American Chemical Society
Published on Web 06/30/2001

Synthesis of Functionalized 3-Substituted 3-Hydroxy-â-lactams
J . Org. Chem., Vol. 66, No. 15, 2001 5209
Sch em e 1
these fields into various types of carbonylic compounds,
the allenylation of azetidine-2,3-diones has not been
reported yet. Furthermore, the information available on
the use of â-lactams as chiral building blocks on the
propargylation and allylation reactions is still very scarce;
only Cho has recently reported the propargylmetalation
of 6-oxopenicillanates in anhydrous and aqueous tetrahy-
drofuran.13 Bose14a and Paquette14b have independently
reported the allylindation of azetidine-2,3-diones. How-
ever, the asymmetric version was achieved with poor
diastereoselectivity on azetidine-2,3-diones bearing a
chiral auxiliary at nitrogen.14b
Recently, organometallic reactions in aqueous media
have elicited considerable interest because of their syn-
thetic advantages (many reactive functional groups, such
as hydroxy and carboxylic functions, do not require the
protection-deprotection protocol in such reactions, and
many water-soluble compounds do not need to be con-
verted into their derivatives and can be reacted directly)
as well as its potential as an environmentally benign
chemical process (the use of anhydrous inflammable
solvents can be avoided and the burden of solvent
disposal may be reduced).15 As part of our research on
the synthesis and synthetic applications of chiral, func-
tionalized 2-azetidinones,16 we decided to pursue a “green
chemistry” approach for the stereoselective incorporation
of new substituents in the â-lactam ring. In this context,
we wish to report now full details of the manner in which
enantiomerically pure azetidine-2,3-diones and a variety
of allyl, propargyl, or allenyl organometallics undergo
coupling.17
ology. Enantiopure 3-acetoxy-2-azetidinones 2a -e were
obtained from imines of (R)-2,3-O-isopropylideneglycer-
aldehyde through Staudinger reaction with acetoxyacetyl
chloride in the presence of Et3N as single cis enantio-
mers,18 which via transesterification with sodium meth-
oxide in methanol gave 3-hydroxy-2-azetidinones 3a -e.
Azetidine-2,3-diones 1a -e were available in high yield
and without detectable racemization by Swern oxidation
of the corresponding 3-hydroxy-â-lactam 3 (Scheme 1).19
Having obtained the ketones, the next stage was set
to carry out the key coupling reactions. We reasoned that
by placing a chiral auxiliary at C4 we might be able to
control the stereochemistry of the new C3-substituted C3-
hydroxy quaternary center. First, the carbonyl allylation
of azetidine-2,3-diones 1 was explored in anhydrous
conditions. Compounds 1 may be considered similar to
N-protected R-amino aldehydes, most of which are rela-
tively unstable both chemically and configurationally in
a number of addition reactions.20 However, the Lewis acid
promoted addition of allyltrimethylsilane and allyltribu-
tylstannane to enantiopure oxo compounds 1 gave homo-
allylic alcohols 4a -c as single diastereoisomers (Scheme
2).21
Resu lts a n d Discu ssion
The starting substrates, azetidine-2,3-diones 1, were
prepared in optically pure form using standard method-
(11) For recent reviews of allylmetal additions, see: (a) Roush, W.
R.; Chemler, C. R. In Modern Carbonyl Chemistry; Otera, J ., Ed.;
Wiley-VCH: Weinheim, 2000; Chapter 11. (b) Denmark, S. E.; Alm-
stead, N. G. In Modern Carbonyl Chemistry; Otera, J ., Ed.; Wiley-
VCH: Weinheim, 2000; Chapter 10. (c) Thomas, E. J . Chem. Commun.
1997, 411. (d) Fleming, I.; Barbero, A.; Walter, D. Chem. Rev. 1997,
97, 2063. (e) Marshall, J . A. Chem. Rev. 1996, 96, 31. (f) Stereoselective
Synthesis, Methods of Organic Chemistry (Houben-Weyl), Edition
E21; Helmchen, G., Hoffmann, R., Mulzer, J ., Schaumann, E., Eds.;
Thieme: Stuttgart, 1996; Vol. 3, pp 1357-1602. (g) Yamamoto, Y.;
Asao, N. Chem. Rev. 1993, 93, 2207.
(12) For reviews, see: (a) Marshall, J . A. Chem. Rev. 2000, 100,
3163. (b) Yamamoto, H. In Comprehensive Organic Synthesis; Trost,
B. M., Ed.; Pergamon Press: Oxford, 1991; Vol. 2, Chapter 1.3. (c)
Panek, J . S. In Comprehensive Organic Synthesis; Schreiber, S. L., Ed.;
Pergamon Press: Oxford, 1991; Vol. 1, p 595.
(13) Cho, Y. S.; Lee, J . E.; Pae, N. A.; Choi, K. I.; Koh, H. Y.
Tetrahedron Lett. 1999, 40, 1725.
(14) (a) J ayaraman, M.; Manhas, M. S.; Bose, A. K. Tetrahedron Lett.
1997, 38, 709. (b) Paquette, L. A.; Rothhaar, R. R.; Isaac, M.; Rogers,
L. M.; Rogers R. D. J . Org. Chem. 1998, 63, 5463.
(17) For the preliminary communication of a part of this work, see:
(a) Alcaide, B.; Almendros, P.; Aragoncillo, C. Org. Lett. 2000, 2, 1411.
(b) Alcaide, B.; Almendros, P.; Aragoncillo, C. Tetrahedron Lett. 1999,
40, 7537.
(18) For recent reviews on the ketene-imine approach to â-lactams,
see: (a) Palomo, C.; Aizpurua, J . M.; Ganboa, I.; Oiarbide, M. Eur. J .
Org. Chem. 1999, 3223. (b) Tidwell, T. T. Ketenes; Wiley: New York,
1995; pp 518-527. (c) Georg, G. I.; Ravikumar, V. T. In The Organic
Chemistry of â-Lactams; Georg, G. I., Ed.; VCH: Weinheim, New York,
1993; Chapter 3, p 295. (d) Van der Steen, F. H.; Van Koten, G.
Tetrahedron 1991, 47, 7503. (e) Ghosez, L.; Marchand-Brynaert, J . In
Comprehensive Organic Synthesis; Trost, B., Fleming, I., Eds.; Perga-
mon: Oxford, 1991; Vol. 5, p 85.
(19) For a related oxidation of enantiopure R-hydroxy-â-lactams,
see: (a) Palomo, C.; Aizpurua, J . M.; Ganboa, I.; Carreaux, F.; Cuevas,
C.; Maneiro, E.; Ontoria, J . M. J . Org. Chem. 1994, 59, 3123. For a
review on the synthesis and chemistry of azetidine-2,3-diones: (b)
Alcaide, B.; Almendros, P. Org. Prep. Proced. Int. 2001, 33, 315.
(20) For a recent example, see: Myers, A. G.; Zhong, B.; Movassaghi,
M.; Kung, D. W.; Lanman, B. A.; Kwon, S. Tetrahedron Lett. 2000, 41,
1359 and references therein.
(15) For recents reviews on organic reactions in aqueous media,
see: (a) Li, C. J .; Chan, T. H. Organic Reactions in Aqueous Media;
J ohn Wiley & Sons: New York, 1997. (b) Lubineau, A.; Auge´, J .;
Queneau, Y. In Organic Synthesis in Water; Grieco, P. A., Ed.; Blackie
Academic & Professional: London, 1998. (c) Paquette, L. A. In Green
Chemistry: Frontiers in Benign Chemical Synthesis and Processing;
Anastas, P. T., Williamson, T. C., Eds.; Oxford University Press: New
York, 1998. (d) Li, C. J .; Chan, T. H. Tetrahedron 1999, 55, 11149. (e)
Lubineau, A.; Auge´, J . Top. Curr. Chem. 1999, 206, 1. (f) Sinou, D.
Top. Curr. Chem. 1999, 206, 41. (g) Fringuelli, F.; Piernatti, O.; Pizzo,
F. Heterocycles 1999, 50, 611. (h) Ribe, S.; Wipf, P. Chem. Commun.
2001, 299.
(16) (a) Alcaide, B.; Almendros, P.; Aragoncillo, C. J . Org. Chem.,
2001, 66, 1612. (b) Alcaide, B.; Almendros, P.; Alonso, J . M.; Aly, M.
F. J . Org. Chem., 2001, 66, 1351. (c) Alcaide, B.; Sa´ez, E. Tetrahedron
Lett. 2000, 41, 1647. (d) Alcaide, B.; Almendros, P.; Salgado, N. R. J .
Org. Chem. 2000, 65, 3310. (e) Alcaide, B.; Aly, M. F.; Rodr´ıguez, C.;
Rodr´ıguez-Vicente, A. J . Org. Chem. 2000, 65, 3453. (f) Alcaide, B.;
Almendros, P.; Aragoncillo, C. Chem. Commun. 2000, 757.

5210 J . Org. Chem., Vol. 66, No. 15, 2001
Ta ble 1. Ster eoselective Allyla tion of Azetid in e-2,3-d ion es 1 in Aqu eou s Med ia a
Alcaide et al.
product
R1
PMP
PMP
PMP
PMP
PMP
PMP
PMP
PMP
PMP
PMP
PMP
PMP
PMP
R2
R3
promoter
T (oC)/t (h)
solvent
THF/H2O
THF/H2O
THF/NH4Cl (aq satd)
THF/H2O
THF/NH4Cl (aq satd)
THF/H2O
THF/H2O
THF/H2O
THF/H2O
THF/NH4Cl (aq satd)
THF/NH4Cl (aq satd)
THF/NH4Cl (aq satd)
THF/NH4Cl (aq satd)
THF/H2O
THF/NH4Cl (aq satd)
THF/NH4Cl (aq satd)
THF/NH4Cl (aq satd)
MeOH/NH4Cl (aq satd)
yieldb (%)
(+)-4a
(+)-4a
(+)-4a
(+)-4a
(+)-4a
(+)-4a
(+)-4a
(+)-4a
(+)-4a
(+)-4a
(+)-4d
(+)-4d
(+)-4e
(-)-4b
(-)-4f
(-)-4g
(-)-4h
(+)-5
H
H
H
H
H
H
H
H
H
H
H
H
CH3
H
CH3
H
H
H
H
H
H
H
H
H
H
H
H
H
Mg/BiCl3
In
In
Zn
Zn
In/InCl3
In/HfCl4
Zn/InCl3
Zn/HfCl4
Sn
In
Zn
Zn
In
In
In
In
Sn
20/18
20/18
0/3
20/18
0/3
20/2
20/1.5
20/2
20/6
0/1
0/1.5
0/1.5
0/1.5
20/18
0/1
72
73
73
72
72
73
73
75
75
71c
83
53
85
70
80
100
99
71
COOH
COOH
H
H
H
H
2-propenyl
2-propenyl
3-butenyl
2-propynyl
PMP
0/1
0/1.5
reflux/1
COOH
H
a
All reactions were carried out on 1 mmol scale. PMP ) 4-MeOC6H4. Only one isomer was detected in the 1H NMR spectra of the
crude reaction mixtures before purification. Yield of pure, isolated product with correct analytical and spectral data. c Some acetonide
b
cleavage was observed.
Sch em e 2
the softness of these reagents. A transmetalation of the
initially formed allylmetal with hafnium(indium) chloride
as Lewis acid may be involved.23 The tin-mediated
carbonyl allylation of azetidine-2,3-dione (+)-1a in the
system solvent methanol/NH4Cl (aq satd) proceeded with
concomitant acetonide cleavage, giving rise to the triol
(+)-5 as single diastereomer.
Once we had established the best reaction conditions
to carry out the allylation reaction, our aim was to
evaluate the feasibility of other related metal-mediated
Barbier-type reactions in enantiomerically pure azeti-
dine-2,3-diones, studying the diastereochemistry (syn vs
anti) and the regiochemistry of the connection (e.g.,
allenylation vs propargylation). However, it is not easy
to control selectivity between Barbier-type propargylation
and allenylation with propargylic halides. The reaction
of propargyl bromide with metals has been proposed to
generate an equilibrium between the allenyl and propar-
gyl organometallics. This metallotropic rearrangement
often results in poor regioselection in the final organic
product, because both organometallic species can react
with the carbonyl compounds. Hence, a pertinent syn-
thetic challenge is to tune the regioselectivity toward
either acetylenic or allenic products. In this context, the
synthesis of homopropargyl alcohols from propargylpal-
ladium reported by Tamaru, using the umpolung ap-
proach,24 and the preparation of homopropargyl and
allenyl alcohols from transient allenylindium reagents
or propargylic stannanes, respectively, described by
Marshall,25 are noteworthy.
Since we are pursuing addition reactions with different
organometallic reagents, we wish to explore further the
allylation of R-keto lactams 1 in aqueous media. In the
event, different metal mediators showed total diastereo-
selectivity and good yields (53-100%) on product forma-
tion during allylation reactions of azetidine-2,3-diones 1
with allyl bromide, 2-(bromomethyl)acrylic acid, and
prenyl bromide, in aqueous environmment (Table 1).
Since the main drawbacks of the Barbier-type carbon-
carbon bond formation are long reaction times and only
reactive halides were found to be effective, we thought
that the allylation reaction could proceed with rate
enhancement in the presence of some additives. Indeed,
the addition of ammonium chloride, indium trichloride,
or hafnium chloride to the aqueous medium shortened
reactions times, exhibiting the same facial preference (see
Table 1). It is to be presumed that the ionic strength
enhancement of the reaction solvent provided by the
ammonium chloride accelerated the process.22 Although
the role of the indium- and hafnium-derived additives is
not completely understood, it may be explained in terms
of Lewis acid, which activates the carbonyl group and
(22) It was reported for related 2-aminoaldehydes that changes in
the ionic strength of the solvent can provide modification in the
diastereomeric ratio or accelerated the process. See: Chappell, M. D.;
Halcomb, R. L. Org. Lett 2000, 2, 2003.
(21) Our results are totally consistent with previously published
works on this type of additions to R-amino aldehydes, with no reference
to partial racemization. For a recent example, see: Dias, L. C.; Meira,
P. R. R. Synlett 2000, 37.
(23) For an allyltin-indium trichloride transmetalation, see: Li, X.-
R.; Loh, T.-P. Tetrahedron: Asymmetry 1996, 7, 1996.
(24) Tamaru, Y.; Goto, S.; Tanaka, A.; Shimizu, M.; Kimura, M.
Angew. Chem., Int. Ed. Engl. 1996, 35, 878.

Synthesis of Functionalized 3-Substituted 3-Hydroxy-â-lactams
J . Org. Chem., Vol. 66, No. 15, 2001 5211
Sch em e 3
To achieve the goal of full control of regiochemistry,
we have investigated a number of protocols in anhydrous
and aqueous environments, with a variety of metal
mediators and different prop-2-ynyl systems. First, we
examined the Lewis acid-induced reaction of azetidine-
2,3-diones with propargylsilane or propargylmagnesium
bromide in anhydrous conditions. The reactions of ke-
tones 1a ,b with the above organosilane proceeded at -78
°C with total regiocontrol, inducing exclusively the allenic
products 6a ,b as single diastereoisomers in moderate
yields (44-53%). The nature of the acid catalyst had no
pronounced influence, showing similar results for both
tin tetrachloride and boron trifluoride diethyl etherate
(Scheme 3). By contrast, when azetidine-2,3-dione (+)-
1a was treated with propargyl/allenylmagnesium bro-
mide, the corresponding product was isolated as a
mixture (15:85) of allenic and acetylenic products 6a /7a
(Scheme 3).
The aim of a more efficient approach prompted us to
seek an aqueous metal-induced propargylation/allenyla-
tion reaction. For this purpose, azetidine-2,3-diones 1
were treated with prop-2-ynyl bromides, bearing substit-
uents of varying steric demand at C3, and a broad variety
of metals and reaction conditions in aqueous media. Not
unexpectedly, the diastereoselectivity was complete in all
cases. However, while the chemical yield of the addition
was generally good, the regioselectivity of the process was
a function of the nature of both the metal reagent and
the propargyl bromide and in many cases of the system
solvent as well.
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 homopro-
pargyl alcohol (+)-7a as a single regio- and diastereo-
isomer in a reasonable 70% yield. However, the yield fell
dramatically by performing the zinc-mediated coupling
of the azetidine-2,3-dione (+)-1a and propargyl bromide
in anhydrous THF in the presence of solid NH4Cl. No
reaction was observed in anhydrous THF when the NH4-
Cl was supressed, and the change of the system solvent
from tetrahydrofuran/NH4Cl (aq satd) to methanol/NH4-
Cl (aq satd) resulted in the absence of regioselection. The
tin-mediated reaction between ketone (+)-1a and pro-
pargyl 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 allenyl alcohol was formed
as major product, together with 25% of the homopropar-
gylic alcohol. Indium trichloride and hafnium chloride
were tested as additives in the tin-mediated reaction of
propargyl bromide and azetidine-2,3-dione (+)-1a in
tetrahydrofuran/NH4Cl (aq satd). Interestingly, the analy-
ses of the crude reaction mixture revealed only the
presence of the allenyl alcohol. Manganese, cadmium and
bismuth failed to produce any desired propargylation/
allenylation compound when they were used as metal
promoters. Similar results to those observed for (+)-1a
were obtained in the metal-mediated Barbier-type reac-
tions of different N-substituted azetidine-2,3-diones 1b-d
with propargyl bromide (Table 2).
Since indium in aqueous solution has shown consider-
able promise in the addition of unsaturated halides to
the carbonyl groups, the regio- and diastereoselectivity
of the carbon-carbon bond formation were initially
investigated through the indium-mediated reaction be-
tween the azetidine-2,3-dione (+)-1a and propargyl bro-
mide in aqueous tetrahydrofuran at room temperature.
In the event, the 3-substituted 3-hydroxy-â-lactam moiety
was obtained; however, the observed regioselectivity was
very poor (58:42) in favor of the allenic product. Surpris-
ingly, the regiochemical 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 (+)-6a and (+)-7a being obtained as a
mixture of regioisomers in a ratio of 6a :7a ) 29:71. This
preliminary result encouraged us to find a more conve-
nient reagent for this transformation. To our delight,
Our next aim was to find a carbonyl propargylation/
allenylation method that proceeds in a highly regiose-
lective fashion by the use of 3-substituted prop-2-ynyl
bromides through choice of reaction conditions. Metal-
promoted reactions of azetidine-2,3-diones 1 with pro-
pargyl bromides bearing an aliphatic or an aromatic
substituent at the terminal position, afforded the R-al-
lenic alcohols 8 as essentially regio- and diastereoiso-
merically pure products. This observation is in sharp
contrast to the metal-mediated reaction of propargyl
bromide itself. The results are summarized in Table 3.
The different behavior of the organometallic reagents
derived from various metals and differently substituted
propargyl bromides in a variety of solvents may be due
to structural differences in the organometallic species
involved in the reaction. It may be reasonable to postulate
a metallotropic rearrangement between the propargyl-
metal and allenylmetal species. Both intermediates from
this equilibrium are able to react with the azetidine-2,3-
diones 1, leading to the R-allenic or homopropargylic
alcohols. The formation of alcohols 7 and 8 is consistent
with participation of the six-membered, cyclic transition
(25) (a) Marshall, J . A.; Maxson, K. J . Org. Chem. 2000, 65, 630.
(b) Marshall, J . A.; Yanik, M. M. J . Org. Chem. 1999, 64, 3798. (c)
Marshall, J . A.; Grant, C. M. J . Org. Chem. 1999, 64, 696. (d) Marshall,
J . A.; Yu, R. H.; Perkins, J . E. J . Org. Chem. 1995, 60, 5550.

5212 J . Org. Chem., Vol. 66, No. 15, 2001
Alcaide et al.
Ta ble 2. Regio- a n d Ster eoselective P r op a r gyla tion /Allen yla tion of Azetid in e-2,3-d ion es 1 in Aqu eou s Med ia a
compd
R
metal promoter
system solvent
THF/H2O
THF/NH4Cl (aq satd)
THF/NH4Cl (aq satd)
THF (dry)/NH4Cl (solid)
THF (dry)
MeOH/NH4Cl (aq satd)
THF/NH4Cl (aq satd)
THF/NH4Cl (aq satd)
THF/NH4Cl (aq satd)
THF/NH4Cl (aq satd)
THF/NH4Cl (aq satd)
THF/NH4Cl (aq satd)
6:7 ratiob
yieldc (%)
6a /7a
6a /7a
6a /7a
6a /7a
6a /7a
6a /7a
6a /7a
6a /7a
6a /7a
6b/7b
6c/7c
6d /7d
PMP
PMP
PMP
PMP
PMP
PMP
PMP
PMP
In
In
Zn
Zn
Zn
Zn
Sn
Sn/InCl3
Sn/HfCl4
Zn
Zn
Zn
58:42
29:71
0:100
0:100
50
67
70
34
50:50
75:25
100:0
100:0
0:100
0:100
0:100
65
65
33d
79d
53
PMP
2-propenyl
2-propynyl
4-pentynyl
56
58
a
b
All reactions were carried out on 1 mmol scale. PMP ) 4-MeOC6H4. The ratio was determined by integration of well-resolved signals
in the 1H NMR spectra of the crude reaction mixtures before purification. c Yield of pure, isolated product with correct analytical and
spectral data. Some acetonide cleavage in the homoallenyl alcohol was detected.
d
Ta ble 3. Regio- a n d Ster eoselective Allen yla tion of Azetid in e-2,3-d ion es 1 in Aqu eou s Med ia a
compd
R1
PMP
PMP
PMP
2-propenyl
PMP
PMP
PMP
PMP
PMP
PMP
2-propenyl
2-propynyl
R2
metal promoter
system solvent
8:9 ratiob
yieldc (%)
8a /9a
8a /9a
8a /9a
8b/9b
8c/9c
8c/9c
8c/9c
8c/9c
8c/9c
8c/9c
8d /9d
8e/9e
Me
Me
Me
Me
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Zn
In
Sn
In
Zn
Zn
In
THF/NH4Cl (aq satd)
THF/NH4Cl (aq satd)
THF/NH4Cl (aq satd)
THF/NH4Cl (aq satd)
THF/NH4Cl (aq satd)
THF/H2O
THF/NH4Cl (aq satd)
THF/H2O
THF/NH4Cl (aq satd)
THF/H2O
100:0
100:0
100:0
100:0
80:20
100:0
100:0
100:0
100:0
59
74
16
63
71
16
76
75
75
d
In
Sn
Sn
In
THF/NH4Cl (aq satd)
THF/NH4Cl (aq satd)
100:0
100:0
62
48
In
a
b
All reactions were carried out on 1 mmol scale. PMP ) 4-MeOC6H4. The ratio was determined by integration of well-resolved signals
in the 1H NMR spectra of the crude reaction mixtures before purification. c Yield of pure, isolated product with correct analytical and
spectral data. Acetonide cleavage and further internal acetal formation was observed.
d
structures 10 and 11. A plausible mechanism for the
propargylation/allenylation process is illustrated in Scheme
4.
propargyl bromide. Then, the allenylmetal undergoes
nucleophilic addition to afford homopropargylic alcohols
7 selectively. The different regioselectivities observed in
various system solvents, should be attributed perhaps to
the extent of coordination of the solvent molecules to the
reactive organometallic species, stabilizing one of the
intermediates involved in the metallotropic equilibrium
rather than the other.
It seems reasonable to propose that the different
regiochemical preference observed on the metal-promoted
reactions of propargyl bromide and substituted propargyl
bromides with azetidine-2,3-diones must be controlled by
steric effects.26 Probably, the isomerization of propargyl-
metal to allenylmetal is restricted by the steric effect of
a substituent (R2 ) CH3 or C6H5) in the bromopropyne.
Thus, allenyl alcohols 8 are produced almost exclusively.
Isomerization of the initially formed propargylmetal
species to the corresponding allenyl organometallic can
be induced by the absence of substituent (R2 ) H) at the
Con figu r a tion a l Assign m en t. The stereochemistry
at the C3-heterosubstituted quaternary center for com-
pounds 5-8 was assigned by qualitative homonuclear
NOE difference spectra. Thus, an anti-relative disposition
between the hydroxy group and H4 was established for
compound (+)-4a by the absence of NOE enhancement
in the hydroxylic hydrogen signal when H4 was irradi-
ated. Furthermore, NOE irradiation of the methylenic
hydrogens on compound (+)-4a resulted in 6% enhance-
ment on the signal corresponding to H4, which is in
agreement with the proposed stereochemistry. Com-
(26) For selective formation of propargylmetals and allenylmetals
mediated by steric effects, see: (a) Masuyama, Y.; Watabe, A.; Ito, A.;
Kurusu, Y. Chem. Commun. 2000, 2009. (b) Kobayashi, S.; Nishio K.
J . Am. Chem. Soc. 1995, 117, 6392. (c) Zhang, L.-J .; Huang, Y.-Z.;
Huang, Z.-H. Tetrahedron Lett. 1991, 32, 6579.

Synthesis of Functionalized 3-Substituted 3-Hydroxy-â-lactams
J . Org. Chem., Vol. 66, No. 15, 2001 5213
Sch em e 4
F igu r e 1. Selected NOE effects and stereochemistry of some
3-substituted 3-hydroxy-â-lactams 5-8.
azetidine-2,3-diones undergo coupling with a variety of
propenyl-, propynyl-, and allenylmetal reagents in both
anhydrous and aqueous environments. The method of
choice to mediate the allylation, propargylation or allen-
ylation should be in the most of the cases one involving
aqueous media because of its enviromentally benign
properties and atom economy, allied with a high degree
of chemo-, regio-, and diastereoselectivity. In view of the
simplicity of the present processes for the synthesis of
3-substituted 3-hydroxy-â-lactams, that should be useful
in the elaboration of potentially bioactive compounds,
these reactions are likely to find considerable applica-
tions.
Exp er im en ta l Section
Gen er a l Meth od s. General experimental data and proce-
dures have been previously reported.16a NMR spectra were
recorded in CDCl3 solutions, except otherwise stated. Chemical
shifts are given in ppm relative to TMS (1H, 0.0 ppm) or CDCl3
(13C, 76.9 ppm). Specific rotation [R]D is given in deg per dm
at 20 °C, and the concentration (c) is expressed in g per 100
mL. All commercially available compounds were used without
further purification. The following chemicals were prepared
according to literature procedures: 3-butenamine,27 2,3-O-
(isopropylidene)-D-glyceraldehyde.28 4-Pentynamine was pre-
pared following the procedure of Taylor for 3-butynamine.29
2-Azetidinones (+)-2a and (+)-3a were prepared according to
our previously reported procedures.16d
Tin (IV) Ch lor id e P r om oted Rea ction s betw een Allyl-
t r im et h ylsila n e a n d Azet id in e-2,3-d ion es 1. Gen er a l
P r oced u r e for th e Syn th esis of Hom oa llylic Alcoh ols 4.
A solution of the corresponding R-keto lactam (1.0 mmol) in
dichloromethane (3.5 mL) was added dropwise to a stirred
solution of tin(IV) chloride (1.0 mmol) in dichloromethane (5
mL) at -78 °C. After 5 min, allyltrimethylsilane (1.5 mmol)
was added, and the mixture was stirred for 1 h at -78 °C.
Saturated aqueous sodium hydrogen carbonate (10 mL) was
added, and the mixture was allowed to warm to room tem-
perature before being partitioned between dichloromethane
and water. The organic extract was washed with brine, dried
(MgSO4), and concentrated under reduced pressure. Chroma-
tography of the residue using ethyl acetate/hexanes mixtures
gave analytically pure compounds. Spectroscopic and analyti-
cal data for some representative pure forms of 1 follow.30
pounds (+)-6a and (+)-8a are R-allenic alcohols. A NOE
enhancement of 3% on H4 upon irradiation of the allenic
proton for compound (+)-6a showed a syn stereochem-
istry for these moieties. Absence of NOE enhancement
was observed on the hydroxylic hydrogen when H4 was
irradiated. Furthermore, NOE irradiation of the methyl
group on compound (+)-8a resulted in 2% enhancement
of the signal corresponding to H4, which is consistent
with the proposed stereochemistry. The syn H4-propargyl
moiety stereochemistry for the homopropargylic alcohol
(+)-7a was obvious on the basis of 8% NOE enhancement
in H4 upon irradiation of the methylenic hydrogens.
Similar figures were observed when NOE experiments
were carried out in related â-lactams 5-8, being the
stereochemistry immediately deduced by comparison
with the above results (Figure).
The stereoselectivity in the addition reaction of these
stabilized organometallic reagents with azetidine-2,3-
diones 1 is believed to be controlled by the bulky chiral
auxiliary at C-4, in which one face of the carbonyl group
is blocked preferentially, thus the propenyl-, propynyl-,
and allenylmetal species being delivered to the less
hindered face.
(27) Sato, T.; Nakamura, N.; Ikeda, K.; Okada, M.; Ishibashi, H.;
Ikeda, M. J . Chem. Soc., Perkin Trans. 1 1992, 2399.
(28) Schmid, C.; Bryant, J . D.; Dowlatzedah, M.; Phillips, J .; Prather,
D. E.; Schantz, R. D.; Sear, N. L.; Vianco, C. S. J . Org. Chem. 1991,
56, 4056.
(29) Taylor, E. C.; Macor, J . E.; Pont, J . L. Tetrahedron, 1987, 21,
5145.
Con clu sion s
The present study provides the first insight into the
regio- and stereoselective manner in which enantiopure

5214 J . Org. Chem., Vol. 66, No. 15, 2001
Alcaide et al.
(3R,4S)-4-[(S)-2,2-Dim et h yl-1,3-d ioxola n yl-4-yl]-3-h y-
d r oxy-1-(p -m e t h oxyp h e n yl)-3-(2-p r op e n yl)-2-a ze t id i-
n on e, (+)-4a . From 100 mg (0.342 mmol) of azetidine-2,3-
dione (+)-1a was obtained 86 mg (75%) of compound (+)-4a
as a colorless oil. [R]D ) +53.4 (c 1.0, CHCl3). 1H NMR: δ 1.35
and 1.48 (s, each 3H), 2.58 (dd, 1H, J ) 14.0, 7.6 Hz), 2.69
(dd, 1H, J ) 14.0, 7.0 Hz), 3.79 (s, 3H), 3.80 (dd, 1H, J ) 9.0,
6.8 Hz), 4.02 (d, 1H, J ) 7.6 Hz), 4.29 (dd, 1H, J ) 9.0, 6.7
Hz), 4.46 (q, 1H, J ) 7.0 Hz), 4.59 (brs, 1H), 5.25 (m, 2H),
5.89 (m, 1H), 6.85 and 7.58 (d, each 2H, J ) 9.0 Hz). 13C
NMR: δ 168.4, 156.6, 131.0, 130.6, 120.2, 119.9, 113.9, 109.5,
83.1, 76.6, 66.7, 65.9, 55.3, 40.1, 26.4, 24.9. IR (CHCl3, cm-1):
ν 3332, 1748. MS (CI), m/z: 334 (M+ + 1, 100), 333 (M+, 25).
Anal. Calcd for C18H23NO5: C, 61.85; H, 5.88; N, 4.81. Found:
C, 61.96; H, 5.83; N, 4.85.
(1 mL) was added dropwise, and the mixture was stirred for
18 h at room temperature. Hydrochloric acid (1 M, 10 mL) was
added at 0 °C, and the mixture was allowed to warm to room
temperature, before being extracted with ethyl acetate (3 × 5
mL). The organic extract was washed with brine, dried
(MgSO4), and concentrated under reduced pressure. Chroma-
tography of the residue using ethyl acetate/hexanes (1:1) as
an eluent gave 240 mg (72%) of compound (+)-4a . Anal. Calcd
for C18H23NO5: C, 61.85; H, 5.88; N, 4.81. Found: C, 61.93;
H, 5.91; N, 4.84.
In d iu m P r om oted Rea ction betw een Allyl Br om id e
a n d Azetid in e-2,3-d ion e (+)-1a . Allyl bromide (242 mg, 2.0
mmol) was added to a well-stirred suspension of the R-keto
lactam (+)-1a (291 mg, 1.0 mmol) and indium powder (229
mg, 1.99 mmol) in THF/H2O (1:1, 5 mL) at room temperature.
After 18 h, saturated aqueous sodium hydrogen carbonate (10
mL) was added at 0 °C, and the mixture was allowed to warm
to room temperature before being extracted with ethyl acetate
(3 × 5 mL). The organic extract was washed with brine, dried
(MgSO4), and concentrated under reduced pressure. Chroma-
tography of the residue using ethyl acetate/hexanes (1:1) as
an eluent gave 243 mg (73%) of compound (+)-4a . Anal. Calcd
for C18H23NO5: C, 61.85; H, 5.88; N, 4.81. Found: C, 61.92;
H, 5.84; N, 4.84.
In d iu m -P r om oted Rea ction betw een Allyl Br om id e
a n d Azetid in e-2,3-d ion es 1 in a n Aqu eou s Med iu m Con -
ta in in g NH4Cl. Gen er a l P r oced u r e for th e Syn th esis of
Hom oa llylic Alcoh ols 4. Allyl bromide (363 mg, 3.0 mmol)
was added to a well-stirred suspension of the corresponding
R-keto lactam (1.0 mmol) and indium powder (688 mg, 6.0
mmol) in THF/NH4Cl (aq satd) (1:5, 5 mL) at 0 °C. After
disappearance of the starting material (TLC), the mixture was
extracted with ethyl acetate (3 × 5 mL). The organic extract
was washed with brine, dried (MgSO4), and concentrated
under reduced pressure. Chromatography of the residue using
ethyl acetate/hexanes mixtures gave analytically pure com-
pounds. Spectroscopic and analytical data for some represen-
tative pure forms of 4 follow.
From 100 mg (0.342 mmol) of azetidine-2,3-dione (+)-1a ,
83 mg (73%) of compound (+)-4a . Anal. Calcd for C18H23NO5:
C, 61.85; H, 5.88; N, 4.81. Found: C, 61.77; H, 5.91; N, 4.84.
(3R,4S)-1-(3-Bu ten yl)-4-[(S)-2,2-dim eth yl-1,3-dioxolan yl-
4-yl]-3-h ydr oxy-3-(2-pr open yl)-2-azetidin on e, (-)-4g. From
70 mg (0.293 mmol) of azetidine-2,3-dione (-)-1c, 82 mg (100%)
of compound (-)-4g was obtained as a colorless oil. [R]D ) -8.1
(c 0.7, CHCl3). 1H NMR: δ 1.34 and 1.43 (s, each 3H), 2.34
(m, 2H), 2.53 (td, 2H, J ) 14.9, 7.6 Hz), 3.23 (dt, 1H, J ) 13.7,
6.3 Hz), 3.45 (d, 1H, J ) 8.3 Hz), 3.52 (dt, 1H, J ) 13.7, 6.3
Hz), 4.17 (dd, 1H, J ) 8.5, 6.6 Hz), 4.31 (m, 1H), 5.13 (m, 4H),
5.80 (m, 2H). 13C NMR: δ 171.2, 135.1, 131.7, 119.6, 117.0,
109.4, 83.4, 76.7, 66.7, 65.0, 40.1, 31.7, 26.7, 25.0. IR (CHCl3,
cm-1): ν 3334, 1743. MS (CI), m/z: 282 (M+ + 1, 100), 281
(M+, 14). Anal. Calcd for C15H23NO4: C, 64.03; H, 8.24; N, 4.98.
Found: C, 64.10; H, 8.21; N, 4.95.
(3R,4S)-4-[(S)-2,2-Dim et h yl-1,3-d ioxola n yl-4-yl]-3-h y-
d r oxy-3-(2-p r op en yl)-1-(2-p r op yn yl)-2-a zetid in on e, (-)-
4c. From 110 mg (0.492 mmol) of azetidine-2,3-dione (-)-1d
was obtained 84 mg (64%) of compound (-)-4c as a colorless
1
oil. [R]D ) -33.6 (c 0.7, CHCl3). H NMR: δ 1.35 and 1.46 (s,
each 3H), 2.26 (t, 1H, J ) 2.4 Hz), 2.49 (dd, 1H, J ) 14.1, 7.6
Hz), 2.51 (dd, 1H, J ) 14.0, 7.0 Hz), 3.68 (d, 1H, J ) 5.4 Hz),
3.84 (dd, 1H, J ) 17.6, 2.4 Hz), 3.89 (dd, 1H, J ) 9.0, 4.6 Hz),
3.96 (s, 1H), 4.17 (dd, 1H, J ) 9.0, 6.8 Hz), 4.37 (m, 1H), 4.44
(dd, 1H, J ) 17.6, 2.7 Hz), 5.24 (m, 2H), 5.89 (m, 1H). 13C
NMR: δ 170.3, 131.3, 120.0, 110.1, 84.5, 76.6, 75.4, 72.6, 66.5,
63.8, 39.2, 30.4, 26.5, 24.9. IR (CHCl3, cm-1): ν 3329, 1744.
MS (CI), m/z: 266 (M+ + 1, 100), 265 (M+, 13). Anal. Calcd for
C
14H19NO4: C, 63.38; H, 7.22; N, 5.28. Found: C, 63.46; H,
7.26; N, 5.25.
Tin (IV) Ch lor id e P r om oted Rea ction betw een Allyl-
tr ibu tyltin a n d Azetid in e-2,3-d ion e (+)-1a . A cooled solu-
tion of tin(IV) chloride (313 mg, 1.2 mmol) in dichloromethane
(1.2 mL) was added dropwise to a stirred solution of allyl-
tributyltin (397 mg, 1.2 mmol) in dichloromethane (4.5 mL)
at -78 °C. After 5 min, a solution of the R-keto-â-lactam (+)-
1a (291 mg, 1.0 mmol) in dichloromethane (1 mL) was added
dropwise, and the mixture was stirred for 1 h at -78 °C.
Saturated aqueous sodium hydrogen carbonate (10 mL) was
added, and the mixture was allowed to warm to room tem-
perature before being partitioned between dichloromethane
and water. The organic extract was washed with brine, dried
(MgSO4), and concentrated under reduced pressure. Chroma-
tography of the residue using ethyl acetate/hexanes (1:1
containing 1% of triethylamine) as an eluent gave 233 mg
(70%) of compound (+)-4a . Anal. Calcd for C18H23NO5: C,
61.85; H, 5.88; N, 4.81. Found: C, 61.94; H, 5.92; N, 4.84.
Bor on Tr iflu or id e Dieth yl Eth er a te P r om oted Rea c-
tion betw een Allyltr ibu tyltin a n d Azetid in e-2,3-d ion e
(+)-1a . A solution of the R-keto-â-lactam (+)-1a (291 mg, 1.0
mmol) in dichloromethane (1 mL) was added dropwise to a
stirred solution of boron trifluoride diethyl etherate (213 mg,
1.5 mmol) in dichloromethane (4 mL) at -78 °C. After 5 min,
allyltributyltin (397 mg, 1.2 mmol) was added, and the mixture
was stirred for 1 h at -78 °C. Saturated aqueous sodium
hydrogen carbonate (10 mL) was added, and the mixture was
allowed to warm to room temperature before being partitioned
between dichloromethane and water. The organic extract was
washed with brine, dried (MgSO4), and concentrated under
reduced pressure. Chromatography of the residue using ethyl
acetate/hexanes (1:1 containing 1% of triethylamine) as an
eluent gave 183 mg (55%) of compound (+)-4a . Anal. Calcd
for C18H23NO5: C, 61.85; H, 5.88; N, 4.81. Found: C, 61.78;
H, 5.84; N, 4.79.
Zin c-P r om oted Rea ction betw een Allyl Br om id e a n d
Azetid in e-2,3-d ion e (+)-1a . Allyl bromide (242 mg, 2.0 mmol)
was added to a well-stirred suspension of the R-keto lactam
(+)-1a (291 mg, 1.0 mmol) and zinc powder (229 mg, 1.99
mmol) in THF/H2O (1:1, 5 mL) at room temperature. After 18
h, saturated aqueous sodium hydrogen carbonate (10 mL) was
added at 0 °C, and the mixture was allowed to warm to room
temperature, before being extracted with ethyl acetate (3 × 5
mL). The organic extract was washed with brine, dried
(MgSO4), and concentrated under reduced pressure. Chroma-
tography of the residue using ethyl acetate/hexanes (1:1) as
an eluent gave 240 mg (72%) of compound (+)-4a . Anal. Calcd
for C18H23NO5: C, 61.85; H, 5.88; N, 4.81. Found: C, 61.77;
H, 5.91; N, 4.83.
Zin c-P r om oted Rea ction betw een Allyl Br om id e a n d
Azetid in e-2,3-d ion e (+)-1a in a n Aqu eou s Med iu m Con -
ta in in g NH4Cl. Allyl bromide (363 mg, 3.0 mmol) was added
to a well-stirred suspension of the R-keto lactam (+)-1a (291
mg, 1.0 mmol) and zinc powder (392 mg, 6.0 mmol) in THF/
NH4Cl (aq satd) (1:5, 5 mL) at 0 °C. After 3 h at 0 °C, the
mixture was allowed to warm to room temperature before
Ma gn esiu m /Bism u th (III) Ch lor id e P r om oted Rea ction
betw een Allyl Br om id e a n d Azetid in e-2,3-d ion e (+)-1a .
Allyl bromide (187 mg, 1.54 mmol) was added to a well-stirred
suspension of bismuth(III) chloride (501 mg, 1.59 mmol) and
metallic magnesium (57 mg, 2.36 mmol) in THF/water (4:1, 4
mL) at room temperature. After 20 min, a solution of the
R-keto lactam (+)-1a (291 mg, 1.0 mmol) in tetrahydrofuran
(30) Experimental procedures as well as full spectroscopic and
analytical data for compounds not included in this Experimental
Section are described in the Supporting Information.

Synthesis of Functionalized 3-Substituted 3-Hydroxy-â-lactams
J . Org. Chem., Vol. 66, No. 15, 2001 5215
being extracted with ethyl acetate (3 × 5 mL). The organic
extract was washed with brine, dried (MgSO4), and concen-
trated under reduced pressure. Chromatography of the residue
using ethyl acetate/hexanes (1:1) as an eluent gave 240 mg
(72%) of compound (+)-4a . Anal. Calcd for C18H23NO5: C,
61.85; H, 5.88; N, 4.81. Found: C, 61.93; H, 5.84; N, 4.78.
In d iu m /In d iu m Tr ich lor id e P r om oted Rea ction be-
tw een Allyl Br om id e a n d Azetid in e-2,3-d ion e (+)-1a . Allyl
bromide (242 mg, 2.0 mmol) was added to a well-stirred
suspension of the R-keto lactam (+)-1a (291 mg, 1.0 mmol),
indium powder (229 mg, 1.99 mmol), and indium trichloride
(442 mg, 2.0 mmol) in THF/H2O (1:1, 5 mL) at room temper-
ature. After 2 h, saturated aqueous sodium hydrogen carbonate
(10 mL) was added at 0 °C, and the mixture was allowed to
warm to room temperature before being extracted with ethyl
acetate (3 × 5 mL). The organic extract was washed with brine,
under reduced pressure. Chromatography of the residue using
ethyl acetate/hexanes mixtures gave analytically pure com-
pounds. Spectroscopic and analytical data for some represen-
tative pure forms of 7 follow.
(+)-(3R,4S)-4-[(S)-2,2-Dim eth yl-1,3-d ioxola n -4-yl]-3-h y-
d r oxy-1-(p -m e t h oxyp h e n yl)-3-(2-p r op yn yl)-2-a ze t id i-
n on e, (+)-7a . From 43 mg (0.148 mmol) of azetidine-2,3-
dione (+)-1a was obtained 34 mg (70%) of compound (+)-7a
as a colorless oil. [R]D ) +57.4 (c 1.0, CHCl3). 1H NMR: δ 1.37
and 1.48 (s, each 3H), 2.09 (t, 1H, J ) 2.4 Hz), 2.80 (t, 2H,
J ) 2.4 Hz), 3.80 (s, 3H), 3.94 (dd, 1H, J ) 9.3, 6.8 Hz), 4.26
(d, 1H, J ) 6.8 Hz), 4.28 (dd, 1H, J ) 8.8, 6.8 Hz), 4.47 (m,
2H), 6.87 and 7.56 (d, 2H, J ) 9.0 Hz). 13C NMR: δ 166.9,
156.9, 130.3, 120.2, 114.1, 109.9, 82.7, 76.3, 72.1, 72.0, 66.7,
65.7, 55.4, 26.4, 25.7, 25.2. IR (CHCl3, cm-1): ν 3346, 1744.
MS (CI), m/z: 332 (M+ + 1, 100), 331 (M+, 32). Anal. Calcd for
dried (MgSO4), and concentrated under reduced pressure.
Chromatography of the residue using ethyl acetate/hexanes
(1:1) as an eluent gave 243 mg (73%) of compound (+)-4a . Anal.
Calcd for C18H23NO5: C, 61.85; H, 5.88; N, 4.81. Found: C,
61.93; H, 5.91; N, 4.78.
C
18H21NO5: C, 65.24; H, 6.39; N, 4.23. Found: C, 65.32; H,
6.31; N, 4.19.
(-)-(3R,4S)-4-[(S)-2,2-Dim eth yl-1,3-d ioxola n -4-yl]-3-h y-
d r oxy-1-(2-p r op en yl)-3-(2-p r op yn yl)-2-a zetid in on e, (-)-
7b. From 64 mg (0.284 mmol) of azetidine-2,3-dione (-)-1b
was obtained 40 mg (53%) of compound (-)-7b as a colorless
In d iu m /Ha fn iu m (IV) Ch lor id e P r om oted Rea ction be-
tw een Allyl Br om id e a n d Azetid in e-2,3-d ion e (+)-1a . Allyl
bromide (242 mg, 2.0 mmol) was added to a well-stirred
suspension of the R-keto lactam (+)-1a (291 mg, 1.0 mmol),
indium powder (229 mg, 1.99 mmol), and hafnium(IV) chloride
(442 mg, 2.0 mmol) in THF/H2O (1:1, 5 mL) at room temper-
ature. After 1.5 h, saturated aqueous sodium hydrogen car-
bonate (10 mL) was added at 0 °C, and the mixture was
allowed to warm to room temperature before being extracted
with ethyl acetate (3 × 5 mL). The organic extract was washed
with brine, dried (MgSO4), and concentrated under reduced
pressure. Chromatography of the residue using ethyl acetate/
hexanes (1:1) as an eluent gave 243 mg (73%) of compound
(+)-4a . Anal. Calcd for C18H23NO5: C, 61.85; H, 5.88; N, 4.81.
Found: C, 61.93; H, 5.91; N, 4.78.
Tin (IV) Ch lor id e P r om oted Rea ction s betw een P r o-
p a r gyltr im eth ylsila n e a n d Azetid in e-2,3-d ion es 1. Gen -
er a l P r oced u r e for th e Syn th esis of R-Allen ic Alcoh ols
6. A solution of the corresponding R-keto lactam (1.0 mmol)
in dichloromethane (3.5 mL) was added dropwise to a stirred
solution of tin(IV) chloride (1.5 mmol) in dichloromethane (5
mL) at -78 °C. After 5 min, propargyltrimethylsilane (225 mg,
2 mmol) was added, and the mixture was stirred for 3 h at
-78 °C. Saturated aqueous sodium hydrogen carbonate (10
mL) was added, and the mixture was allowed to warm to room
temperature before being partitioned between dichloromethane
and water. The organic extract was washed with brine, dried
(MgSO4), and concentrated under reduced pressure. Chroma-
tography of the residue using ethyl acetate/hexanes mixtures
gave analytically pure compounds. Spectroscopic and analyti-
cal data for some representative pure forms of 6 follow.
(3R,4S)-4-[(S)-2,2-Dim et h yl-1,3-d ioxola n yl-4-yl]-3-h y-
d r oxy-1-(p-m eth oxyp h en yl)-3-(1,2-p r op a d ien yl)-2-a zeti-
d in on e, (+)-6a . From 47 mg (0.161 mmol) of azetidine-2,3-
dione (+)-1a was obtained 23 mg (44%) of compound (+)-6a
as a colorless oil: [R]D ) +47.9 (c 0.6, CHCl3). 1H NMR: δ
1.36 and 1.51 (s, each 3H), 3.80 (s, 3H), 3.82 (dd, 1H, J ) 9.1,
6.4 Hz), 4.21 (d, 1H, J ) 7.4 Hz), 4.32 (dd, 1H, J ) 9.1, 6.7
Hz), 4.51 (q, 1H, J ) 6.7 Hz), 5.11 (d, 2H, J ) 6.7 Hz), 5.53 (t,
1H, J ) 6.7 Hz), 6.87 and 7.63 (d, each 2H, J ) 9.0 Hz). 13C
NMR: δ 207.2, 166.7, 156.7, 130.8, 120.0, 114.0, 109.8, 90.9,
81.5, 80.7, 76.5, 67.4, 66.8, 55.5, 26.5, 25.0. IR (CHCl3, cm-1):
ν 3330, 2990, 1939, 1746. MS (CI), m/z: 332 (M+ + 1, 100),
331 (M+, 19). Anal. Calcd for C18H21NO5: C, 65.24; H, 6.39;
N, 4.23. Found: C, 65.32; H, 6.35; N, 4.20.
1
oil. [R]D ) -49.5 (c 1.5, CHCl3). H NMR: δ 1.35 and 1.45 (s,
each 3H), 2.09 (t, 1H, J ) 2.7 Hz), 2.69 (dd, 2H, J ) 2.7, 1.5
Hz), 3.69 (d, 1H, J ) 16.1 Hz), 3.75 (d, 1H, J ) 6.8 Hz), 3.87
(dd, 2H, J ) 9.0, 5.0 Hz), 4.19 (dd, 1H, J ) 9.0, 7.0 Hz), 4.24
(ddt, 1H, J ) 15.1, 4.9, 1.5 Hz), 4.37 (ddd, 2H, J ) 11.7, 6.6,
4.9 Hz), 4.79 (s, 1H), 5.26 (m, 2H), 5.78 (m, 1H). 13C NMR: δ
169.4, 131.4, 119.1, 109.9, 83.1, 78.1, 75.8, 71.6, 66.6, 64.5, 43.8,
26.6, 25.3, 24.9. IR (CHCl3, cm-1): ν 3343, 1745. MS (CI), m/z:
266 (M+ + 1, 100), 265 (M+, 22). Anal. Calcd for C14H19NO4:
C, 65.24; H, 6.39; N, 4.23. Found: C, 65.32; H, 6.31; N, 4.19.
Zin c-P r om oted Rea ction betw een P r op a r gyl Br om id e
a n d Azetid in e-2,3-d ion e (+)-1a in a n An h yd r ou s Me-
d iu m . Propargyl bromide (57 mg, 0.48 mmol, 54 µL of a 80%
solution in toluene) was added to a well-stirred suspension of
the R-keto lactam (+)-1a (92 mg, 0.32 mmol), zinc dust (24.8
mg, 0.38 mmol), and ammonium chloride (20.6 mg, 0.38 mmol)
in dry THF (3 mL) at room temperature. After 1.5 h, saturated
aqueous ammonium chloride (3 mL) was added at 0 °C, and
the mixture was extracted with ethyl acetate (3 × 5 mL). The
organic extract was washed with brine, dried (MgSO4), and
concentrated under reduced pressure. Chromatography of the
residue using dichloromethane/ethyl acetate (9:1) as an eluent
gave 36 mg (34%) of compound (+)-7a . Anal. Calcd for C18H21
-
NO5: C, 65.24; H, 6.39; N, 4.23. Found: C, 65.16; H, 6.33; N,
4.25.
Tin /Ha fn iu m (IV) Ch lor id e P r om oted Rea ction be-
tw een P r op a r gyl Br om id e a n d Azetid in e-2,3-d ion e (+)-
1a . Propargyl bromide (64 mg, 0.538 mmol, 60 µL of a 80%
solution in toluene) was added to a well-stirred suspension of
the R-keto lactam (+)-1a (52 mg, 0.179 mmol), tin powder (43
mg, 0.358 mmol), and hafnium(IV) chloride (57 mg, 0.179
mmol) in THF/NH4Cl (aq satd) (1:5, 2.0 mL) at 0 °C. After 2 h
at room temperature, the mixture was extracted with ethyl
acetate (3 × 5 mL). The organic extract was washed with brine,
dried (MgSO4), and concentrated under reduced pressure.
Chromatography of the residue using ethyl acetate/hexanes
(1:3) as an eluent gave 47 mg (79%) of compound (+)-6a . Anal.
Calcd for C18H21NO5: C, 65.24; H, 6.39; N, 4.23. Found: C,
65.30; H, 6.41; N, 4.21.
In d iu m -P r om oted Rea ction betw een 1-Br om o-2-bu -
tyn e a n d Azetid in e-2,3-d ion es 1. Gen er a l P r oced u r e for
t h e Syn t h esis of R-Allen ic Alcoh ols (+)-8a a n d (-)-8b .
1-Bromo-2-butyne (3.0 mmol) was added to a well-stirred
suspension of the corresponding R-keto lactam (1.0 mmol) and
indium powder (6.0 mmol) in THF/NH4Cl (aq satd) (1:5, 5 mL)
at 0 °C. After disappearance of the starting material (TLC),
the mixture was extracted with ethyl acetate (3 × 5 mL). The
organic extract was washed with brine, dried (MgSO4), and
concentrated under reduced pressure. Chromatography of the
residue using ethyl acetate/hexanes mixtures gave analytically
pure compounds. Spectroscopic and analytical data for some
representative pure forms of 8 follow.
Zin c-P r om oted Rea ction betw een P r op a r gyl Br om id e
a n d Azetid in e-2,3-d ion es 1. Gen er a l P r oced u r e for th e
Syn th esis of Hom op r op a r gylic Alcoh ols 7. Propargyl
bromide (3.0 mmol) was added to a well-stirred suspension of
the corresponding R-keto lactam (1.0 mmol) and zinc dust (6.0
mmol) in THF/NH4Cl (aq satd) (1:5, 5 mL) at 0 °C. After
disappearance of the starting material (TLC), the mixture was
extracted with ethyl acetate (3 × 5 mL). The organic extract
was washed with brine, dried (MgSO4), and concentrated

5216 J . Org. Chem., Vol. 66, No. 15, 2001
Alcaide et al.
(3R,4S)-4-[(S)-2,2-Dim et h yl-1,3-d ioxola n yl-4-yl]-3-h y-
dr oxy-1-(p-m eth oxyph en yl)-3-(1-m eth yl-1,2-pr opadien yl)-
2-azetidin on e, (+)-8a. From 50.5 mg (0.173 mmol) of azetidine-
2,3-dione (+)-1a was obtained 44 mg (74%) of compound (+)-
2-a zetid in on e, (+)-8c. From 50 mg (0.170 mmol) of azetidine-
2,3-dione (+)-1a was obtained 53 mg (76%) of compound (+)-
1
8c as a colorless oil. [R]D ) +48.2 (c 0.9, CHCl3). H NMR: δ
1.36 and 1.46 (s, each 3H), 3.77 (dd, 1H, J ) 8.8, 6.8 Hz), 3.79
(s, 3H), 4.00 (brs, 1H), 4.28 (dd, 1H, J ) 8.8, 6.8 Hz), 4.37 (d,
1H, J ) 6.8 Hz), 4.55 (q, 1H, J ) 6.8 Hz), 5.29 (s, 2H), 6.84
and 7.57 (dd, each 2H, J ) 7.0, 2.5 Hz), 7.28 (m, 1H), 7.35 and
7.64 (m, each 2H). 13C NMR: δ 207.6, 166.1, 156.7, 132.5,
130.7, 128.6, 128.4, 127.8, 120.1, 113.9, 109.8, 105.9, 84.2, 80.9,
76.5, 66.7, 66.3, 55.4, 26.4, 25.2. IR (CHCl3, cm-1): ν 3332,
2988, 1938, 1746. MS (CI), m/z: 408 (M+ + 1, 100), 407 (M+,
15). Anal. Calcd for C24H25NO5: C, 70.75; H, 6.18; N, 3.44.
Found: C, 70.83; H, 6.16; N, 3.43.
1
8a as a colorless oil. [R]D ) +75.4 (c 0.7, CHCl3). H NMR: δ
1.36 and 1.51 (s, each 3H), 1.85 (t, 3H, J ) 3.0 Hz), 3.79 (s,
3H), 3.80 (dd, 1H, J ) 8.8, 6.4 Hz), 4.14 (brs, 1H), 4.24 (d, 1H,
J ) 7.7 Hz), 4.32 (dd, 1H, J ) 8.8, 6.8 Hz), 4.49 (q, 1H, J )
7.0 Hz), 4.98 (dd, 2H, J ) 6.4, 3.0 Hz), 6.86 and 7.63 (dd, each
2H, J ) 7.0, 2.5 Hz). 13C NMR: δ 205.2, 166.6, 156.7, 130.7,
120.0, 114.0, 109.7, 98.6, 83.5, 79.4, 76.8, 66.8, 66.5, 55.4, 26.6,
25.0, 13.9. IR (CHCl3, cm-1): ν 3340, 2991, 1940, 1742. MS
(CI), m/z: 346 (M+ + 1, 100), 345 (M+, 20). Anal. Calcd for
C
19H23NO5: C, 66.07; H, 6.71; N, 4.06. Found: C, 66.13; H,
Tin -P r om ot ed R ea ct ion b et w een 1-Br om o-3-p h en yl-
2-p r op yn e a n d Azetid in e-2,3-d ion e (+)-1a . 1-Bromo-3-
phenyl-2-butyne (99.5 mg, 0.51 mmol) was added to a well-
stirred solution of the azetidine-2,3-dione (+)-1a (49.7 mg, 0.17
mmol) and tin powder (121.1 mg, 1.02 mmol) in THF/NH4Cl
(aq satd) (1:7, 2.25 mL) at 0 °C. The mixture was allowed to
warm to room temperature and was stirred at room temper-
ature for 30 h, before being extracted with ethyl acetate (3 ×
5 mL). The organic extract was washed with brine, dried
(MgSO4), and concentrated under reduced pressure. Chroma-
tography of the residue using ethyl acetate/hexanes (1:3
containing 1% of triethylamine) as an eluent gave 52 mg (75%)
6.65; N, 4.00.
(3R,4S)-4-[(S)-2,2-Dim et h yl-1,3-d ioxola n yl-4-yl]-3-h y-
dr oxy-3-(1-m eth yl-1,2-pr opadien yl)-1-(2-pr open yl)-2-azet-
id in on e, (-)-8b. From 61 mg (0.271 mmol) of azetidine-2,3-
dione (-)-1b was obtained 47 mg (63%) of compound (-)-8b
as a colorless oil. [R]D ) -53.4 (c 0.7, CHCl3). 1H NMR: δ 1.34
and 1.42 (s, each 3H), 1.81 (t, 3H, J ) 3.2 Hz), 3.71 (m, 3H),
4.18 (dd, 1H, J ) 8.8, 6.8 Hz), 4.20 (ddt, 1H, J ) 15.4, 4.9, 1.6
Hz), 4.38 (m, 1H), 4.48 (brs, 1H), 4.91 (dd, 2H, J ) 6.1, 3.1
Hz), 5.23 (m, 2H), 5.76 (m, 1H). 13C NMR: δ 205.1, 169.2,
131.4, 118.6, 109.7, 98.5, 84.2, 78.7, 76.4, 66.7, 64.9, 43.5, 26.7,
25.0, 13.9. IR (CHCl3, cm-1): ν 3336, 2990, 1940, 1744. MS
(CI), m/z: 280 (M+ + 1, 100), 279 (M+, 17). Anal. Calcd for
of isomerically pure compound (+)-8c. Anal. Calcd for C24H25
-
NO5: C, 70.75; H, 6.18; N, 3.44. Found: C, 70.67; H, 6.15; N,
3.42.
C
15H21NO4: C, 64.50; H, 7.58; N, 5.01. Found: C, 64.58; H,
7.55; N, 5.03.
In d iu m -P r om oted Rea ction betw een 1-Br om o-3-p h en -
yl-2-p r op yn e a n d Azetid in e-2,3-d ion es 1 in a n Aqu eou s
Med iu m Con ta in in g NH4Cl. Gen er a l P r oced u r e for th e
Syn th esis of R-Allen ic Alcoh ols 8c-e. 1-Bromo-3-phenyl-
2-propyne (3.0 mmol) was added to a well-stirred suspension
of the corresponding R-keto lactam (1.0 mmol) and indium
powder (6.0 mmol) in THF/NH4Cl (aq satd) (1:5, 5 mL) at 0
°C. After disappearance of the starting material (TLC), the
mixture was extracted with ethyl acetate (3 × 5 mL). The
organic extract was washed with brine, dried (MgSO4), and
concentrated under reduced pressure. Chromatography of the
residue using ethyl acetate/hexanes mixtures gave analytically
pure compounds. Spectroscopic and analytical data for some
representative pure forms of 8 follow.
Ack n ow led gm en t. Support for this work by the
DGI-MCYT (Project No. BQU2000-0645) is gratefully
acknowledged. C.A. thanks the Comunidad Auto´noma
de Madrid for a fellowship.
Su p p or tin g In for m a tion Ava ila ble: Spectroscopic and
analytical data for compounds 1a -e, 2b-e, 3b-e, (-)-4b, (-)-
4g, (+)-5, (-)-6b, (-)-7c, (+)-7d , (-)-8d , and (-)-8e; as well
as general experimental procedures for compounds 1a -e, 2b-
e, 3a -e, 4a -g, (+)-5, (+)-6a , (+)-7a , (+)-8a , and (+)-8c. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(3R,4S)-4-[(S)-2,2-Dim et h yl-1,3-d ioxola n yl-4-yl]-3-h y-
dr oxy-1-(p-m eth oxyph en yl)-3-(1-ph en yl-1,2-pr opadien yl)-
J O015704L