Metal-mediated carbonyl-1,3-butadien-2-ylation by 1,4-bis(methanesulfonyl)-2-butyne or 1,4-dibromo-2-butyne in aqueous media: Asymmetric synthesis of 3-substituted 3-hydroxy-β-lactams

Article abstract of DOI:10.1021/jo016247b

Metal-mediated 1,3-butadien-2-ylation reactions between 1,4-dibromo-2-butyne or 1,4-bis(methane-sulfonyl)-2-butyne and optically pure azetidine-2,3-diones were investigated in aqueous media, offering a convenient asymmetric entry to the potentially bioactive 3-substituted 3-hydroxy-β-lactam moiety. The diastereoselectivity of the addition reaction was controlled by the bulky chiral auxiliary at C4. However, while the regioselectivity of the process was full, the chemical yield of the addition was a function of the nature of both the metal reagent and the system solvent as well. In addition, 2-azetidinone-tethered 1,3-butadienes can easily be transformed into other functionalities via Diels-Alder reaction.

Full text of DOI:10.1021/jo016247b

J . Org. Chem. 2002, 67, 1925-1928
1925
Meta l-Med ia ted Ca r bon yl-1,3-bu ta d ien -2-yla tion by
1,4-Bis(m eth a n esu lfon yl)-2-bu tyn e or 1,4-Dibr om o-2-bu tyn e in
Aqu eou s Med ia : Asym m etr ic Syn th esis of 3-Su bstitu ted
3-Hyd r oxy-â-la cta m s
Benito Alcaide,* Pedro Almendros, and Raquel Rodr´ıguez-Acebes
Departamento de Quı´mica Orga´nica I, Facultad de Quı´mica, Universidad Complutense,
28040-Madrid, Spain
alcaideb@quim.ucm.es
Received October 30, 2001
Metal-mediated 1,3-butadien-2-ylation reactions between 1,4-dibromo-2-butyne or 1,4-bis(methane-
sulfonyl)-2-butyne and optically pure azetidine-2,3-diones were investigated in aqueous media,
offering a convenient asymmetric entry to the potentially bioactive 3-substituted 3-hydroxy-â-lactam
moiety. The diastereoselectivity of the addition reaction was controlled by the bulky chiral auxiliary
at C4. However, while the regioselectivity of the process was full, the chemical yield of the addition
was a function of the nature of both the metal reagent and the system solvent as well. In addition,
2-azetidinone-tethered 1,3-butadienes can easily be transformed into other functionalities via Diels-
Alder reaction.
In tr od u ction
Thus, searching for new synthetic equivalents accessible
for simple starting materials is of interest. In view of the
particular effort devoted to organometallic reactions in
aqueous media because of its synthetic advantages as
well as its potential as an environmentally benign
chemical process,8 Chan and colleagues have reported the
indium-mediated 1,3-butadien-2-ylation of simple alde-
hydes in aqueous medium.9 To the best of our knowledge,
however, the zinc-promoted 1,3-butadien-2-ylation or the
metal-promoted 1,3-butadien-2-ylation using propargylic
dimesylates have never been reported. As part of our
ongoing project in the synthesis of natural products and
derivatives from 2-azetidinones,10 we decided to pursue
eco-friendly approachs to 3-substituted 3-hydroxy-â-
lactams, because of the importance both as substrates
for the “â-lactam synthon method” and for studies of
biological activity. The 3-substituted 3-hydroxy-â-lactam
moiety represents an efficient carboxylate mimic,11 and
it is present in several pharmacologically active mono-
bactams such as sulfazecin and related products,12 and
in enzyme inhibitors such as tabtoxin and its analogues.13
The complexity of organic target molecules is con-
stantly increasing, and novel strategies allowing the
efficient formation of new carbon-carbon bonds between
functionalized moieties are needed. Among the most
fundamental and important reactions for constructing
carbon-carbon bonds are the allylation and the propar-
gylation/allenylation of aldehydes and ketones (carbo-
nyls) with organometallic reagents.1,2 In contrast, the
analogous reaction involving butadienylmetals has been
much less investigated. The use of lithium-,3 magnesium-
4
,
tin-,5 silicon-,6 and boron-based7 reagents has been
reported in anhydrous organic solvents. However, 2-(1,3-
butadienyl)magnesium chloride has the serious disad-
vantage of poor regioselectivity, and its lithium counter-
part must be prepared indirectly from the corresponding
stannnane. The preparation of the others above organo-
metallic derivatives (stannane, silane, and boronate)
generally requires tedious protocols, and these reagents
are not recommended from an atom economy criterion.
* To whom correspondence should be addressed. Fax: +34-
913944103.
(8) For recents reviews on organic reactions in aqueous media, see:
(a) Li, C. J .; Chan, T. H. Tetrahedron 1999, 55, 11149. (b) Lubineau,
A.; Auge´, J . Top. Curr. Chem. 1999, 206, 1. (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.
(9) Lu, W.; Ma, J .; Yang, Y.; Chan, T. H. Org. Lett. 2000, 2, 3469.
(10) (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.; Almendros, P.;
Aragoncillo, C. Chem. Commun. 2000, 757. (d) Alcaide, B.; Almendros,
P.; Aragoncillo, C. Org. Lett. 2000, 2, 1411. For the applications of
4-oxoazetidine-2-carbaldehydes as efficient chiral synthons, see: (e)
Alcaide, B.; Almendros, P. Chem. Soc. Rev. 2001, 30, 226. For a review
on the chemistry of azetidine-2,3-diones, see: (f) Alcaide, B.; Almen-
dros, P. Org. Prep. Proced. Int. 2001, 33, 315.
(1) 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) Thomas, E. J . Chem.
Commun. 1997, 411. (c) Fleming, I.; Barbero, A.; Walter, D. Chem.
Rev. 1997, 97, 2063. (d) Marshall, J . A. Chem. Rev. 1996, 96, 6, 31. (e)
Yamamoto, Y.; Asao, N. Chem. Rev. 1993, 93, 2207.
(2) For reviews on allenylation/propargylation, 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.
(3) Wada, E.; Kanemasa, S.; Fujiwara, I.; Tsuge, O. Bull. Chem. Soc.
J pn. 1985, 58, 1942.
(4) Nunomoto, S.; Yamashita, Y. J . Org. Chem. 1979, 44, 4788.
(5) Luo, M.; Iwabuchi, Y.; Hatakeyama, S. Chem. Commun. 1999,
267.
(11) (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.
(6) Nishiyama, T.; Esumi, T.; Iwabuchi, Y.; Irie, H.; Hatakeyama,
S. Tetrahedron Lett. 1998, 39, 43.
(7) Soundararajan, R.; Li, G.; Brown, H. C. J . Org. Chem. 1996, 61,
100.
(12) Imada, A.; Kitano, K.; Kintana, K.; Muroi, M.; Asai, M. Nature
1981, 289, 590.
10.1021/jo016247b CCC: $22.00 © 2002 American Chemical Society
Published on Web 02/22/2002

1926 J . Org. Chem., Vol. 67, No. 6, 2002
Alcaide et al.
Sch em e 1
through the indium-mediated reaction between the aze-
tidine-2,3-dione (+)-1a and 1,4-dibromo-2-butyne in aque-
ous tetrahydrofuran (1:1) at room temperature. In the
event, the 3-(1,3-butadien-2-yl) 3-hydroxy-â-lactam (+)-
4a was obtained in 54% as the only regio- and stereo-
isomer (Table 1, entry 1). Because water is an economical
solvent, we decided to increase the amount of water in
the Barbier-type reaction. However, when the reaction
was conducted in a THF/H2O (1:5) mixture, the coupling
was not as efficient as before (18% yield). A higher
proportion of THF beyond the 1:1 ratio in the solvent did
not seem to improve the yield further. It was reported
for the Barbier-type allylation of 2-aminoaldehydes in
aqueous media that changes in the ionic strength of the
solvent can provide modification in the diastereomeric
ratio or accelerated the process,17 and we have described
a conversion enhancement for the carbonyl-allenylation
reaction in the presence of ammonium chloride.10d In
contrast, the ionic strength enhancement of the reaction
solvent provided by the ammonium chloride was coun-
terproductive for the indium-mediated 1,3-butadien-2-
ylation. Thus, moving from THF/H2O (1:1) to THF/NH4Cl
(aq satd) (1:1) decreased the yield for the indium-
promoted reaction between 1,4-dibromo-2-butyne and
azetidine-2,3-dione (+)-1a (Table 1, entries 1 and 3). The
reaction time was increased by 20 (Table 1, entry 4) as
the solvent changed from tetrahydrofuran/H2O (1:1) to
a methanol/H2O (1:1) mixed solvent. No reaction was
observed in THF/NaHCO3 (aq satd) (1:1). When the above
coupling was promoted by zinc in THF/NH4Cl (aq satd)
(1:5), it gave rise to the optically pure 1,3-butadien-2-yl
alcohol (+)-4a as a single isomer in 30% yield. The yield
fell considerably by performing the zinc-mediated reac-
tion in THF/H2O (1:1) (Table 1, entry 7). Tin, cadmium,
and bismuth failed to produce any desired product when
they were used as metal promoters. These results suggest
that the metal-promoted carbonyl-1,3-butadien-2-ylation
in aqueous media may be quite sensitive to various
factors.
Next, we explored 1,4-bis(methanesulfonyl)-2-butyne
3 as a Barbier-type 1,3-butadien-2-ylating reagent, rather
than 1,4-dibromo-2-butyne 2, because the mesylates are
superior to the halides for ease of preparation and the
stability of propargylic substrates.18 The bismesylate 3
was then reacted with azetidine-2,3-diones 1, sodium
iodide, and indium in different aqueous media to afford
the corresponding (buta-1,3-dien-2-yl)methanol deriva-
tives 4 in moderate yield (up to 42%). In all cases, the
same regioselectively was observed, but the conversion
was enhanced as the system solvent changed from THF/
H2O (1:1) to THF/NH4Cl (aq satd) (1:5). No reaction was
observed when the indium was supressed by using
another metal promoter. Similar results were observed
in the metal-mediated reactions of different N-substituted
R-keto-lactams 1 with the dibromide 2 or the bismesylate
3 (see Table 1). From a synthetic point of view, the use
of 1,4-dibromo-2-butyne is potentially advantageous over
the use of 1,4-bis(methanesulfonyl)-2-butyne because a
slightly higher yield was obtained. However, it is note-
worthy that 1,4-dibromo-2-butyne is a powerful vesicant
and lachrymator,19 and on a multigram-scale the bisme-
In addition, these compounds with correct absolute
configurations serve as precursors to the corresponding
R-hydroxy-â-amino acids (isoserines), which are key
components of a large number of therapeutically impor-
tant compounds. As an example, (2R,3S)-3-amino-2-hy-
droxy-5-methylhexanoic acid (norstatine) and (3R,4S)-4-
amino-3-hydroxy-5-methylheptanoic acid (statine) are
residues for peptide inhibitors of enzymes, such as renin14
and HIV-1 protease.15 Moreover, phenylisoserine ana-
logues are used to synthesize new taxoids.16 Herein, we
wish to report the metal-mediated 1,3-butadien-2-ylation
of enantiomerically pure azetidine-2,3-diones 1 in aque-
ous media using 1,4-dibromo-2-butyne 2 or 1,4-bis(meth-
anesulfonyl)-2-butyne 3, which resulted in the corre-
sponding 3-butadienyl 3-hydroxy-â-lactams.
Resu lts a n d Discu ssion
The starting azetidine-2,3-diones 1 were efficiently
prepared in optically pure form from imines of (R)-2,3-
O-isopropylideneglyceraldehyde, via Staudinger reaction
with acetoxyacetyl chloride in the presence of Et3N,
followed by sequential transesterification and Swern
oxidation, as we previously reported (Scheme 1).10f Our
aim was set to carry out the key coupling reactions,
evaluating the regiochemistry of the connection (e.g.,
butadienylation vs homoallenylation) and the diastere-
ochemistry (syn vs anti). The interest in an enviromen-
tally benign approach prompted us to seek an aqueous
metal-induced 1,3-butadien-2-ylation reaction. To achieve
full stereocontrol, we placed a bulky chiral auxiliary at
C4 that might be able to control the stereochemistry of
the new C3-substituted C3-hydroxy quaternary center.
For the purpose of full control of regiochemistry, azeti-
dine-2,3-diones 1 were treated with 1,4-dibromo-2-butyne
2 and a broad variety of metals and reaction conditions
in aqueous media. Not unexpectedly, the diastereoselec-
tivity was complete in all cases. However, while the
regioselectivity of the process was full, the chemical yield
of the addition was a function of the nature of both the
metal reagent and the system solvent as well.
Since indium chemistry has captured much recent
attention largely due to the discovery that indium can
mediate in aqueous media the smooth coupling of allylic
halides with aldehydes to give the corresponding homoal-
lylic alcohols,8 the regio- and diastereoselectivity of the
carbon-carbon bond formation were initially investigated
(13) (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.
(14) Thaisrivongs, S.; Pals, D. T.; Kroll, L. T.; Turner, S. R.; Han,
F.-S. J . Med. Chem. 1987, 30, 976.
(15) Huff, J . R. J . Med. Chem. 1991, 34, 2305.
(16) (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.
(17) Chappell, M. D.; Halcomb, R. L. Org. Lett 2000, 2, 2003.
(18) For selective propargylation/allenylation reactions by propar-
gylic mesylates, see: (a) Masuyama, Y.; Watabe, A.; Ito, A.; Kurusu,
Y Chem. Commun. 2000, 2009. (b) Marshall, J . A.; Chobanian, H. R.
J . Org. Chem. 2000, 65, 8357.

Asymmetric Synthesis of 3-Substituted 3-Hydroxy-â-lactams
J . Org. Chem., Vol. 67, No. 6, 2002 1927
Ta ble 1. Regio- a n d Ster eoselective 1,3-Bu ta d ien -2-yla tion of Azetid in e-2,3-d ion es 1 in Aqu eou s Med ia a
entry
ketone
R
X
metal
system solvent
THF/H2O (1:1)
THF/H2O (1:5)
THF/NH4Cl (aq satd) (1:1)
MeOH/H2O (1:1)
THF/NaHCO3 (aq satd) (1:1)
THF/NH4Cl (aq satd) (1:5)
THF/H2O (1:1)
THF/NH4Cl (aq satd) (1:5)
THF/H2O (1:1)
THF/H2O (1:1)
THF/H2O (1:1)
THF/H2O (1:1)
THF/NH4Cl (aq satd) (1:5)
THF/NH4Cl (aq satd) (1:5)
THF/NH4Cl (aq satd) (1:5)
t (h)
compdb
yieldc (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
(+)-1a
(+)-1a
(+)-1a
(+)-1a
(+)-1a
(+)-1a
(+)-1a
(+)-1a
(+)-1a
(-)-1b
(-)-1c
(-)-1d
(-)-1b
(-)-1c
(-)-1d
PMP
PMP
PMP
PMP
PMP
PMP
PMP
PMP
Br
Br
Br
Br
Br
Br
Br
MsO
MsO
Br
Br
Br
MsO
MsO
MsO
In
In
In
In
In
Zn
Zn
In
In
In
In
In
In
In
In
1
1
4
(+)-4a
(+)-4a
(+)-4a
(+)-4a
54
18
19
26
20
18
18
4
5
1
1
1
4
4
(+)-4a
(+)-4a
(+)-4a
(+)-4a
(-)-4b
(+)-4c
(+)-4d
(-)-4b
(+)-4c
(+)-4d
30
9
42
32
62
38
45
33
37
34
PMP
2-propenyl
2-propynyl
3-butenyl
2-propenyl
2-propynyl
3-butenyl
4
a
b
All reactions were carried out on 1 mmol scale. PMP ) 4-MeOC6H4. Obtained as single regio- and stereoisomers, to judge by the 1H
NMR spectra of the crude reaction mixtures before purification. c Yield of pure, isolated product with correct analytical and spectral data.
Sch em e 2
of the 3-butadienyl 3-hydroxy-â-lactams 4 becomes much
higher by assuming that the (buta-1,3-dien-2-yl)methanol
moiety is a placeholder for further conversions. As shown
in Scheme 2, the Diels-Alder reaction with concomitant
aromatization proceeded by treating the compound (+)-
4a with dimethyl acetylenedicarboxylate, affording cy-
cloadduct (+)-5. Next, we studied the reactivity of
2-azetidinone-tethered diene (+)-4a with a cyclic dieno-
phile. Intermolecular Diels-Alder cycloaddition of diene
(+)-4a with N-methylmaleimide proceeded to give prod-
ucts (+)-6 and (+)-7 in a 5:1 ratio, which were separated
by column chromatography (Scheme 2).21
Con clu sion s
In conclusion, we have achieved a highly regio- and
diastereoselective metal-mediated 1,3-butadien-2-ylation
of azetidine-2,3-diones in aqueous media, which afforded
the potentially bioactive 3-substituted 3-hydroxy-â-lac-
tam moiety. In addition, the present study provides the
first insight into the manner in which the carbonyl group
and 1,4-bis(methanesulfonyl)-2-butyne undergo metal-
mediated coupling. The simple reaction protocol, in
combination with options for further transformations of
the resulting adducts, makes this process more useful.
sylate protocol may be practically useful. Nonetheless,
there remains much room for improvement in respect to
yield.
The stereochemistry at the C3-heterosubstituted qua-
ternary center in compounds 4 was established by qua-
litative homonuclear NOE difference spectra performed
on 3-hydroxy â-lactams 4. The facial selectivity of these
addition reactions may be controlled by the bulky chiral
auxiliary at C-4 in which one face of the ketone is blocked,
thus the organometallic reagent being delivered prefer-
entially to the less hindered face.
Exp er im en ta l Section
Gen er a l Meth od s. General experimental data and proce-
dures have been previously reported.10a 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
2-Functionalized-1,3-butadienes are quite useful build-
ing blocks in organic synthesis because the butadiene
moiety can easily be transformed into other functional-
ities, specially via Diels-Alder reaction.20 The usefulness
(20) Bear, B. R.; Sparks, S. M.; Shea, K. J . Angew. Chem., Int. Ed.
2001, 40, 820.
(21) For the utility of related â-lactam-tethered dienes in the
preparation of 3- or 4-substituted 2-azetidinones, see: (a) Sharma, A.
K.; Mazumdar, S. N.; Mahajan, M. P. J . Org. Chem. 1996, 61, 5506.
(b) Alcaide, B.; Almendros, P.; Salgado, N. R.; Mart´ınez-Alca´zar, M.
P.; Herna´ndez-Cano, F. Eur. J . Org. Chem. 2001, 2001.
(19) J ohnson, A. W. J . Chem. Soc. 1946, 1009.

1928 J . Org. Chem., Vol. 67, No. 6, 2002
Alcaide et al.
mL. Flash column chromatography was performed on silica
gel (230-400 mesh). All commercially available compounds
were used without further purification.
lactam 1 (1.0 mmol), sodium iodide (6.0 mmol), and indium
powder (1.99 mmol) in THF/NH4Cl (aq satd) (1:5, 5 mL) at 0
°C. After 4 h at room temperature, the mixture was extracted
with ethyl acetate, washed with brine, dried (MgSO4), and
concentrated under reduced pressure. Chromatography of the
residue eluting with ethyl acetate/hexanes mixtures gave
analytically pure compounds 4.
Gen er a l P r oced u r e for th e In d iu m -P r om oted Rea c-
tion betw een 1,4-Dibr om o-2-bu tyn e a n d Azetid in e-2,3-
d ion es in Aqu eou s Med iu m . 1,4-Dibromo-2-butyne 2 (2.0
mmol) was added to a well-stirred suspension of the corre-
sponding R-keto lactam 1 (1.0 mmol) and indium powder (1.99
mmol) in THF/H2O (1:1, 5 mL) at 0 °C. After 1 h at room
temperature, saturated aqueous ammonium chloride (2 mL)
was added at 0 °C, and the mixture was allowed to warm to
room temperature before being extracted with ethyl acetate.
The organic extract was washed with brine, dried (MgSO4),
and concentrated under reduced pressure. Chromatography
of the residue eluting with ethyl acetate/hexane mixtures gave
analytically pure compounds 4. Spectroscopic and analytical
data for some representative forms of 4 follow.22
(3R,4S)-3-(1,3-Bu ta d ien -2-yl)-4-[(S)-2,2-d im eth yl-1,3-d i-
oxola n -4-yl]-3-h yd r oxy-1-(p -m et h oxyp h en yl)-2-a zet id i-
n on e, (+)-4a . From 43.5 mg (0.15 mmol) of azetidine-2,3-dione
(+)-1a was obtained 30.9 mg (54%) of compound (+)-4a as a
colorless oil. [R]D ) +341.9 (c 0.8, CHCl3). 1H NMR: δ 1.35
and 1.46 (s, each 3H), 3.72 (m, 1H), 3.73 (s, 3H), 4.12 (d, 1H,
J ) 6.8 Hz), 4.29 (dd, 1H, J ) 8.8, 6.8 Hz), 4.53 (q, 1H, J )
6.8 Hz), 4.80 (brs, 1H), 5.17 (dd, 1H, J ) 11.1, 1.1 Hz), 5.37
and 5.46 (s, each 1H), 5.48 (dd, 1H, J ) 17.3, 1.2 Hz), 6.25
(ddd, 1H, J ) 17.6, 11.1, 0.8 Hz), 6.87 and 7.61 (d, each 2H, J
) 9.3 Hz). 13C NMR: δ 166.9, 156.8, 143.3, 133.5, 130.6, 120.1,
117.4, 115.5, 114.1, 109.8, 85.4, 66.5, 66.2, 65.8, 55.4, 26.5, 25.1.
IR (CHCl3, cm-1): ν 3340, 1742. MS (CI) m/z: 346 (M+ + 1,
100), 345 (M+, 17). Anal. Calcd for C19H23NO5: C, 66.07; H,
6.71; N, 4.06. Found: C, 66.14; H, 6.66; N, 4.01.
(3R,4S)-3-(1,3-Bu t a d ien -2-yl)-1-(3-b u t en yl)-4-[(S)-2,2-
dim eth yl-1,3-dioxola n -4-yl]-3-h ydr oxy-2-a zetid in on e, (+)-
4d . From 54 mg (0.226 mmol) of azetidine-2,3-dione (-)-1d
was obtained 22 mg (34%) of compound (+)-4d as a colorless
1
oil. [R]D ) +1.1 (c 0.8, CHCl3). H NMR: δ 1.36 and 1.45 (s,
each 3H), 2.37 (m, 2H), 3.27 (m, 1H), 3.57 (d, 1H, J ) 7.3 Hz),
3.67 (m, 2H), 4.22 (dd, 1H, J ) 8.7, 6.7 Hz), 4.18 (s, 1H), 4.41
(dt, 1H, J ) 7.0, 5.8 Hz), 5.08 (m, 2H), 5.19 (dd, 1H, J ) 11.0,
1.5 Hz), 5.33 and 5.37 (s, each 1H), 5.54 (dd, 1H, J ) 17.6, 1.6
Hz), 5.77 (m, 1H), 6.25 (ddd, 1H, J ) 17.3, 11.0, 0.9 Hz). 13C
NMR: δ 169.1, 143.6, 134.8, 133.7, 117.3, 117.1, 114.8, 109.7,
85.8, 76.1, 66.6, 65.6, 40.4, 31.6, 26.6, 25.0. IR (CHCl3, cm-1):
ν 3343, 1745. MS (CI) m/z: 294 (M+ + 1, 100), 293 (M+, 19).
Anal. Calcd for C16H23NO4: C, 65.51; H, 7.90; N, 4.77. Found:
C, 65.59; H, 7.88; N, 4.75.
P r oced u r e for th e P r ep a r a tion of Ad d u ct (+)-5. To a
solution of the diene (+)-4a (52 mg, 0.151 mmol) and hydro-
quinone (cat.) in toluene (10 mL) was added dimethyl acety-
lenedicarboxylate (26 mg, 0.181 mmol). The resulting solution
was heated in a sealed tube at 180 °C for 22 h. The reaction
mixture was allowed to cool to room temperature, and the
solvent was removed under reduced pressure. Chromatography
of the residue eluting with dichloromethane/ethyl acetate (9:
1) gave 36 mg (48%) of analytically pure adduct (+)-5 as a
colorless oil. [R]D ) +54.1 (c 1.2, CHCl3). 1H NMR: δ 1.37 and
1.43 (s, each 3H), 3.82 (s, 3H), 3.83 (m, 1H), 3.90 and 3.91 (s,
each 3H), 4.17 (d, 1H, J ) 6.3 Hz), 4.31 (dd, 1H, J ) 8.8, 6.8
Hz), 4.56 (q, 1H, J ) 6.6 Hz), 6.91 (d, 2H, J ) 9.0 Hz), 7.53
(dd, 1H, J ) 8.2, 1.8 Hz), 7.63 (d, 2H, J ) 9.0 Hz), 7.71 (d, 2H,
J ) 8.0 Hz), 7.76 (d, 1H, J ) 1.9 Hz). 13C NMR: δ 167.3, 157.2,
141.8, 133.0, 131.7, 129.7, 127.5, 125.4, 120.5, 114.3, 110.2,
85.0, 76.0, 69.3, 66.5, 55.5, 26.4, 25.2. IR (CHCl3, cm-1): ν 3343,
1725, 1745. MS (EI), m/z: 486 (M+ + 1, 38), 485 (M+, 100).
Anal. Calcd for C25H27NO9: C, 61.85; H, 5.61; N, 2.89. Found:
C, 61.77; H, 5.63; N, 2.90.
(3R,4S)-3-(1,3-Bu ta d ien -2-yl)-4-[(S)-2,2-d im eth yl-1,3-d i-
oxola n -4-yl]-3-h yd r oxy-1-(2-p r op en yl)-2-a zetid in on e, (-)-
4b. From 48 mg (0.213 mmol) of azetidine-2,3-dione (-)-1b
was obtained 37 mg (62%) of compound (-)-4b as a colorless
1
oil. [R]D ) -14.7 (c 0.7, CHCl3). H NMR: δ 1.28 and 1.37 (s,
each 3H), 3.60 (d, 1H, J ) 6.1 Hz), 3.72 (ddt, 1H, J ) 15.1,
7.3, 1.0 Hz), 3.76 (dd, 1H, J ) 8.9, 5.3 Hz), 4.20 (dd, 1H, J )
8.9, 7.0 Hz), 4.29 (ddt, 1H, J ) 15.4, 4.6, 1.7 Hz), 4.44 (td, 1H,
J ) 6.6, 5.4 Hz), 5.24 (m, 3H), 5.33 and 5.41 (s, each 1H), 5.54
(dd, 1H, J ) 17.3, 1.5 Hz), 5.76 (m, 1H), 6.26 (ddd, 1H, J )
17.3, 11.0, 0.9 Hz). 13C NMR: δ 169.1, 143.5, 133.8, 131.2,
118.8, 117.3, 115.1, 109.9, 86.2, 75.6, 66.5, 65.1, 43.4, 26.5, 24.9.
IR (CHCl3, cm-1): ν 3342, 1744. MS (CI) m/z: 280 (M+ + 1,
100), 279 (M+, 21). Anal. Calcd for C15H21NO4: C, 64.50; H,
7.58; N, 5.01. Found: C, 64.58; H, 7.56; N, 5.00.
Ack n ow led gm en t. Support for this work by the
DGI-MCYT (Project BQU2000-0645) is gratefully ac-
knowledged. R.R.-A. thanks the MCYT for a predoctoral
grant.
Gen er a l P r oced u r e for th e In d iu m -P r om oted Rea c-
tion betw een 1,4-Bis(m eth a n esu lfon yl)-2-bu tyn e a n d
Azetid in e-2,3-d ion es in a n Aqu eou s Med iu m Con ta in in g
NH4Cl. 1,4-Bis(methanesulfonyl)-2-butyne 3 (3.0 mmol) was
added to a well-stirred suspension of the corresponding R-keto-
Su p p or tin g In for m a tion Ava ila ble: Spectroscopic and
analytical data for compounds 1a -d , 3, (+)-4d , (+)-6, and (+)-
7, as well as general experimental procedures for compounds
1a -d , 3, 4a -d , (+)-6, and (+)-7. This material is available
free of charge via the Internet at http://pubs.acs.org.
(22) Full spectroscopic and analytical data for compounds not
included in this Experimental Section are described in the Supporting
Information.
J O016247B