Straightforward Asymmetric Entry to Highly Functionalized 3-Substituted 3-Hydroxy-p-lactams via Baylis-Hillman or Bromoallylation Reactions

Article abstract of DOI:10.1021/jo035472l

The reaction of various activated vinyl systems, including 2-cyclopenten-1-one, with enantiopure azetidine-2,3-diones 1 was promoted by DABCO to afford the corresponding optically pure Baylis-Hillman adducts 2 without detectable epimerization. However, th

Full text of DOI:10.1021/jo035472l

Str a igh tfor w a r d Asym m etr ic En tr y to High ly F u n ction a lized
3-Su bstitu ted 3-Hyd r oxy-â-la cta m s via Ba ylis-Hillm a n or
Br om oa llyla tion Rea ction s
Benito Alcaide,*,† Pedro Almendros,*,‡ Cristina Aragoncillo,† and Raquel Rodr´ıguez-Acebes†
Departamento de Qu´ımica Orga´nica I, Facultad de Qu´ımica, Universidad Complutense de Madrid,
28040-Madrid, Spain, and Instituto de Qu´ımica Orga´nica General, CSIC, J uan de la Cierva 3,
28006-Madrid, Spain
alcaideb@quim.ucm.es; iqoa392@iqog.csic.es
Received October 7, 2003
The reaction of various activated vinyl systems, including 2-cyclopenten-1-one, with enantiopure
azetidine-2,3-diones 1 was promoted by DABCO to afford the corresponding optically pure Baylis-
Hillman adducts 2 without detectable epimerization. However, the reaction of R-keto lactams 1
with but-3-yn-2-one was not as successful, giving the corresponding â-halo Baylis-Hillman adduct
in low yield. Metal-mediated bromoallylation reaction between 2,3-dibromopropene and azetidine-
2,3-diones 1 was investigated in aqueous media. Surprisingly, indium was unable to promote the
bromoallylation reaction of R-keto lactams 1, but the Sn-Hf4Cl-promoted bromoallylation of ketones
1 proceeded efficiently to achieve bromohomoallyl alcohols 5 as single diastereomers. On this basis,
simple and fast protocols for the asymmetric synthesis of the potentially bioactive 3-substituted
3-hydroxy-â-lactam moiety were developed.
In tr od u ction
A stereoselective carbon-carbon bond formation is one
of the most important reactions to construct a carbon
skeleton in organic synthesis. The Baylis-Hillman reac-
tion is an atom economical carbon-carbon bond-forming
reaction leading to multifunctional derivatives.7 These
products have been utilized as building blocks for natural
products and biologically active compounds. This reaction
in general involves the coupling of the R-position of
electron-deficient alkenes with aldehydes in the presence
of a suitable catalyst (tertiary amine, tertiary phosphine,
or Lewis acid). However, as the typical Baylis-Hillman
reaction suffers from a slow reaction rate and limited
scope of substrates, most of the recent publications have
focused on these aspects.8 On the other hand, propenyl-
metal compounds have been of increasing interest in
organic synthesis. In particular, diastereoselective addi-
Since 3-substituted 3-hydroxy-â-lactams are important
substrates both for studies of biological activity and as
versatile building blocks for â-amino acid synthesis,
development of practical methods for their stereocon-
trolled preparation is of interest. The 3-substituted
3-hydroxy-â-lactam moiety represents an efficient car-
boxylate mimic,1 and it is present in several pharmaco-
logically active monobactams such as sulfazecin and
related products,2 and in enzyme inhibitors such as
tabtoxin and its analogues.3 In addition, these compounds
with correct absolute configurations serve as precursors
to the corresponding R-hydroxy-â-amino acids (iso-
serines), which are key components of a large number of
therapeutically important compounds. As an example,
(2R,3S)-3-amino-2-hydroxy-5-methylhexanoic acid (norsta-
tine) and (3R,4S)-4-amino-3-hydroxy-5-methylheptanoic
acid (statine) are residues for peptide inhibitors of
enzymes, such as renin4 and HIV-1 protease.5 Moreover,
phenylisoserine analogues are used to synthesize new
taxoids.6
(4) Thaisrivongs, S.; Pals, D. T.; Kroll, L. T.; Turner, S. R.; Han,
F.-S. J . Med. Chem. 1987, 30, 976.
(5) Huff, J . R. J . Med. Chem. 1991, 34, 2305.
(6) (a) Lucatelli, C.; Viton, F.; Gimbert, Y.; Greene, A. E. J . Org.
Chem. 2002, 67, 9468. (b) Ojima, I.; Wang, T.; Delaloge, F. Tetrahedron
Lett. 1998, 39, 3663. (c) Ojima, I.; Kuduk, S. D.; Pera, P.; Veith, J . M.;
Bernacki, R. J . J . Med. Chem. 1997, 40, 267.
(7) For reviews, see: (a) Basavaiah, D.; Rao, A. J .; Satyanarayana,
T. Chem. Rev. 2003, 103, 811. (b) Nyoung, K. J .; Young, L. K. Curr.
Org. Chem. 2002, 6, 627. (c) Langer, P. Angew. Chem., Int. Ed. Engl.
2000, 39, 3049. (d) Ciganek, E. Org. React. 1997, 51, 201. (e) Basavaiah,
D.; Rao, P. D.; Hyma, R. S. Tetrahedron 1996, 52, 8001.
(8) For selected recent references, see: (a) Basavaiah, D.; Rao, A.
J . Tetrahedron Lett. 2003, 44, 4365. (b) Basavaiah, D.; Rao, A. J . Chem.
Commun. 2003, 604. (c) Keck, G. E.; Welch, D. S. Org. Lett. 2002, 4,
3687. (d) Patra, A.; Batra, S.; J oshi, B. S.; Roy, R.; Kundu, B.; Bhaduri,
A. P. J . Org. Chem. 2002, 67, 5783. (e) Pei, W.; Wei, H.-X.; Li, G. Chem.
Commun. 2002, 2412. (f) Rose, P. M.; Clifford, A. A.; Rayner, C. M.
Chem. Commun. 2002, 968. (g) Aggarwal, V. K.; Dean, D. K.; Mereu,
A.; Williams, R. J . Org. Chem. 2002, 67, 510. (h) Cai, J .; Zhou, Z.; Zhao,
G.; Tang, C. Org. Lett. 2002, 4, 4723. (i) Yu, C.; Hu, L. J . Org. Chem.
2002, 67, 219.
* Corresponding author.
† Universidad Complutense de Madrid.
‡ Instituto de Qu´ımica Orga´nica General.
(1) (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.
(2) Imada, A.; Kitano, K.; Kintana, K.; Muroi, M.; Asai, M. Nature
1981, 289, 590.
(3) (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.
10.1021/jo035472l CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/13/2004
826
J . Org. Chem. 2004, 69, 826-831

Highly Functionalized 3-Substituted 3-Hydroxy-â-lactams
SCHEME 1
compounds has not been well documented. This situation
is mainly due to the fact that under normal conditions,
racemization of the carbonyl compound is observed after
prolongate exposure times to catalyst,15 or due to poor
diastereoselection.16 A model reaction of R-keto lactam
(+)-1a was carried out by sequentially adding 1.5 equiv
of methyl vinyl ketone and 1.0 equiv of azetidine-2,3-
dione to a dichloromethane solution of TiCl4 (2 equiv) at
-78 °C to give the Baylis-Hillman adduct (+)-2a in 40%
yield. Preliminary results encouraged us to screen other
catalysis for the above reaction for better yield. We were
pleased to find that use of DABCO under appropriate
conditions also gave (+)-2a with improved yield. Thus,
reaction of azetidine-2,3-dione (+)-1a (1 equiv) with
methyl vinyl ketone (10 equiv) in the presence of DABCO
(1 equiv) in acetonitrile at -20 °C for 1 h gave function-
alized allylic alcohol (+)-2a in good yield (80%) and
complete diastereoselectivity. However, when the reac-
tion was carried out at ambient temperature maintaining
the molar ratio of reagents (ketone/DABCO/alkene ) 1:1:
10), partial epimerization was observed. The volatility
of the reactant alkene facilitates its convenient removal
even when used in excess. Next, the effect of the amount
of catalyst (tertiary amine) on the conversion rate was
studied, finding that the process can be significantly
accelerated on increasing the amount of DABCO, without
detectable racemization. In terms of achieving good yields
with a reasonable rate of reaction, 50 mol % of DABCO
seemed to be the catalyst amount of choice for this
reaction. The effect of altering the reaction solvent
(acetonitrile, tetrahydrofuran, diethyl ether, or dichlo-
romethane) was then explored. There is not a significant
solvent effect in the observed yield, but enhancing solvent
polarity slightly improved the yield. Besides, the reaction
proceeded more quickly in polar solvents, with the best
yield and reaction rate obtained in acetonitrile, which
became the solvent of choice. Other alkenes and R-keto
lactams were screened for the Baylis-Hillman reaction.
Adducts 2a -k can be prepared as single diastereomers
by the DABCO-promoted reaction of various activated
vinyl systems with the appropriate azetidine-2,3-dione
1, and performing the experiment in acetonitrile at -20
°C (Table 1). The reaction with the cyclic ketone 2-cyclo-
penten-1-one took place after extended reaction time,
because of the difficulty of performing the Baylis-
Hillman reaction with â-substituted olefinic substrates
due to steric reasons.
tion of allylmetallic reagents to chiral aldehydes plays
an important role in stereoselective synthesis.9 In con-
trast, the analogous reaction involving bromoallylmetals
has been scarcely investigated,10 despite being able to
provide useful intermediates, the corresponding bromo-
homoallylic alcohols.11 Continuing with our work on the
asymmetric synthesis of nitrogenated compounds of
biological interest,12 we now report full details of the
Baylis-Hillman reaction of enantiopure azetidine-2,3-
diones,13 which resulted in the corresponding 3-function-
alized 3-hydroxy-â-lactams. In addition, a study on the
metal-mediated bromoallylation of these R-keto lactams
in aqueous media with use of 2,3-dibromopropene is also
described.
Resu lts a n d Discu ssion
Starting materials, azetidine-2,3-diones 1a -h , were
efficiently prepared in optically pure form from aromatic
or aliphatic (R)-2,3-O-isopropylideneglyceraldehyde-de-
rived imines, via Staudinger reaction with acetoxyacetyl
chloride in the presence of Et3N, followed by sequential
transesterification and Swern oxidation, as we previously
reported (Scheme 1).14
Surprisingly, so far the synthesis of Baylis-Hillman
adducts derived from chiral nonracemic R-amino carbonyl
(9) For recent reviews of allylmetal additions, see: (a) Denmark, S.
E.; Fu, J . Chem. Rev. 2003, 103, 2763. (b) Roush, W. R.; Chemler, C.
R. In Modern Carbonyl Chemistry; Otera, J ., Ed.; Wiley-VCH: Wein-
heim, Germany, 2000; Chapter 11. (c) Denmark, S. E.; Almstead, N.
G. In Modern Carbonyl Chemistry; Otera, J ., Ed.; Wiley-VCH: Wein-
heim, Germany, 2000; Chapter 10. (d) Thomas, E. J . Chem. Commun.
1997, 411. (e) Marshall, J . A. Chem. Rev. 1996, 96, 31. (f) Yamamoto,
Y.; Asao, N. Chem. Rev. 1993, 93, 2207.
(10) (a) Trost, B. M.; Coppola, B. P. J . Am. Chem. Soc. 1982, 104,
6879. (b) Mandai, T.; Nokami, J .; Yano, T.; Yoshinaga, Y.; Otera, J . J .
Org. Chem. 1984, 49, 172.
(11) See, for example: Trost, B. M.; Corte, J . R.; Gudiksen, M. S.
Angew. Chem., Int. Ed. 1999, 38, 3662.
Next, we decided to explore the Lewis acid-mediated
reaction of electron-deficient alkynes with azetidine-2,3-
diones 1 as an entry to â-halo Baylis-Hillman adducts.17
However, the reaction of R-keto lactam (+)-1a with but-
3-yn-2-one under a variety of conditions was not very
(12) See, for instance: (a) Alcaide, B.; Almendros, P.; Alonso, J . M.;
Aly, M. F. Chem. Eur. J . 2003, 9, 3415. (b) Alcaide, B.; Almendros, P.;
Pardo, C.; Rodr´ıguez-Ranera, C.; Rodr´ıguez-Vicente, A. J . Org. Chem.
2003, 68, 3106. (c) Alcaide, B.; Almendros, P.; Alonso, J . M.; Redondo,
M. C. J . Org. Chem. 2003, 68, 1426. (d) Alcaide, B.; Almendros, P.;
Aragoncillo, C. Chem. Eur. J . 2002, 8, 1719. (e) Alcaide, B.; Almendros,
P.; Aragoncillo, C.; Redondo, M. C. Chem. Commun. 2002, 1472. (f)
Alcaide, B.; Almendros, P.; Aragoncillo, C. Chem. Eur. J . 2002, 8, 3646.
(13) For the preliminary communication of a part of this work, see:
Alcaide, B.; Almendros, P.; Aragoncillo, C. Tetrahedron Lett. 1999, 40,
7537.
(15) Drewes, S. E.; Khan, A. A.; Rowland, K. Synth. Commun. 1993,
23, 183.
(16) (a) Iwabuchi, Y.; Sugihara, T.; Esumi, T.; Hatakeyama, S.
Tetrahedron Lett. 2001, 42, 7867. (b) Nayak, S. K.; Thijs, L.; Zwanen-
burg, B. Tetrahedron Lett. 1999, 40, 981. (c) Manickum, T.; Roos, G.
Synth. Commun. 1991, 21, 2269.
(17) This coupling is called the chalcogeno-Baylis-Hillman reaction.
For selected references, see: (a) Kinoshita, S.; Kinoshita, H.; Iwamura,
T.; Watanabe, S.-i.; Kataoka, T. Chem. Eur. J . 2003, 9, 1496. (b) Wei,
H.-X.; Chen, D.; Xu, X.; Li, G.; Pare´, P. W. Tetrahedron: Asymmetry
2003, 14, 971. (c) Wei, H.-X.; Gao, J . J .; Li, G.; Pare´, P. W. Tetrahedron
Lett. 2002, 43, 5677. (d) Li, G.; Wein, H.-X.; Phelps, B. S.; Purkiss, D.
W.; Kim, S. H. Org. Lett. 2001, 3, 823. (e) Kataoka, T.; Kinoshita, H.;
Kinoshita, S.; Iwamura, T.; Watanabe, S.-i. Angew. Chem., Int. Ed.
2000, 39, 2358.
(14) (a) Alcaide, B.; Almendros, P.; Aragoncillo, C.; Rodr´ıguez-
Acebes, R. J . Org. Chem. 2001, 66, 5208. For a review on the chemistry
of azetidine-2,3-diones, see: (b) Alcaide, B.; Almendros, P. Org. Prepr.
Proced. Int. 2001, 33, 315.
J . Org. Chem, Vol. 69, No. 3, 2004 827

Alcaide et al.
in many cases.18 On the other hand, two general protocols
are available for the carbonyl-allylation with use of
organic halides: the stepwise Grignard procedure where
the propenylmetal reagent is preformed and then added
to the carbonyl compound, or the in situ Barbier proce-
dure where the allylic organometallic species is formed
in the presence of the carbonyl. Since indium-mediated
allylation of aldehydes has attracted much interest
among organic chemists due to its compatibility with
many common organic functional groups and stability
under aqueous conditions,19 we decided to introduce the
halovinyl moiety on the â-lactam ring via indium-
promoted Barbier-type bromoallylation of azetidine-2,3-
diones in an aqueous environment.
TABLE 1. Ba ylis-Hillm a n Rea ction of En a n tiop u r e
Azetid in e-2,3-d ion es 1a
sub-
strate
catalyst
(mol %)
t
yield
R
EWG
(h)b productc (%)e
(+)-1a PMP
(+)-1a PMP
(+)-1a PMP
(+)-1a PMP
(+)-1a PMP
(+)-1a PMP
(+)-1a PMP
(+)-1a PMP
COMe TiCl4 (200)f
COMe DABCO (10)
COMe DABCO (20)
COMe DABCO (50)
COMe DABCO (100)
21 (+)-2a
72 (+)-2a
16 (+)-2a
40
80
80
80
80
90
87
69
69
47
73
68
70
54
40
2
1
(+)-2a
(+)-2a
Unfortunately, when the reaction of azetidine-2,3-dione
(+)-1a with 2,3-dibromopropene was conducted in the
presence of indium in aqueous tetrahydrofuran, the
corresponding bromoallylated product was not formed.
Next, using a standard protocol we screened different
metal mediators (zinc, tin, bismuth, and cadmium) but
no coupling product was observed. Since the incorpora-
tion of water-stable additives could improve both yield
and conversion rate, we explored further the metal-
promoted bromoallylation of azetidine-2,3-dione (+)-1a
in the presence of different Lewis or protic acids. Disap-
pointingly, indium was again unable to promote the
bromoallylation reaction of R-keto lactam (+)-1a even in
the presence of several additives. However, the addition
of ammonium chloride to the aqueous medium containing
zinc, 2,3-dibromopropene, and ketone (+)-1a was effec-
tive, achieving the bromohomoallylic alcohol (+)-4a in a
low 30% yield after several days of reaction. This
encouraging observation prompted us to investigate tin,
bismuth, and cadmium as promoters. When bismuth or
cadmium were used the reaction did not proceed at all.
To our delight, when the above reaction was mediated
by tin and was conducted in a saturated aqueous solution
of NH4Cl in THF at room temperature, it gave rise to
the optically pure bromohomoallyl alcohol (+)-4a as a
single diastereoisomer in a reasonable 73% yield after
26 h of reaction. The use of THF as cosolvent was
necessary to increase the solubility of both starting
material and product. The addition of indium(III) chlo-
ride, indium(III) triflate, hafnium(IV) chloride, hydro-
chloric acid, and hydrobromic acid to the aqueous media
of the tin-promoted bromoallylation reaction shortened
reaction times while retaining the same facial preference
(Table 2). The tin-mediated carbonyl bromoallylation of
azetidine-2,3-dione (+)-1a in water/tetrahydrofuran in
the presence of hydrobromic acid proceeded with con-
comitant acetonide cleavage, requiring an extra protec-
tion step with 2,2-dimethoxypropane to afford the product
(+)-4a . From these results, we chose the Sn-Hf4Cl-
promoted bromoallylation in our study with different
substituted azetidine-2,3-diones 1. Good or excellent
yields (74-98%) were obtained in the metal-mediated
CN
DABCO (50)
24 (+)-2bd
CO2Me DABCO (50)
SO2Ph DABCO (50)
3
(-)-2c
30 (+)-2d
(-)-1b 2-propenyl COMe DABCO (50)
(-)-1c 3-butenyl COMe DABCO (50)
(+)-1d 4-pentenyl COMe DABCO (50)
(+)-1e 2-propynyl COMe DABCO (50)
(-)-1f 3-butynyl COMe DABCO (50)
(+)-1g 4-pentynyl COMe DABCO (50)
2 (-)-2e
12 (+)-2f
12 (+)-2g
5
2
9
(+)-2h
(+)-2i
(+)-2j
(+)-1a PMP
g
DABCO (50) 168 (+)-2k
a
b
PMP ) 4-MeOC6H4. Reaction progress was followed by TLC
but could also be noted by the disappearance of the yellow color
of the appropriate azetidine-2,3-dione. c Analysis of the 1H NMR
spectra (300 MHz) of the crude reaction mixtures revealed
d
compounds 2 as the only detected isomer. A 97:3 diastereomeric
ratio was determined by integration of well-resolved signals in the
1H NMR spectra (300 MHz) of the crude reaction mixture before
purification. Thus, one of the vinylic hydrogens for the major
isomer appeared as a singlet at δ 6.41 ppm, while the correspond-
ing vinylic hydrogen for the minor isomer appeared as a singlet
at δ 6.46 ppm. e Yield of pure, isolated product with correct
analytical and spectral data. f This experiment was carried out
g
in dichloromethane at -78 °C. Compound (+)-2k was prepared
with 2-cyclopenten-1-one.
SCHEME 2
successful. In the end, the coupling product (-)-3 was
achieved with concomitant acetonide cleavage as a single
E-isomer in low yield, in the presence of trimethylsilyl
iodide under BF3‚Et2O-induced catalysis (Scheme 2). The
mechanism for the formation of the E-isomer is believed
to involve an allenolate species, which is formed by the
addition of an iodide ion to the ynone.
The appealing properties of organometallic reactions
in aqueous media include their synthetic 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 converted into their
derivatives and can be reacted directly), its potential as
an environmentally benign chemical process (the use of
anhydrous flammable solvents can be avoided and the
burden of solvent disposal may be reduced), as well as a
unique reactivity and selectivity that are not often
attained under dry conditions, making them profitable
(18) For recents reviews on organic reactions in aqueous media,
see: (a) Lindstro¨m, U. M. Chem. Rev. 2002, 102, 2751. (b) Manabe,
K.; Kobayashi, S. Chem. Eur. J . 2002, 8, 4095. (c) Ribe, S.; Wipf, P.
Chem. Commun. 2001, 299. (d) Li, C. J .; Chan, T. H. Tetrahedron 1999,
55, 11149. (e) Lubineau, A.; Auge´, J . Top. Curr. Chem. 1999, 206, 1.
(f) 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.
(19) Synthesis 2003, issue 5, Special Topic, Carreira, E. M., Ed.
828 J . Org. Chem., Vol. 69, No. 3, 2004

Highly Functionalized 3-Substituted 3-Hydroxy-â-lactams
TABLE 2. Br om oa llyla tion Rea ction of En a n tiop u r e
Azetid in e-2,3-d ion es 1a
F IGURE 1. Model to explain the observed stereochemistry
by delivery of the nucleophile to the less hindered face.
sub-
strate
t
yield
R
metal additive (h)b productc (%)d
(+)-1a PMP
In
NH4Cl
NH4Cl
NH4Cl
InCl3
In(OTf)3
HfCl4
HCl
72
96
26
3
6
2
2
2
4
4
is probably due to the smaller difference in steric demand
between the two substituents on the carbonyl carbon,
which leads to the stereoselection, in ketones than in
aldehydes. On azetidine-2,3-diones 1, the full stereocon-
trol was achieved due to the presence of a bulky chiral
group at C4, which was able to control the stereochem-
istry of the new C3-substituted C3-hydroxy quaternary
center. One face of the carbonyl group is blocked prefer-
entially, thus the nucleophile species is delivered to the
less hindered face, and as a consequence the diastereo-
selectivity was complete in all cases (Figure 1).
(+)-1a PMP
Zn
Sn
Sn
Sn
Sn
Sn
Sn
Sn
Sn
Sn
Sn
(+)-4a
(+)-4a
(+)-4a
(+)-4a
(+)-4a
(+)-4a
(+)-4a
(-)-4b
(+)-4c
(-)-4d
(+)-4e
30
73
64
75
85
48
50
80
74
92
98
(+)-1a PMP
(+)-1a PMP
(+)-1a PMP
(+)-1a PMP
(+)-1a PMP
(+)-1a PMP
HBr
(-)-1b 2-propenyl
(-)-1c 3-butenyl
(+)-1e 2-propynyl
HfCl4
HfCl4
HfCl4
HfCl4
4
3
(-)-1f
3-butynyl
a
b
PMP ) 4-MeOC6H4. Reaction progress was followed by TLC
but could also be noted by the disappearance of the yellow color
of the appropriate azetidine-2,3-dione. c Analysis of the 1H NMR
spectra (300 MHz) of the crude reaction mixtures before purifica-
Con clu sion s
d
tion revealed compounds 4 as the only detected isomer. Yield of
In conclusion, we have achieved an efficient DABCO-
promoted Baylis-Hillman reaction of enantiopure aze-
tidine-2,3-diones, which proceeded with full stereocontrol.
In addition, a metal-mediated procedure for the bromoal-
lylation reaction of optically pure R-keto lactams in
aqueous media has been developed. The simple reaction
protocols for achieving the functionalized adducts, in
combination with the chemical and biological interest of
the 3-substituted 3-hydroxy-â-lactam moiety, makes
these processes very appealing.
pure, isolated product with correct analytical and spectral data.
The yield with hydrobromic acid as additive refers to the overall
yield after the diol protection step with 2,2-dimethoxypropane.
bromoallylation reaction of different N-substituted R-keto-
lactams 1 (Table 2). The formation of these bromo-
homoallylic alcohols can be easily followed by the varia-
tion of coloration of the reaction. Usually, the color of the
mixtures containing azetidine-2,3-diones is bright yellow.
In the present bromoallylation reaction, the color became
pale as the reaction proceeded, and finally turned color-
less.
Exp er im en ta l Section
In the dilute acidic medium provided by the presence
of hydrochloric or hydrobromic acids, protonation of the
carbonyl occurs, facilitating the addition process by the
nucleophile. It is presumed that the ionic strength
enhancement of the reaction solvent provided by the
ammonium chloride accelerated the process.20 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 both the carbonyl group
as well as the softness of these reagents. A transmeta-
lation of the initially formed allylmetal with indium(III)
chloride, indium(III) triflate, or hafnium(IV) chloride as
Lewis acids may be involved.21
Gen er a l. General experimental data and procedures have
been previously reported.12 1H NMR and 13C NMR spectra
were recorded at 300 or 75 MHz, respectively. NMR spectra
were recorded in CDCl3 solutions, except where 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 com-
pounds were used without further purification.
Gen er a l P r oced u r e for th e TiCl4-P r om oted Ba ylis-
Hillm a n Rea ction . A solution of titanium(IV) chloride (2.0
mmol, 1.0 M solution in CH2Cl2) in dichloromethane (4.3 mL)
was added dropwise to a stirred solution of the appropriate
azetidine-2,3-dione 1 (1.5 mmol) in dichloromethane (5.0 mL)
at -78 °C. After 5 min, a solution of the corresponding
activated olefin (2.0 mmol) in dichloromethane (2 mL) was
added dropwise, and the mixture was stirred at -78 °C until
complete disappearance of the R-keto-â-lactam (TLC). Satu-
rated aqueous sodium hydrogen carbonate (5 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 eluting with ethyl acetate/hexane mixtures gave
analytically pure compounds 2.
The stereochemistry at the C3-heterosubstituted qua-
ternary center for compounds 2, 3, and 4 was assigned
by qualitative homonuclear NOE difference spectra. The
stereoselective reaction of carbon nucleophiles with ke-
tones instead of aldehydes has been less reported. This
(20) Modification in the diastereomeric ratio or acceleration of the
process has been reported on changing the ionic strength of the solvent
in the allylation of enantiopure 2-aminoaldehydes: (a) Chappell, M.
D.; Halcomb, R. L. Org. Lett 2000, 2, 2003. In a recent paper on the
allylation of mucohalic acids, it has been suggested that the role NH4-
Cl plays is perhaps 2-fold: (1) to activate the carbonyl group and (2)
to polish the metal surface. See: Zhang, J .; Blazecka, P. G.; Berven,
H.; Belmont, D. Tetrahedron Lett. 2003, 44, 5579.
Gen er a l P r oced u r e for th e DABCO-P r om oted Ba ylis-
Hillm a n Rea ction . Syn th esis of Com p ou n d s 2a -k . A
solution of the appropriate azetidine-2,3-dione 1 (0.20 mmol)
in acetonitrile (2 mL) was added dropwise to a stirred solution
of DABCO (11.2 mg, 0.10 mmol) in acetonitrile (2 mL) at -20
(21) For an allyltin-indium trichloride transmetalation, see: Li, X.-
R.; Loh, T.-P. Tetrahedron: Asymmetry 1996, 7, 1996.
J . Org. Chem, Vol. 69, No. 3, 2004 829

Alcaide et al.
°C. After 5 min, the corresponding activated olefin (2.00 mmol)
was added at -20 °C and the reaction mixture was placed in
a -20 °C freezer until complete disappearance of the ketone
(TLC). The mixture was concentrated under reduced pressure.
Chromatography of the residue eluting with hexanes/ethyl
acetate mixtures gave analytically pure compounds 2. Spec-
troscopic and analytical data for some representative forms
of 2 follow.22
1a (291 mg, 1.0 mmol), tin powder (178 mg, 1.5 mmol), and
48% HBr (0.2 mmol) in THF/H2O (1:1, 10 mL) at room
temperature. After 1.5 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 (4 × 10 mL). The organic extract was
washed with brine, dried (MgSO4), and concentrated under
reduced pressure. The crude diol was dissolved in 2,2-
dimethoxypropane (5 mL) and PPTS (25 mg, 0.1 mmol) was
added. The reaction was stirred at room temperature for 16 h
before being concentrated under reduced pressure. Chroma-
tography of the residue with ethyl acetate/hexanes (1:2) as an
eluent gave 206 mg (50%) of compound (+)-4a . Anal. Calcd
for C18H22NO5Br: C, 52.44; H, 5.38; N, 3.40. Found: C, 52.56;
H, 5.36; N, 3.41.
(3R,4S)-3-(1-Acet ylvin yl)-4-[(S)-2,2-d im et h yl-1,3-d iox-
ola n -4-yl]-3-h yd r oxy-1-(p -m et h oxyp h en yl)-2-a zet id in o-
n e, (+)-2a . From 220 mg (0.75 mmol) of azetidine-2,3-dione
(+)-1a and after 1 h at -20 °C was obtained 207 mg (80%) of
compound (+)-2a as a pale yellow solid after purification by
flash chromatography (hexanes/ethyl acetate, 1/1). Mp 155-
1
157 °C (hexanes/ethyl acetate). [R]D +120.1 (c 1.0, CHCl3). H
NMR: δ 1.34 and 1.43 (s, each 3H), 2.40 (s, 3H), 3.79 (s, 3H),
3.81 (dd, 1H, J ) 8.8, 6.6 Hz), 4.09 (d, 1H, J ) 7.1 Hz), 4.26
(dd, 1H, J ) 8.8, 6.6 Hz), 4.58 (q, 1H, J ) 6.6 Hz), 4.96 (br s,
1H), 5.96 (s, 1H), 6.30 (s, 1H), 6.87 and 7.58 (d, each 2H, J )
9.0 Hz). 13C NMR: δ 199.3, 166.4, 156.8, 145.0, 130.9, 129.4,
120.4, 114.1, 109.7, 83.9, 76.3, 67.1, 66.4, 55.4, 26.6, 26.5, 25.1.
Tin -P r om oted Rea ction betw een 2,3-Dibr om op r op en 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. 2,3-Dibromopropene (600 mg, 3 mmol)
was added to a well-stirred suspension of the R-keto lactam
(+)-1a (291 mg, 1.0 mmol) and tin powder (178 mg, 1.5 mmol)
in THF/NH4Cl (aq satd) (1:5, 10 mL) at room temperature.
After 26 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 × 10 mL). The organic extract was washed with brine, dried
(MgSO4), and concentrated under reduced pressure. Chroma-
tography of the residue with ethyl acetate/hexanes (1:2) as an
eluent gave 301 mg (73%) of compound (+)-4a . Anal. Calcd
for C18H22NO5Br: C, 52.44; H, 5.38; N, 3.40. Found: C, 52.34;
H, 5.41; N, 3.42.
Tin -P r om oted Rea ction betw een 2,3-Dibr om op r op en 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 In Cl3. 2,3-Dibromopropene (600 mg, 3 mmol) was
added to a well-stirred suspension of the R-keto lactam (+)-
1a (291 mg, 1.0 mmol), tin powder (178 mg, 1.5 mmol), and
indium(III) chloride (44 mg, 0.2 mmol) in THF/H2O (1:1, 10
mL) at room temperature. After 3 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 (4 × 10 mL). The organic
extract was washed with brine, dried (MgSO4), and concen-
trated under reduced pressure. Chromatography of the residue
with ethyl acetate/hexanes (1:2) as an eluent gave 264 mg
(64%) of compound (+)-4a . Anal. Calcd for C18H22NO5Br: C,
52.44; H, 5.38; N, 3.40. Found: C, 52.34; H, 5.36; N, 3.42.
Tin -P r om oted Rea ction betw een 2,3-Dibr om op r op en 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 In (OTf)3. 2,3-Dibromopropene (600 mg, 3 mmol)
was added to a well-stirred suspension of the R-keto lactam
(+)-1a (291 mg, 1.0 mmol), tin powder (178 mg, 1.5 mmol),
and indium(III) triflate (112 mg, 0.2 mmol) in THF/H2O (1:1,
10 mL) at room temperature. After 6 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 (4 × 10 mL). The organic
extract was washed with brine, dried (MgSO4), and concen-
trated under reduced pressure. Chromatography of the residue
with ethyl acetate/hexanes (1:2) as an eluent gave 309 mg
(75%) of compound (+)-4a . Anal. Calcd for C18H22NO5Br: C,
52.44; H, 5.38; N, 3.40. Found: C, 52.35; H, 5.43; N, 3.38.
In d iu m -P r om oted Rea ction betw een 2,3-Dibr om op r o-
p en 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 HfCl4. Gen er a l P r oced u r e for th e Syn th esis
of Br om oh om oa llylic Alcoh ols 4. 2,3-Dibromopropene (600
mg, 3 mmol) was added to a well-stirred suspension of the
appropriate R-keto lactam 1 (1.0 mmol), tin powder (178 mg,
1.5 mmol), and hafnium(IV) chloride (64 mg, 0.2 mmol) in
THF/H2O (1:1, 10 mL) at room temperature. After dissappear-
ance of the starting material (TLC), 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 × 10 mL). The organic
IR (KBr, cm-1): ν 3431, 1738, 1676. MS (CI), m/z: 362 (M+
+
1, 100), 361 (M+, 5). Anal. Calcd for C19H23NO6: C, 63.15; H,
6.42; N, 3.88. Found: C, 63.01; H, 6.64; N, 4.11.
P r oced u r e for th e Syn th esis of th e â-Ha lo Ba ylis-
Hillm a n Ad d u ct (-)-3. Trimethylsilyl iodide (31 µL, 0.225
mmol) was added to a stirred solution of 4-butyn-2-one (12 µL,
0.243 mmol) in dichloromethane (1.0 mL) at -78 °C. After 1
h, boron trifluoride diethyl etherate (28 µL, 0.225 mmol) and
a solution of the R-keto-â-lactam (+)-1a (50 mg, 0.172 mmol)
in dichloromethane (1.5 mL) were sequentially added dropwise
at -78 °C. Saturated aqueous sodium hydrogen carbonate (3
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 eluting with ethyl acetate/hexanes (1:1
containing 1% of methanol) gave 28 mg (33%) of analytically
pure compound (-)-3 as a colorless oil.
(3R,4S)-3-(1-Acetyliodovin yl)-4-[(S)-1,2-dih ydr oxyeth yl]-
3-h yd r oxy-1-(p-m eth oxyp h en yl)-2-a zetid in on e, (-)-3. [R]D
1
-29.4 (c 1.1, CHCl3). H NMR: δ 2.05 (s, 3H), 3.78 (d, 1H, J
) 9.0 Hz), 3.84 (s, 3H), 4.30 (m, 4H), 4.71 (d, 1H, J ) 9.3 Hz),
4.98 (d, 1H, J ) 12.2 Hz), 6.95 and 7.29 (d, each 2H, J ) 9.0
Hz), 7.76 (d, 1H, J ) 12.7 Hz). 13C NMR: δ 198.0, 171.2, 159.8,
154.5, 129.6, 118.7, 115.3, 114.8, 100.9, 77.3, 70.1, 68.6, 55.6,
31.0. IR (CHCl3, cm-1): ν 3440, 1738, 1680. MS (CI), m/z: 447
(M+, 100). Anal. Calcd for C16H18INO6: C, 42.97; H, 4.06; N,
3.13. Found: C, 43.06; H, 4.03; N, 3.10.
Tin -P r om oted Rea ction betw een 2,3-Dibr om op r op en 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 HCl. 2,3-Dibromopropene (600 mg, 3 mmol) was
added to a well-stirred suspension of the R-keto lactam (+)-
1a (291 mg, 1.0 mmol), tin powder (178 mg, 1.5 mmol), and
35% HCl (0.2 mmol) in THF/H2O (1:1, 10 mL) at room
temperature. After 1.5 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 × 10 mL). The organic extract was
washed with brine, dried (MgSO4), and concentrated under
reduced pressure. Chromatography of the residue with ethyl
acetate/hexanes (1:2) as an eluent gave 198 mg (48%) of
compound (+)-4a . Anal. Calcd for C18H22NO5Br: C, 52.44; H,
5.38; N, 3.40. Found: C, 52.55; H, 5.41; N, 3.38.
Tin -P r om oted Rea ction betw een 2,3-Dibr om op r op en 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 HBr . 2,3-Dibromopropene (600 mg, 3 mmol) was
added to a well-stirred suspension of the R-keto lactam (+)-
(22) Full spectroscopic and analytical data for compounds not
included in this Experimental Section are described in the Supporting
Information.
830 J . Org. Chem., Vol. 69, No. 3, 2004

Highly Functionalized 3-Substituted 3-Hydroxy-â-lactams
extract was washed with brine, dried (MgSO4), and concen-
trated under reduced pressure. Chromatography of the residue
eluting with hexanes/ethyl acetate mixtures gave analytically
pure compounds 4. Spectroscopic and analytical data for some
representative forms of 4 follow.
82.8, 76.0, 66.4, 64.8, 55.3, 45.9, 26.2, 25.2. IR (CHCl3, cm-1):
ν 3428, 1740. MS (EI), m/z 413 (M+ + 2, 100), 411 (M+, 98).
Anal. Calcd for C18H22NO5Br: C, 52.44; H, 5.38; N, 3.40.
Found: C, 52.34; H, 5.34; N, 3.36.
(3R,4S)-3-(2-Br om o-a llyl)-4-[(S)-2,2-d im eth yl-1,3-d iox-
ola n -4-yl]-3-h yd r oxy-1-(p -m et h oxyp h en yl)-2-a zet id in o-
n e, (+)-4a . From 61 mg (0.21 mmol) of azetidine-2,3-dione (+)-
1a was obtained 73 mg (85%) of compound (+)-4a as a colorless
oil after purification by flash chromatography (hexanes/ethyl
Ack n ow led gm en t. We would like to thank the DGI-
MCYT (Project BQU2003-07793-C02-01) for financial
support. C.A. and R.R.-A. thank the CAM and MCYT,
respectively, for predoctoral grants.
1
acetate, 2/1). [R]D +92.4 (c 1.0, CHCl3). H NMR: δ 1.37 and
Su p p or tin g In for m a tion Ava ila ble: Compound charac-
terization data and experimental procedures for compounds
1a -h , 2b-k , and 4b-e. This material is available free of
charge via the Internet at http://pubs.acs.org.
1.44 (s, each 3H), 2.96 and 3.15 (d, each 1H, J ) 14.7 Hz),
3.80 (s, 3H), 3.93 (dd, 1H, J ) 8.9, 6.5 Hz), 4.26 (dd, 1H, J )
9.0, 6.1 Hz), 4.52 (m, 2H), 5.69 (d, 1H, J ) 1.7 Hz), 5.87 (d,
1H, J ) 1.9 Hz), 6.87 and 7.53 (d, each 2H, J ) 9.0 Hz). 13C
NMR: δ 167.6, 156.7, 130.3, 125.0, 122.6, 120.1, 114.0, 109.7,
J O035472L
J . Org. Chem, Vol. 69, No. 3, 2004 831