Metal-assisted synthesis of enantiopure spirocyclic β-lactams from azetidine-2,3-diones

Article abstract of DOI:10.1016/j.tetlet.2004.06.130

A novel approach to enantiopure spirocyclic β-lactams has been developed by using different intramolecular metal-catalyzed cyclization reactions in monocyclic unsaturated alcohols. A novel approach to enantiopure spirocyclic β-lactams has been developed b

Full text of DOI:10.1016/j.tetlet.2004.06.130

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 6429–6431
Metal-assisted synthesis of enantiopure spirocyclic b-lactams from
azetidine-2,3-diones
b,
a,b
Benito Alcaide,a, Pedro Almendros, Teresa Martınez-del Campo and
*
*
´
a
´
Raquel Rodrıguez-Acebes
a
´
´
´
Departamento de Quımica Organica I, Facultad de Ciencias Quımicas, Universidad Complutense de Madrid, 28040-Madrid, Spain
b
´ ´
Instituto de Quımica Organica General, CSIC, Juan de la Cierva 3, 28006-Madrid, Spain
Received 17 May 2004; revised 17 June 2004; accepted 30 June 2004
Available online 19 July 2004
Abstract—A novel approach to enantiopure spirocyclic b-lactams has been developed by using different intramolecular metal-cat-
alyzed cyclization reactions in monocyclic unsaturated alcohols. The access to cyclization precursors, 2-azetidinone-tethered homo-
allylic alcohols, (buta-1,3-dien-2-yl)methanols, and a-allenols was achieved by regio and stereoselective addition of stabilized
organo-indium reagents to azetidine-2,3-diones in aqueous environment.
ꢀ 2004 Elsevier Ltd. All rights reserved.
The importance of b-lactam antibiotics for the treatment
of bacterial infections is well documented.1 Besides, the
ever-growing new applications of 2-azetidinones in fields
ranging from enzyme inhibition2 to the use of these
products as starting materials to develop new synthetic
methodologies,3 has triggered a renewed interest in the
building of new b-lactam systems. In particular, spirocy-
clic b-lactams behave as b-turn mimetics,4 as well as
cholesterol absorption inhibitor,5 they are precursors
of a,a-disubstituted b-amino acids,6 and the spiranic
b-lactam moiety is present in chartellines, a family of
marine natural products.7
contribution we wish to connect the chemistry of
unsaturated alcohols with catalytic cyclization reactions
for the synthesis of enantiopure spirocyclic b-lactams
from azetidine-2,3-diones.
Starting substrates, enantiopure azetidine-2,3-diones
(+)-1a and (+)-1b, were prepared from the correspond-
ing
(R)-2,3-O-isopropylideneglyceraldehyde-derived
imine, via Staudinger reaction with acetoxyacetyl chlo-
ride in the presence of Et3N, followed by sequential
transesterification and Swern oxidation.10 Homoallyl
alcohol (+)-2, (buta-1,3-dien-2-yl) alcohol (+)-3, and a-
allenyl alcohols (+)-4a–d were regiospecifically prepared
through metal-mediated Barbier-type carbonyl-allyla-
tion, -1,3-butadien-2-ylation, or -allenylation reactions
of a-keto lactams 1 in aqueous media, using our meth-
odologies (Scheme 1).10 Ring-closing metathesis
(RCM) is one of the most powerful and reliable ap-
proaches to construct a ring system.11 Indeed, transfor-
mation of alcohols 2 and 3 in diolefin precursors
followed by RCM proved to be a straightforward access
to spirocyclic b-lactams containing five- or six-mem-
bered oxacycles (Scheme 2). Of interest was the exposure
of the triene derived from the butadienol (+)-3 to Grub-
bsÕ catalyst. As expected from the literature precedent,12
only the least substituted double bond of the 1,3-diene
system reacted, to give the six-membered spiro com-
pound (+)-8, which bears an exocyclic methylene. No
traces of the five-membered regioisomer (+)-7 could be
detected.
Until now, relatively few efforts have been devoted to
the synthesis of spiro b-lactams. Besides, all these syn-
theses were exclusively performed via cycloaddition
reactions, mainly involving the ketene–imine cycloaddi-
tion.8 The highly selective properties of metals would
seem to recommend their application to the preparation
of spirocycles. Consequently, as an alternative to the
existing cycloaddition strategies, we thought in using
metal-containing reagents for developing a novel and
versatile entry to diversely functionalized spiranic-2-aze-
tidinones. Based on our previous experience on the syn-
thesis and synthetic applications of b-lactams,9 in this
Keywords: b-lactams; Metals; Oxacycles; Spirocycles.
*
Corresponding authors. Tel.: +34-91394-4314; fax: +34-91394-
4103; e-mail addresses: alcaideb@quim.ucm.es; iqoa392@iqog.csic.es
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.06.130

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B. Alcaide et al. / Tetrahedron Letters 45 (2004) 6429–6431
OH
R3
R2
R1
OH
O
O
OH
O
H
N
OH
i)
O
O
O
O
In/NH4Cl
THF/H2O
N
N
R3
Br
+
O
O
R1
N
PMP
O
PMP
(+)-4a, R1 = PMP, R2 = Me
(+)-4d, R1 = Bn, R2 = Ph
(–)-9a (100%)
(–)-9b (100%)
(+)-2 (73%)
(+)-1a
R3
OH
O
O
O
H
R2
R2
R1
OH
ii)
O
O
O
O
O
R3
N
In
N
R1
O
+
+
O
N
N
Br
Br
THF/H2O
PMP
PMP
O
(+)-4a, R1 = PMP, R2 = Me
(+)-4b, R1 = PMP, R2 = Ph
(+)-10a (85%)
(+)-10b (100%)
)
(+)-1a
+)-3 (54%)
Me
Me
O
R2
R2
R2
R2
OH
O
O
O
Ph
H
N
OH
O
O
O
iii)
+
In/NH4Cl
THF/H2O
NHPMP
OH
R2
Ph
N
N
Me
N
O
O
PMP
O
PMP
R1
Br
O
R1
(–)-11 (33%)
(+)-12 (12%)
(+)-4a
(+)-4a, R1 = PMP, R2 = Me (74%)
(+)-4b, R1 = PMP, R2 = Ph (76%)
(+)-4c, R1 = Bn, R2 = Me (94%)
(+)-4d, R1 = Bn, R2 = Ph (98%)
(+)-1a, R1 = PMP
(+)-1b, R1 = Bn
Scheme 3. Key: R2 =[(S)-2,2-dimethyl-1,3-dioxalan-4-yl]. Reagents
and conditions: (i) AgNO3 (1equiv), acetone–H2O (1:1), reflux, 9a:
3h, 9b: 6h; (ii) allyl bromide (5equiv), 5 mol% PdCl2, DMF, rt, 10a:
2h; (iii) PhI (1:1equiv), 5mol% Pd(PPh3)4, K2CO3 (4equiv), DMF,
85ꢁC, 45h.
Scheme 1.
X
mation of epoxide (À)-11 involves concomitant ring
opening of the b-lactam nucleus, probably because of
the ring strain of the intermediate spirocyclic oxirane-
b-lactam, which cannot survive under the reactions con-
ditions.
OH
O
R
O
R
R
iv)
iii)
i) or ii)
N
N
N
iii)
O
PMP
O
PMP
O
PMP
(+)-2
(+)-6 (40%)
(+)-5a, X = H2 (76%)
(+)-5b, X = O (60%)
In conclusion, a novel entry to enantiopure diversely
functionalized spiranic b-lactams has been developed
by using intramolecular metal-promoted cyclization
reactions in monocyclic homoallylic alcohols, (buta-
1,3-dien-2-yl)methanols, and a-allenols. The ring-clos-
ing metathesis of diolefin derivatives of the above alcoh-
ols proved to be a straightforward access to spirocyclic
b-lactams containing five- or six-membered oxacycles.
The metal-based cyclization reactions of the b-lactam-
tethered a-allenic alcohols constitute a versatile entry
to spiranic dihydrofuran- b-lactam derivatives. These re-
sults open up the possibility of future application to chi-
ral building blocks other than 2-azetidinones. Other
aspects of this chemistry are currently under investiga-
tion in our laboratory.
O
OH
O
R
R
R
i)
iii)
X
N
N
N
O
PMP
O
PMP
O
PMP
(+)-7
(+)-3
(+)-8 (40%)
Scheme 2. Key: R=[(S)-2,2-dimethyl-1,2-dioxalan-4-yl]. Reagents and
conditions: (i) allyl bromide (1.6equiv), TBAI (cat), NaOH (aq 50%)–
DCM (1:1), rt, 16h; (ii) acryloyl chloride (2equiv), HNa (2equiv),
THF, from 0ꢁC to rt, 16h; (iii) 5mol% Cl2(Cy3P)2Ru@CHPh, toluene,
reflux, 5a: 7h, 5b: 33h, 6: 1 6h,8: 12h; (iv) methyl propiolate
(1.2equiv), Et3N (2equiv), DCM, 0ꢁC, 30min.
Considering that allenes bearing a nucleophilic center
can be cyclized on treatment with a wide variety of tran-
sition metal catalysts,13 we turned our attention to me-
tal-based cyclization reactions in our b-lactam-tethered
a-allenic alcohols 4. Our initial work began with the sil-
ver-induced reaction of a-allenols (+)-4a and (+)-4d, to
give, with concomitant acetonide cleavage, the spirocy-
clic dihydrofurans (À)-9a and (À)-9b in quantitative
yields. Next, we explored the palladium-catalyzed cycliz-
ative coupling reaction of a-allenols (+)-4a and (+)-4b
with unsaturated organic halides. Under optimized con-
ditions, allyl bromide efficiently gave the disubstituted
spiro dihydrofuran-b-lactams (+)-10a and (+)-10b,14
while phenyl iodide afforded as main product the oxira-
ne b-amino acid (À)-11, together with the regioisomeric
spiranic five-membered ring (+)-12 (Scheme 3). The for-
Acknowledgements
Support for this work by the DGI-MCYT (Project
BQU2003-07793-C02-01) is gratefully acknowledged.
R.R.-A. thanks the MCYT for a predoctoral grant.
T.M.-C. thanks the UCM and CSIC, for studentships
´
´
(Ôbeca de colaboracionÕ and Ôbeca de introduccion a la
´
investigacionÕ, respectively).
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14. Representative experimental procedure for the synthesis of
enantiopure spirocyclic b-lactams. General procedure for
the palladium-catalyzed coupling reaction of a-allenols 4
with allyl bromide. Palladium(II) chloride (0.005mmol)
was added to a stirred solution of the corresponding a-
allenol 4 (0.10mmol) in N,N-dimethylformamide (0.6mL).
The reaction mixture was stirred under argon atmosphere
until disappearance of the starting material (TLC). Water
(0.5mL) was added before being extracted with ethyl
acetate (3·4mL). The organic phase was washed with
water (2·2mL), dried (MgSO4) and concentrated under
reduced pressure. Chromatography of the residue eluting
with hexanes/ethyl acetate mixtures gave analytically pure
spiranic 2-azetidinones 10. Selected data: Spiranic di-
hydrofuran-b-lactam (+)-10a. From 64mg (0.186mmol) of
the a-allenol (+)-4a, compound (+)-10a (61mg, 85%) was
´
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1
obtained as a colorless oil. [a]D +21.08 (c 0.8, CHCl3). H
NMR (CDCl3): d 7.73 and 6.89 (d, each 2H, J=9.3Hz),
5.75 (m, 1H), 5.12 (dq, 1H, J=6.8, 1.5Hz), 5.05 (q, 1H,
J=0.7Hz), 4.74 and 4.56 (dd, each 1H, J=12.7, 2.0Hz),
4.45 (m, 1H), 4.25 (dd, 1H, J= 8.5, 7.1Hz), 4.08 (d, 1H,
J=8.5Hz), 3.81(s, 3H), 3.53 (dd, 1H, J=8.8, 6.1Hz), 2.92
(m, 2H), 1.65 (t, 3H, J=2.0Hz), 1.54 and 1.34 (s, each
3H). 13C NMR (CDCl3): d 166.2, 156.5, 134.6, 133.6,
131.0, 125.4, 119.7, 116.7, 114.0, 109.8, 101.2, 78.3, 77.4,
66.6, 66.5, 55.4, 29.6, 26.6, 24.6, 8.5. IR (CHCl3, cmÀ1): m
1747. MS (EI), m/z: 386 (M++1, 22), 385 (M+, 6), 149
(100). (Anal. Calcd for C22H27NO5: C, 68.55; H, 7.06; N,
3.63. Found: C, 68.66; H, 7.01; N, 3.65).
9. See, for instance: (a) Alcaide, B.; Almendros, P.; Alonso,
J. M. J. Org. Chem. 2004, 69, 993; (b) Alcaide, B.;