Divergent reactivity of 2-azetidinone-tethered allenols with electrophilic reagents: Controlled ring expansion versus spirocyclization

Article abstract of DOI:10.1002/adsc.200900864

A dual reactivity of 2-azetidinone-tethered allenols may occur by judicious choice of the electrophilic reagents, namely halogenating versus selenating reagents. Using common substrates, structurally different compounds, namely tetramic acids (from N-bromosuccinimide) or spirocyclic seleno-ss-lactams (from N-phenylselenophthalimide), can be readily synthesized by these divergent protocols.

Full text of DOI:10.1002/adsc.200900864

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DOI: 10.1002/adsc.200900864
Divergent Reactivity of 2-Azetidinone-Tethered Allenols with
Electrophilic Reagents: Controlled Ring Expansion versus
Spirocyclization
Benito Alcaide,a,* Pedro Almendros,b,* Amparo Luna,a and M. Rosario Torresc
a
Grupo de Lactamas y Heterociclos Bioactivos, Departamento de Quꢀmica Orgꢁnica I, Unidad Asociada al CSIC, Facultad
de Quꢀmica, Universidad Complutense de Madrid, 28040 Madrid, Spain
Fax : (+34)-91-394-4103; e-mail: alcaideb@quim.ucm.es
Instituto de Quꢀmica Orgꢁnica General, Consejo Superior de Investigaciones Cientꢀficas, CSIC, Juan de la Cierva 3, 28006
b
Madrid, Spain
Fax : (+34)-91-564-4853; e-mail: Palmendros@iqog.csic.es
CAI Difracciꢂn de Rayos X, Facultad de Quꢀmica, Universidad Complutense de Madrid, 28040 Madrid, Spain
c
Received: December 14, 2009; Published online: March 4, 2010
Dedicated to Prof. Dr. Antonio Garcꢀa Martꢀnez on the occasion of his retirement.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900864.
Abstract: A dual reactivity of 2-azetidinone-teth-
ered allenols may occur by judicious choice of the
electrophilic reagents, namely halogenating versus
selenating reagents. Using common substrates,
structurally different compounds, namely tetramic
acids (from N-bromosuccinimide) or spirocyclic
seleno-b-lactams (from N-phenylselenophthalim-
mosuccinimide (NBS) versus N-phenylselenophthal-
imide (NPSP)] which permits the selective synthesis
AHCTUNGTRENNUNG
of pyrrolidine-2,4-diones (tetramic acids)[6] and spiro-
cyclic seleno-b-lactams.[7,8] Tetramic acids were ach-
ieved through a chemo-, regio-, and diastereoselective
ring expansion while spiranic 2-azetidinones were ob-
tained by a regioselective selenocycloetherification.
We employed three different systems in our initial
screening of halogenating reagents for the model
system 2-azetidinone-tethered allenol 1a.[9] Initially,
the use of molecular bromine was tested. Next, both
tribromoisocyanuric acid (TBCA)[10] and NBS were
investigated. Substrate 1a gave full conversion in all
cases. Bromine gave a complex mixture of products
(Table 1, entry 1). Interestingly, the use of TBCA as
bromide source regiospecifically provided pyrrolidine-
ACHTUNGTRENNUNGide), can be readily synthesized by these divergent
protocols.
Keywords: allenes; chemoselectivity; heterocycles;
rearrangement; regioselectivity
Allenes are a class of compounds with two cumulative 2,4-dione 2a, but as a 80:20 mixture of diastereoiso-
carbon-carbon double bonds, which are versatile syn- mers (Table 1, entry 2). To our delight, these results
thetic intermediates in organic synthesis.[1] On the were improved with NBS, which afforded compound
other hand, in addition of the key role that b-lactams 2 as single isomer, in a totally selective fashion
have played in medicinal chemistry, namely, the fight (Table 1, entry 3). Solvent screening demonstrated
against pathogenic bacteria, enzyme inhibition, or that dichloromethane was the best choice in the reac-
gene activation,[2] the use of 2-azetidinones as chiral tion (Table 1, entry 5). Next, we studied the reaction
building blocks in organic synthesis is now well estab- of allenol 1a with different halogen sources such as
lished.[3] A process which involves a selective chemi- molecular iodine, N-iodosuccinimide (NIS), and bis-
cal reaction, even if the structure of the substrate sug-
(pyridine)iodonium tetrafluoroborate (Ipy2BF4).[11]
ACHTUNGTRENNUNG
gests numerous possibilities for reactivity, represents However, only a small amount of iodotetramic acid
an attractive strategy.[4] As part of a program aimed derivative 2b was isolated (Table 1, entries 6–8). No-
at expanding the use of allenes and b-lactams in or- ticeably, the conversion of allenic b-lactam 1a into tet-
ganic synthesis,[5] we report herein an unprecedented ramic acid 2a occurs chemo-, regio-, and diastereospe-
example of control of the reactivity of 2-azetidinone- cifically. The chemospecificity arises from the exclu-
tethered allenols with electrophilic reagents [N-bro- sive cleavage of the C2–C3 bond of the four-mem-
Adv. Synth. Catal. 2010, 352, 621 – 626
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Benito Alcaide et al.
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Table 1. Selective ring expansion reaction of 2-azetidinone-tethered allenol 1a to tetramic acid derivatives 2a or 2b under
modified halogenation conditions.
Entry
Reagent
Solvent
Time [h]
X
Yield [%][a]
1
2
3
4
5
6
7
8
Br2
THF/H2O (15:1)
THF/H2O (15:1)
MeCN/H2O (15:1)
THF/H2O (15:1)
CH2Cl2
THF/H2O (15:1)
DMSO
THF/H2O (15:1)
1
0.5
1
6
1.5
5
Br
Br
Br
Br
Br
I
–
TBCA
NBS
NBS
NBS
I2
(À)-2a (74)[b]
(À)-2a (58)
(À)-2a (81)
(À)-2a (96)
(À)-2b (20)
(À)-2b (10)
(À)-2b (23)
Ipy2BF4
NIS
24
48
I
I
[a]
Yield of pure, isolated product with correct analytical and spectral data. TBCA=tribromoisocyanuric acid; NBS=N-bro-
mosuccinimide; Ipy2BF4 =bis(pyridine) iodonium tetrafluoroborate; NIS=N-iodosuccinimide.
A separable mixture (80:20) of diastereoisomers was observed.
AHCTUNGTRENNUNG
[b]
bered nucleus, while the regiospecificity comes from expansion reactions in substituted allenes of type 1 in-
the sole attack to the proximal allene carbon atom cludes the control in the stereoselection during the
with concomitant placement of the bromine to the formation of the all carbon stereocentres. Excellent
central allenic position. Besides, the reaction is dia- yields and selectivities were achieved for the carbon-
stereospecific so that just one diastereomer is formed. carbon bond cleavage in the electrophilic ring open-
The structure and stereochemistry of the tetramic ing reaction of allenic b-lactams 1b–d and 1h to
acid 2a was determined by X-ray diffraction analy- afford functionalized tetramic acids 2c-e and 2i
sis,[12] and its ORTEP drawing is shown in Figure 1.
(Scheme 1). Substrates 1e–g gave a chromatographi-
Next, we investigated the substrate scope in this in- cally separable mixture of major products 2f–h and
teresting rearrangement reaction. An additional chal- their corresponding minor diastereomers 3f–h. Com-
lenge that exists in the development of selective ring pounds 2 and 3 are remarkable since they bear a qua-
ternary stereocentre, the formation of all carbon qua-
ternary centres in an asymmetric manner being one of
the most difficult problems in organic chemistry, not
least because the process requires the creation of a
[13]
À
new C C bond at a hindered centre.
To demonstrate that the above protocol can be con-
sidered in complex synthetic planning, it was success-
fully used for the mono-ring expansion of bis-b-
lactam 1i. The precursors were obtained in an optical-
ly pure form from 4-oxoazetidine-2-carbaldehyde 4.[14]
Thus, C4,C4’-bis-b-lactam 5 was prepared by treat-
ment of aldehyde 4 with p-anisidine followed by
ketene-imine cyclization. Acetoxy-bis-b-lactam 5 was
conveniently converted into allenic bis-b-lactam 1i by
sequential transesterification, Swern oxidation, and
indium-mediated Barbier-type carbonyl-allenylation
reactions (Scheme 2). Worthy of note, the correspond-
ing tetramic acid derivative 2j, which show the selec-
tive bond breakage of the allenic b-lactam ring allow-
ing differentiation between two chemically equivalent
functional groups within the same molecule, could be
exclusively obtained (Scheme 2). The results in
Figure 1. ORTEP-representation of the structure of pyrroli-
dine-2,4-dione 2a in the solid state.
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Divergent Reactivity of 2-Azetidinone-Tethered Allenols with Electrophilic Reagents
Scheme 1. Controlled ring expansion reaction of 2-azetidinone-tethered allenols 1b–h to tetramic acid derivatives 2c–i and
3f–h under selective bromination conditions. Reagents and conditions: i) NBS, CH2Cl2, room temperature, 2d: 0.5 h; 2e:
1.5 h, 2i: 1 h. ii) TBCA, THF/H2O (15:1), room temperature, 2c: 0.5 h; 2g: 1 h. PMP=4-MeOC6H4; Tol=4-MeC6H4.
be accessed by variation of the electrophilic reagent.
We hypothesized that the product selectivity could be
impacted by modulating the relative stability of the
three-membered heterocyclic cation generated during
the course of the reaction. An initial validation of our
hypothesis included the exposure of 2-azetidinone-
tethered allenol 1a to different sources of selenirani-
um ion, an attractive challenge from both synthetic
and biological points of view.[7,15] After extensive ex-
perimentation, gratifyingly, we found that treatment
of substrate 1a with the binary system consisting in an
excess amount of NPSP (N-phenylselenophthali-
mide)[16] and catalytic amount of the Brønsted acid
PTSA in dichloromethane at room temperature gave
rise exclusively to the desired spirocyclic seleno-b-
Scheme 2. Controlled ring expansion reaction of allenic bis-
lactam 7a (Table 2). In the absence of PTSA, adduct
7a was obtained in lower yield. Solvent screening re-
vealed that other solvents such as 1,2-dichloroethane
and MeCN/H2O (15:1) gave lower conversion, where-
as retaining the selectivity towards spirocyclization.
When N-phenylselenosuccinimide (NPSS) or PhSeBr
were used instead NPSP under otherwise comparable
conditions, the reaction proceeded less effectively to
afford the desired selenaderivative 7a.
b-lactam 1i to b-lactam/tetramic acid hybrid 2j under selec-
tive bromination conditions. Reagents and conditions: i)
PMPNH2, MgSO4, CH2Cl2, room temperature, 20 h. ii)
AcOCH2COCl, Et3N, room temperature, CH2Cl2, room tem-
perature, 14 h. iii) NaOMe, MeOH, 08C, 40 min. iv)
(COCl)2, DMSO, Et3N, CH2Cl2, À788C, 1 h. v) In, 1-bromo-
but-2-yne, THF/NH4Cl (aqueous saturated), room tempera-
ture, 20 h. vi) NBS, CH2Cl2, room temperature, 45 min.
PMP=4-MeOC6H4.
Under the optimized reaction conditions, we inves-
tigated the generality of the selenocycloetherification
Scheme 1 and Scheme 2 point to a steric effect of the reaction. Differently functionalized 2-azetidinone-
substituents of the b-lactam ring at N1 and C4, indi- tethered allenes 1b, 1f, and 1i cleanly underwent the
cating that bulky non-planar substituents at C4 have a spirocyclization to regiospecifically furnish selena-ad-
positive influence on the diastereoselectivity of the re- ducts 7b–d in good yields (Scheme 3). The investiga-
action. Attached-ring adduct 2j can be regarded as tion of various allenic-b-lactam substrates in this reac-
the hybrid of the pharmacologically relevant subunits tion revealed that spiroadducts 7 were produced in all
of b-lactam and tetramic acid.
cases as the sole reaction products; tetramic acid de-
Next, we were attracted to the possibility that rivatives not even being present in detectable
either heterocycle (tetramic acid or spirocycle) could amount.
Adv. Synth. Catal. 2010, 352, 621 – 626
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Benito Alcaide et al.
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Table 2. Selective selenocycloetherification reaction of 2-azetidinone-tethered allenol 1a to spirocyclic b-lactam 7a under
modified selenation conditions.
Entry
Reagent
Solvent
Time (h)
Catalyst
Yield [%][a]
1
2
3
4
5
6
7
8
PhSeBr
NPSS
NPSS
NPSP
NPSP
NPSP
NPSP
NPSP
MeCN/H2O (15:1)
MeCN/H2O (15:1)
CH2Cl2
MeCN/H2O (15:1)
DCE
CH2Cl2
CH2Cl2
CH2Cl2
22
40
22
40
40
40
40
40
–
–
30
–
10
–
15
17
54
64
PTSA (15 mol%)
–
PTSA (15 mol%)
–
PTSA (10 mol%)
PTSA (15 mol%)
[a]
Yield of pure, isolated product with correct analytical and spectral data. NPSS=N-phenylselenosuccinimide; NPSP=N-
phenylselenophthalimide; DCE=1,2-dichloroethane; PTSA=p-toluenesulfonic acid.
Scheme 3. Controlled selenocycloetherification reaction of
Scheme 4. Mechanistic explanation for the NBS- or NPSP-
mediated preparation of tetramic acids 2 and spirocyclic
seleno b-lactams 7 from common precursor allenols 1.
2-azetidinone-tethered allenols 1b, 1f, and 1i to spirocyclic
seleno b-lactam derivatives under selective selenation condi-
tions. Reagents and conditions: i) NPSP, 15 mol% PTSA,
CH2Cl2, room temperature, 7b: 48 h; 7c: 40 h, 7d: 48 h.
PMP=4-MeOC6H4. Diox=(S)-2,2-dimethyl-1,3-dioxolan-4-
yl; Tol=4-MeC6H4; NPSP=N-phenylselenophthalimide;
PTSA=p-toluenesulfonic acid.
be explained by the presence of the C4 substituent,
which leads to the formation of the anti adduct to
avoid steric repulsion between the C4 group and the
bromoalkenyl moiety. On the other hand, cations 10
A plausible mechanism for the formation of ad- suffer highly regioselective nucleophilic attack of the
ducts 2 and 7 is illustrated in Scheme 4. It should be oxygenated moiety to the former distal allenic carbon
noted that C-attack and O-attack to the allene moiety to afford the final spirocyclic products, rather than
À
could both be possible in this type of reaction. When evolve by the activation of the strained C C s bond
NBS is used as the reactant, allenols 1 initially gener- of the four-membered ring.
ate bromonium species 9. Alternatively, the related
In summary, we have demonstrated for the first
seleniranium species 10 could also be formed in the time that electrophilic reagents are capable of modu-
presence of NPSP. Thus, cations 9 evolve to rear- lating 2-azetidinone-tethered allenol reactivity. These
À
ranged tetramic acids via intramolecular 1,2 C C reactions can be tuned by using morphologically relat-
bond migration, which is chemospecific because of ed NBS or NPSP as the reagents. From common sub-
the exclusive breakage of the C2–C3 bond of the strates, structurally different compounds, namely tet-
four-membered heterocycle. The stereoselectivity may ramic acids or spirocyclic seleno-b-lactams, can be
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Adv. Synth. Catal. 2010, 352, 621 – 626

Divergent Reactivity of 2-Azetidinone-Tethered Allenols with Electrophilic Reagents
Chemical Synthesis of Antibiotics and Related Microbial
readily synthesized by our divergent protocols. A
more in-depth study of the reaction mechanisms in-
volved in these processes and the understanding of
their scope and limitations is underway.
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Experimental Section
Typical Procedure for the Ring-Expansion Reaction
to Tetramic Acids using 2-Azetidinone-Tethered
Allenol 1a and N-Bromosuccinimide
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[6] The substituted pyrrolidine-2,4-dione scaffold is a key
pattern present in tetramic acids, a class of compounds
exhibiting interesting biological properties ranging
from antibacterial to antitumoral activities. For reviews,
see: a) B. J. L. Royles, Chem. Rev. 1995, 95, 1981; b) A.
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To a solution of the 2-azetidinone-tethered allenol (+)-1a
(50 mg, 0.15 mmol) in dichloromethane (6.5 mL) was added
N-bromosuccinimide (35 mg, 0.196 mmol). The reaction
mixture was stirred at room temperature for 90 min. Satu-
rated aqueous sodium hydrogen carbonate (1.5 mL) was
added, before being partitioned between dichloromethane
and water. The organic extract was washed with brine, dried
(MgSO4), concentrated under reduced pressure, and purified
by flash column chromatography on silica gel (hexanes/ethyl
acetate=2:1) to afford the product (À)-2a as a colorless
solid; mp 137–1398C; [a]D: À12.5 (c 0.6 in CHCl3);
1H NMR (300 MHz, CDCl3, 258C): d=7.32 and 6.95 (d, J=
8.8 Hz, each 2H), 6.03 and 5.85 (d, J=3.0 Hz, each 1H),
4.65 (d, J=2.3 Hz, 1H), 4.51 (td, J=6.6, 2.2 Hz, 1H), 3.81
(m, 4H), 3.42 (dd, J=8.9, 6.1 Hz, 1H), 1.60 and 1.42 (s, each
3H), 1.26 (s, 3H); 13C NMR (75 MHz, CDCl3, 258C): d=
206.1, 171.7, 158.6, 129.8, 126.5, 125.7, 121.2, 114.4, 109.8,
75.1, 68.4, 64.5, 59.7, 55.4, 26.1, 24.6, 17.6; IR (CHCl3): n=
1760, 1703, 1513, 1251 cmÀ1; HR-MS (EI): m/z=424.0756,
calcd for C19H23BrNO5 [M+H]+: 424.0760.
Acknowledgements
Support for this work by the DGI-MICINN (Projects
CTQ2006-10292 and CTQ2009-09318), CAM (Project
S2009/PPQ-1752), and UCM-BSCH (Grant GR58/08) are
gratefully acknowledged. We thank Gonzalo Gꢀmez-Campil-
los for his help in the preparation of some materials.
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[12] X-ray data of 2a: crystallized from ethyl acetate/n-
hexane at 208C; C19H22BrNO5 (Mr =424.29); ortho-
rhombic; space group: P2(1)2(1)2(1); a=7.7011(7) ꢆ,
b=9.4066(9) ꢆ; c=27.809(3) ꢆ.; b=90 deg.; V=
2014.5(3) ꢆ3; Z=4; cd=1.399 mgmÀ3; m=2.068 mmÀ1
;
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FACHTUNGTRENNUNG(000)=872. A transparent crystal of 0.313ꢇ0.424ꢇ
0.460 mm3 was used. 4380 [R
ACTHNUTRGNE(UNG int)=0.0422] independent
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626
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