Expeditious entry to enantiopure mono- and bis(tricyclic) β-lactams by single or double [2+2] cycloaddition of allenynes

Article abstract of DOI:10.1002/ejoc.201001233

A thermal methodology for the expeditious preparation of structurally novel strained tricyclic β-lactams containing a cyclobutene ring has been developed. Besides, the first examples accounting for the intramolecular double [2+2] cycloaddition of bis(alle

Full text of DOI:10.1002/ejoc.201001233

FULL PAPER
DOI: 10.1002/ejoc.201001233
Expeditious Entry to Enantiopure Mono- and Bis(Tricyclic) β-Lactams by
Single or Double [2+2] Cycloaddition of Allenynes
Benito Alcaide,*[a] Pedro Almendros,*[b] Cristina Aragoncillo,*[a] and
Gonzalo Gómez-Campillos[a]
Keywords: Allenes / Alkynes / Cyclization / Lactams / Radicals / Small ring systems
A thermal methodology for the expeditious preparation of
structurally novel strained tricyclic β-lactams containing a
cyclobutene ring has been developed. Besides, the first ex-
allenyne)s, which have been prepared by copper-promoted
alkyne homo- or cross-coupling reactions. The bis(tricyclic)
ring structures bearing a central seven-membered ring arise
amples accounting for the intramolecular double [2+2] cyclo- from the regioselective cyclization of the alkyne with the dis-
addition of bis(allenyne)s have been achieved through ther-
tal bond of the allene, most likely via a radical intermediate.
molysis of C2-symmetric or unsymmetric bis(β-lactam–
ommend their application to the preparation of function-
alized tricyclic β-lactams.[4] Our combined interest in the
area of β-lactams and the synthetic use of allenes[5] led us
to explore single and double [2+2] allenyne cyclization stra-
tegies for developing a versatile entry to novel fused tricyclic
and attached-ring bis(tricyclic) β-lactams containing cyclo-
butene rings.[6]
Introduction
The importance of cyclobutane-containing compounds
both as target molecules as well as useful building blocks
for the construction of more complex structures has been
widely demonstrated.[1] However, relatively few methods for
the preparation of four-membered carbocycles are available
in comparison with superior cyclohomologues. In particu-
lar, the [2+2] cycloaddition of allenes with alkynes repre-
sents an important strategy for the preparation of cyclobut-
ene derivatives with high atom economy.[2] Unfortunately,
this process has suffered from low stereo- and positional
selectivity (considering the intramolecular [2+2] cycload-
dition of allenynes, two regioisomers can be formed, the
proximal cycloadduct by reaction of the alkyne with the
internal 2π component, and the distal cycloadduct by reac-
tion with the external 2π component of the allene moiety).
On the other hand, the enormous interest in β-lactams in
medicinal chemistry, as key structural features of many an-
tibiotics and serine protease inhibitors, and as valuable syn-
thetic intermediates in organic chemistry, has triggered con-
siderable research efforts toward the enantioselective syn-
thesis of these compounds.[3] The appealing properties of
intramolecular cycloaddition reactions would seem to rec-
Results and Discussion
Starting substrates, enantiopure acetonide-2-azetidi-
nones 1a and 1b, were obtained as single cis enantiomers
through ketene–imine cyclization following our previous
procedure.[7] Terminal alkynes 1 were functionalized as
their corresponding phenyl, 2-thiophenyl, 2-pyridyl, and
propynylphenyl derivatives 2a–g by treatment with the ap-
propriate iodoarene or phenylacetylene under Sonogashira
or Cadiot–Chodkiewicz conditions (Scheme 1). Standard
acetonide hydrolysis of compounds 1 and 2 followed by oxi-
dative cleavage of the resulting diols smoothly provided 4-
oxoazetidine-2-carbaldehydes 4a–i (Scheme 1).[8] Cycliza-
tion precursors, allenynes 5a–k, were readily obtained be-
ginning from the appropriate 4-oxoazetidine-2-carbal-
dehydes 4 through regio- and stereocontrolled indium-me-
diated Barbier-type carbonyl–allenylation reaction in aque-
ous media, adopting our methodology (Scheme 2).[9]
Although, in theory, an intramolecular cycloaddition of
β-lactam–enynes could be used to prepare tricycles, there
is no report in the literature involving [2+2] cycloaddition
reaction of 2-azetidinone-tethered alkynes. Because of the
inherent instability imparted by the cumulated double bond
in allenes, cycloaddition reactions take place easily in com-
parison with an isolated double bond. Having obtained al-
lenynols 5, the next stage was set the key [2+2] process on
[a] Grupo de Lactamas y Heterociclos Bioactivos,
Departamento de Química Orgánica I,
Unidad Asociada al CSIC, Facultad de Química,
Universidad Complutense de Madrid,
28040 Madrid, Spain
Fax: +34-91-39444103
E-mail: alcaideb@quim.ucm.es
[b] Instituto de Química Orgánica General,
Consejo Superior de Investigaciones Científicas, CSIC,
Juan de la Cierva 3, 28006 Madrid, Spain
Fax: +34-91-5644853
E-mail: Palmendrosb@iqog.csic.es
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001233.
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Expeditious Entry to Enantiopure Mono- and Bis(Tricyclic) β-Lactams
Scheme 1. Preparation of 4-oxoazetidine-2-carbaldehydes 4. Reagents and conditions: (i) ArI (1 mol-%), Pd(PPh3)2Cl2 (2 mol-%), CuI,
Et3N, DMSO, 50 °C, 4 h; 2a: ArI = iodobenzene; 2b: ArI = 1-iodo-4-methoxybenzene; 2c: ArI = 2-iodopyridine; 2d: ArI = 2-iodothi-
ophene; 2e: ArI = 1-bromo-4-iodobenzene. (ii) NBS, AgOAc, acetone, darkness, r.t., 4 h. (iii) Phenylacetylene, MeOH/CH2Cl2, CuCl,
NH2OH·HCl, EtNH2, 0 °C, 18 h. (iv) (a) PTSA, THF/H2O, Δ, 2 h; (b) NaIO4, NaHCO3 (aq. sat.), CH2Cl2, r.t., 4a: 2 h; 4b: 2 h; 4c: 24 h;
4d: 24 h; 4e: 72 h; 4f: 18 h; 4g: 18 h; 4h: 24 h; 4i: 24 h. PTSA = p-toluenesulfonic acid.
aled tube. Unfortunately, no conversion was found. A vari-
ety of experimental variables, such as the temperature and
solvent, were systematically examined, but not even a trace
amount of the expected tricycle was detected in the crude
reaction mixtures. We therefore speculated how the presence
of a substituent at the alkyne moiety may influence the re-
activity. Thus, a range of alkynyl-substituted building
blocks 5 was exposed to thermal reaction conditions. Ther-
molysis of allenynes 5e–k bearing an aryl, heteroaryl, or
alkynyl group on the alkyne side afforded strained tricyclic
β-lactams 6a–g in reasonable yields and complete regiose-
lectivity (Scheme 3). It is of note that allenynes 5j and 5k
containing a 1,3-diyne functionality reacted with the phen-
ylacetylene group remaining intact. Thus, the mildness of
the method allowed the incorporation of a 1,3-diyne moiety
as a reactive partner, displaying exquisite chemoselectivity
towards the internal alkynic moiety, directing the cycliza-
tion to the exclusive formation of fused tricyclic cyclobut-
ene 6g. The tricyclic ring structures 6a–g bearing a central
seven-membered ring arise from the formal [2+2] cycload-
dition of the alkyne with the distal bond of the allene, most
likely via a diradical intermediate. The regioselectivity of
the process is not affected by the substituent at the alkyne
Scheme 2. Preparation of allenynes 5. Reagents and conditions: carbon atom. No trace amount of the exocyclic methylene
(i) In, THF/NH4Cl (aq. sat.), r.t., 18 h. PMP = 4-MeOC6H4.
regioisomer through cycloaddition, with six-membered cen-
tral ring formation could be detected (Scheme 3), despite
reacting the allene group as a 2π-electron donor. A model the fact that, according to Baldwin’s rules for ring forma-
thermal cyclization of allenynes 5 was carried out by heat- tion, the ease of cyclization increases with decreasing ring
ing a solution of α-allenol 5a in toluene at 110 °C in a se- size (5 Ͼ 6 Ͼ 7).[10]
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Scheme 3. Preparation of tricyclic β-lactams 6. Reagents and conditions: (i) toluene, sealed tube, 110 °C, 6a: 4 h; 6b: 5 h; 6c: 4 h; 6d: 3 h;
6e: 6 h; 6f: 1.5 h; 6g: 2 h. PMP = 4-MeOC6H4.
Because the presence of a 1,3-diyne moiety at the al- Cross-coupling reactions using the Cadiot–Chodkiewicz
lenyne fragment had no effect upon the selectivity of the protocol[12] between bromoallenynes 9a and 9b and al-
cyclization, we decided to explore the double [2+2] cycload- lenynes 5c and 5d catalyzed by CuCl and NH2OH·HCl in
dition in the hitherto difficult to prepare diyne–diallene 70% ethylamine in water solvent produced the correspond-
functionality. To screen the reactivity of the bis(allenyne) ing unsymmetrical bis(β-lactam–allenyne)s 10 in good
moiety, homodimerization of allenynes 5a–d was studied in yields (Scheme 5).
the presence of a copper promoter. The homodimerization
reaction proceeded smoothly to afford desired diyne–diall-
enes 7a–d by using modified classical copper-promoted con-
ditions (Scheme 4).[11] Copper(II) acetate in combination
with potassium carbonate in acetonitrile gave the best per-
formance.
Because it is known that dimers exhibit greater biological
activity in comparison with their monomeric compo-
nents,[13] and despite the lack of reports on double [2+2]
cycloaddition of bis(allenyne)s, the availability of bis(al-
lenyne)s 7 and 10 prompted us to test their reactivity. IR
spectroscopic analysis was undertaken on the crude reac-
tion mixtures after heating at 110 °C. From the IR data, it
is observed that the vibrational frequencies at ca. 2220 and
1940 cm–1, characteristic of CϵC and C=C=C bond
stretching, respectively, completely vanished after thermal
treatment. The disappearance of the CϵC and C=C=C
bands indicates that the thermal reactions involve every sin-
gle acetylenic and allenic unit. We observed the formation
of C2-symmetric attached-ring bis(tricyclic) β-lactams 11a–
d by a double [2+2] allenyne cyclization. As shown in
Scheme 6, unsymmetrical bis(β-lactam–allenyne)s 10a–c
also participate in this chemistry, leading to bis(tricycle)s
12a–c upon thermal treatment. The reactions were so re-
gioselective that the signal for the alkenyl cyclobutene pro-
Scheme 4. Copper-promoted preparation of C2-symmetric bis(al-
lenyne)s 7a–d. Reagents and conditions: (i) Cu(OAc)2, K2CO3,
MeCN, r.t., 4 h. PMP = 4-MeOC6H4.
Having obtained C2-symmetric bis(β-lactam–allenyne)s, tons (corresponding to the internal isomers) were not ob-
1
the next stage was to determine selective heterocoupling served in the H NMR spectra of the unpurified reaction
conditions to achieve unsymmetrical bis(β-lactam–allenyne)s. mixtures. Compounds 11 and 12 are remarkable, as they
We envisioned that the target unsymmetrical allenynes bear a challenging dimeric tricyclic 2-azetidinone structure
could come from the copper-catalyzed Cadiot–Chodkiewicz having both a strained cyclobutene as well as a seven-mem-
cross-coupling reaction of a bromoallenynyl–β-lactam with bered ring. No detectable erosion of the stereochemical in-
a terminal allenyne–β-lactam. Heterocoupling precursors, tegrity at the stereogenic centers under the thermal condi-
bromoallenynes 9, were smoothly prepared from bromo- tions was observed. The depicted distal cycloadducts were
alkyne 3a by aldehyde unmasking followed by allenylation the only isolated isomers; allenynes 5, 7, and 10 showed the
reaction of bromoalkynyl carbaldehyde 8 (Scheme 5). same regiochemical preference. In order to see if products
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Expeditious Entry to Enantiopure Mono- and Bis(Tricyclic) β-Lactams
Scheme 5. Copper-promoted preparation of unsymmetrical bis(allenyne)s 10a–c. Reagents and conditions: (i) (a) PTSA, THF/H2O, Δ,
2 h; (b) NaIO4, NaHCO3 (aq. sat.), CH2Cl2, r.t., 8 h. (ii) In, THF/NH4Cl (aq. sat.), r.t., 18 h. (iii) MeOH/CH2Cl2, CuCl, NH2OH·HCl,
EtNH2, 0 °C, 18 h. PMP = 4-MeOC6H4.
Scheme 6. Synthesis of enantiopure C2-symmetric and unsymmetrical attached-ring bis(tricyclic) β-lactams 11 and 12. Reagents and
conditions: (i) toluene, sealed tube, 110 °C, 11a: 1.5 h; 11b: 2 h; 11c: 1 h; 11d: 3 h; 12a: 1 h; 12b: 1 h; 12c: 1 h. PMP = 4-MeOC6H4.
from a single [2+2] allenyne cyclization could be isolated at must involve a rapid double ring closure of the tetraradical
short reaction times, we stopped the reaction of bis(β-lac- intermediates, before bond rotation can occur.
tam–allenyne) 7a prematurely (30 min). In the event, the
only detectable products were the starting material and bis-
(cyclization) adduct 11a, which may point that both cycliza-
tions occur simultaneously.
A conceivable mechanism for the preparation of bis-
(tricycle)s 11 and 12 from bis(β-lactam–allenyne)s 7 and 10
may initially involve the formation of tetraradical interme-
diates. When a catalytic amount of hydroquinone was
added, the reaction rate was considerably reduced and the
product yield fell dramatically. This fact is consistent with
involvement of a radical mechanism. The formation of
fused strained bis(tricycle)s 11 and 12 can be rationalized
by a mechanism that includes exocyclic tetraradical inter-
mediate 13 through initial double carbon–carbon bond for-
mation, involving the central allene and the proximal alkyne
Scheme 7. A conceivable mechanistic explanation for the thermal
carbon atoms (Scheme 7). For this pathway, the final step double [2+2] allenyne cyclization.
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367

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FULL PAPER
3.38 (br. s, 1 H, OH), 3.23 (dq, J = 13.9, 2.0 Hz, 1 H, CHH) ppm.
13C NMR (75 MHz, CDCl3, 25 °C): δ = 166.4 (NC=O), 152.4 (Cq),
150.2 (CH), 143.9 (Cq), 139.9 (Cq), 139.7 (Cq), 139.5 (Cq), 136.1
Conclusions
In conclusion, we have developed a convenient method-
ology for the synthesis of strained tricyclic β-lactams con- (Cq), 132.1 (CH), 131.9 (CH), 128.3 (CH), 127.2 (CH), 122.1 (CH),
121.4 (CH), 83.6 (CH), 72.9 (CH), 62.1 (CH), 60.8 (CH), 42.8
taining a cyclobutene ring through a totally regioselective
[2+2] cycloaddition reaction of 2-azetidinone-tethered al-
lenynols. Besides, the first examples accounting for the in-
tramolecular double [2+2] cycloaddition of bis(allenyne)s
have been achieved by thermolysis of C2-symmetric or un-
symmetric bis(β-lactam–allenyne)s. A conceivable mecha-
nism for the achievement of bis(tricycle)s from bis(β-lac-
tam–allenyne)s may imply the formation of tetraradical in-
termediates involving the distal allene bonds.
(CH ), 36.3 (CH ) ppm. IR (CHCl ): ν = 3440, 1744, 1643 cm–1.
˜
2
2
3
HRMS (ESI): calcd. for C22H21N2O3 [M + H]+ 361.1552; found
361.1585.
Tricyclic β-Lactam (+)-6f: From allenyne (–)-5j (50 mg, 0.13 mmol).
Chromatography (hexanes/ethyl acetate, 1:1) of the residue gave
compound (+)-6f (32 mg, 64%) as a pale-yellow oil. [α]2D0 = +6.3 (c
1
= 0.4, CHCl3). H NMR (300 MHz, CDCl3, 25 °C): δ = 7.49 (m,
5 H, Ar-H), 7.36 (m, 4 H, Ar-H), 7.28 (m, 1 H, Ar-H), 4.81 (br. s,
1 H, CHOH), 4.74 (dt, J = 19.0, 4.0 Hz, 1 H, NCHH), 4.60 (d, J
= 4.5 Hz, 1 H, CH), 4.27 (d, J = 19.0 Hz, 1 H, NCHH), 4.23 (d, J
= 4.6 Hz, 1 H, CH), 3.69 (s, 3 H, CH3), 3.44 (dt, J = 13.7, 3.2 Hz,
1 H, CHH), 3.34 (br. s, 1 H, OH), 3.18 (dq, J = 13.7, 2.0 Hz, 1 H,
CHH) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 166.5
(NC=O), 145.4 (Cq), 140.3 (Cq), 139.3 (Cq), 131.6 (CH), 128.9
(Cq), 128.5 (CH), 128.4 (CH), 127.9 (Cq), 127.1 (CH), 126.9 (Cq),
122.4 (Cq), 102.1 (Cq), 83.5 (CH), 83.3 (Cq), 71.9 (CH), 61.2 (CH),
Experimental Section
1
General Methods: H NMR and 13C NMR spectra were recorded
with a Bruker Avance AVIII-700 with cryoprobe, Bruker AMX-
500, Bruker Avance-300, Varian VRX-300S, or Bruker AC-200.
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). Low- and high-resolution
mass spectra were taken with an Agilent 6520 Accurate-Mass
QTOF LC–MS spectrometer using the electronic impact (EI) or
electrospray modes (ESI) unless otherwise stated. IR spectra were
recorded with a Bruker Tensor 27 spectrometer. All commercially
available compounds were used without further purification.
59.7 (OCH ), 40.8 (CH ), 39.6 (CH ) ppm. IR (CHCl ): ν = 3433,
˜
3
2
2
3
2232, 1746, 1643 cm–1. HRMS (ESI): calcd. for C25H22NO3 [M +
H]+ 384.1600; found 384.1595.
Bis(tricyclic) β-Lactam (+)-11a: From bis(allenyne) (+)-7a (30 mg,
0.052 mmol). Chromatography (hexanes/ethyl acetate, 1:3) of the
residue gave compound (+)-11a (20 mg, 65%) as a colorless oil.
[α]2D0 = +66.6 (c = 0.5, CHCl3). 1H NMR (700 MHz, CDCl3,
25 °C): δ = 7.50 (m, 4 H, Ar-H), 7.33 (m, 6 H, Ar-H), 4.82 (m, 2
H, 2 CHOH), 4.70 and 4.22 (d, J = 18.2 Hz, each 2 H, 2 NCHH,
2 NCHH), 4.59 (dd, J = 4.8, 1.2 Hz, 2 H, 2 CH), 4.22 (d, J =
4.8 Hz, 2 H, 2 CH), 3.69 (s, 6 H, 2 CH3), 3.35 (dt, J = 13.6, 2.9 Hz,
2 H, 2 CHH), 3.28 (br. s, 2 H, 2 OH), 3.12 (m, 2 H, 2 CHH) ppm.
13C NMR (175 MHz, CDCl3, 25 °C): δ = 166.6 (NC=O), 140.9
(Cq), 139.2 (Cq), 138.6 (Cq), 137.4 (Cq), 128.6 (CH), 128.5 (CH),
127.2 (Cq), 127.0 (CH), 83.6 (CH), 71.7 (CH), 61.3 (CH), 59.8
Preparation of Fused Tricyclic and Attached-Ring Bis(tricyclic) β-
Lactams 6, 11, and 12 as a General Procedure for the Thermal Cycli-
zation of Mono- and Bis(allenyne)s 5, 7, and 10: A solution of the
appropriate allenyne 5, 7, or 10 (0.15 mmol) in toluene (5 mL) was
heated at 110 °C in a sealed tube. After disappearance (1–5 h) of
the starting material (TLC), the mixture was cooled down to room
temperature and concentrated under reduced pressure. Chromatog-
raphy of the residue (ethyl acetate/hexanes) gave analytically pure
compounds. Spectroscopic and analytical data for pure forms of 6,
11, and 12 follow.
(CH ), 40.4 (CH ), 36.3 (CH ) ppm. IR (CHCl ): ν = 3426, 1748,
˜
3
2
2
3
1645 cm–1. HRMS (ESI): calcd. for C34H33N2O6 [M + H]+
565.2339; found 565.2342.
Tricyclic β-Lactam (–)-6a: From allenyne (+)-5e (45 mg,
0.12 mmol). Chromatography (hexanes/ethyl acetate, 1:1) of the
residue gave (–)-6a (25 mg, 54%) as a colorless oil. [α]2D0 = –72.3 (c
Bis(tricyclic) β-Lactam (–)-11b: From bis(allenyne) (+)-7b (30 mg,
0.048 mmol). Chromatography (hexanes/ethyl acetate, 1:20) of the
residue gave compound (–)-11b (20 mg, 67%) as a colorless oil.
[α]2D0 = –95.7 (c = 0.3, CHCl3). 1H NMR (700 MHz, CDCl3, 25 °C):
δ = 7.44 and 6.89 (d, J = 8.8 Hz, each 4 H, Ar-H), 4.79 (s, 2 H,
CHOH), 4.68 and 4.21 (d, J = 15.7 Hz, each 2 H, 2 NCHH, 2
NCHH), 4.58 (d, J = 4.8 Hz, 2 H, 2 CH), 4.20 (d, J = 4.8 Hz, 2
H, 2 CH), 3.83 (s, 6 H, 2 CH3), 3.69 (s, 6 H, 2 CH3), 3.31 (dt, J =
13.6, 2.8 Hz, 2 H, 2 CHH), 3.26 (br. s, 2 H, 2 CHH), 3.12 (d, J =
15.1 Hz, 2 H, 2 OH) ppm. 13C NMR (175 MHz, CDCl3, 25 °C): δ
= 166.5 (NC=O), 158.8 (Cq), 139.7 (Cq), 138.3 (Cq), 136.7 (Cq),
131.8 (Cq), 128.2 (CH), 127.9 (CH), 113.9 (CH), 83.5 (CH), 71.7
(CH), 61.2 (CH), 59.8 (CH3), 55.3 (CH3), 40.4 (CH2), 36.3 (CH2)
1
= 1.0, CHCl3). H NMR (300 MHz, CDCl3, 25 °C): δ = 7.57 (m,
2 H, Ar-H), 7.34 (m, 8 H, Ar-H), 4.96 (dt, J = 18.5, 3.7 Hz, 1 H,
NCHH), 4.82 (br. s, 1 H, CHOH), 4.63 (d, J = 4.6 Hz, 1 H, CH),
4.42 (d, J = 18.5 Hz, 1 H, NCHH), 4.30 (d, J = 4.6 Hz, 1 H, CH),
3.71 (s, 3 H, OCH3), 3.51 (dt, J = 13.8, 3.6 Hz, 1 H, CHH), 3.35
(br. s, 1 H, OH), 3.17 (ddd, J = 13.8, 4.0, 2.3 Hz, 1 H, CHH) ppm.
13C NMR (75 MHz, CDCl3, 25 °C): δ = 166.6 (NC=O), 145.1 (Cq),
139.9 (Cq), 139.8 (Cq), 134.3 (Cq), 133.5 (Cq), 128.8 (CH), 128.7
(CH), 128.3 (CH), 127.2 (CH), 126.7 (CH), 126.6 (CH), 125.9 (Cq),
83.7 (CH), 71.9 (CH), 61.5 (CH), 59.8 (OCH3), 41.2 (CH2), 35.5
(CH ) ppm. IR (CHCl ): ν = 3436, 1745, 1646 cm–1. HRMS (ESI):
˜
2
3
ppm. IR (CHCl ): ν = 3430, 1747, 1650 cm–1. HRMS (ESI): calcd.
calcd. for C23H22NO3 [M + H]+ 360.1600; found 360.1604.
˜
3
for C36H37N2O8 [M + H]+ 625.2550; found 625.2542.
Tricyclic β-Lactam (–)-6c: From allenyne (+)-5g (35 mg,
0.097 mmol). Chromatography (hexanes/ethyl acetate, 1:1) of the
Bis(tricyclic) β-Lactam (+)-11c: From bis(allenyne) (+)-7c (40 mg,
residue gave compound (–)-6c (30 mg, 86%) as a colorless oil. 0.058 mmol). Chromatography (hexanes/ethyl acetate, 1:1) of the
[α]2D0 = –39.2 (c = 1.0, CHCl3). 1H NMR (300 MHz, CDCl3, 25 °C):
δ = 7.68 (m, 2 H, Ar-H), 7.56 (m, 2 H, Ar-H), 7.47 (m, 1 H, Ar-
H), 7.37 (m, 2 H, Ar-H), 7.21 (m, 1 H, Ar-H), 5.02 (dt, J = 19.9,
residue gave compound (+)-11c (28 mg, 71%) as a colorless oil.
[α]2D0 = +29.4 (c = 0.4, CHCl3). 1H NMR (700 MHz, CDCl3,
25 °C): δ = 7.41 (m, 12 H, Ar-H), 7.12 (m, 8 H, Ar-H), 5.31 (d, J
3.8 Hz, 1 H, NCHH), 4.83 (br. s, 1 H, CHOH), 4.65 (m, 1 H, = 4.8 Hz, 2 H, 2 CH), 4.96 (br. s, 2 H, 2 CHOH), 4.78 and 4.29
NCHH), 4.62 (d, J = 3.7 Hz, 1 H, CH), 4.27 (d, J = 4.8 Hz, 1 H, (d, J = 18.0 Hz, each 2 H, 2 NCHH, 2 NCHH), 4.43 (d, J = 4.8 Hz,
CH), 3.69 (s, 3 H, CH3), 3.54 (dt, J = 13.9, 3.5 Hz, 1 H, CHH),
2 H, 2 CH), 3.37 (d, J = 13.8 Hz, 2 H, 2 CHH), 3.15 (d, J =
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Expeditious Entry to Enantiopure Mono- and Bis(Tricyclic) β-Lactams
13.8 Hz, 2 H, 2 CHH) ppm. 13C NMR (175 MHz, CDCl3, 25 °C): residue gave compound (+)-12c (35 mg, 72%) as a colorless oil.
δ = 165.2 (NC=O), 157.1 (Cq), 140.9 (Cq), 139.1 (Cq), 138.6 (Cq),
137.5 (Cq), 129.8 (CH), 128.8 (C), 128.5 (CH), 127.4 (CH), 127.1
[α]2D0 = +123.5 (c = 1.5, CHCl3). 1H NMR (300 MHz, CDCl3,
25 °C): δ = 7.52 (m, 4 H, Ar-H), 7.34 (m, 8 H, Ar-H), 7.18 (m, 2
(CH), 123.3 (CH), 116.1 (CH), 80.9 (CH), 71.6 (CH), 61.8 (CH), H, Ar-H), 7.10 (m, 1 H, Ar-H), 5.32 (d, J = 4.5 Hz, 1 H, CH), 4.97
40.6 (CH ), 36.2 (CH ) ppm. IR (CHCl ): ν = 3428, 1746, and 4.84 (br. s, each 1 H, CHOH), 4.78 and 4.72 (d, J = 19.0 Hz,
˜
2
2
3
1647 cm–1. HRMS (ESI): calcd. for C44H37N2O6 [M + H]+
each 1 H, NCHH, NCHH), 4.61 (d, J = 4.5 Hz, 1 H, CH), 4.44
(d, J = 4.5 Hz, 1 H, CH), 4.31 and 4.25 (d, J = 14.3 Hz, each 1 H,
NCHH, NCHH), 4.24 (d, J = 4.5 Hz, 1 H, CH), 3.70 (s, 3 H,
OCH3), 3.37 and 3.16 (t, J = 13.4 Hz, each 2 H, 2 CHH, 2 CHH)
ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 166.6 (NC=O), 165.1
(NC=O), 157.0 (Cq), 140.9 (Cq), 140.8 (Cq), 139.2 (Cq), 139.0
(Cq), 138.9 (Cq), 138.3 (Cq), 137.6 (Cq), 137.2 (Cq), 133.1 (Cq),
131.6 (Cq), 129.8 (CH), 128.5 (CH), 128.4 (CH), 127.4 (CH), 127.3
(CH), 127.0 (CH), 123.1 (CH), 116.1 (CH), 83.5 (CH), 71.7 (CH),
71.5 (CH), 61.7 (CH), 61.2 (CH), 59.7 (CH3), 40.6 (CH2), 40.3
689.2652; found 689.2657.
Bis(tricyclic) β-Lactam (–)-11d: From bis(allenyne) (+)-7d (60 mg,
0.08 mmol). Chromatography (hexanes/ethyl acetate, 1:1) of the
residue gave compound (–)-11d (46 mg, 78%) as a colorless oil.
[α]2D0 = –7.8 (c = 2.2, CHCl3). 1H NMR (700 MHz, CDCl3, 25 °C):
δ = 7.39 (m, 6 H, Ar-H), 7.04 (m, 12 H, Ar-H), 5.31 (d, J = 4.5 Hz,
2 H, 2 CH), 4.94 (br. s, 2 H, 2 CHOH), 4.79 and 4.28 (m, each 2
H, 2 NCHH, 2 NCHH), 4.42 (d, J = 4.5 Hz, 2 H, 2 CH), 3.84 (s,
6 H, 2 OCH3), 3.35 (m, 2 H, 2 CHH), 3.12 (m, 2 H, 2 CHH) ppm.
13C NMR (175 MHz, CDCl3, 25 °C): δ = 165.2 (NC=O), 158.9
(Cq), 157.0 (Cq), 139.8 (Cq), 138.2 (Cq), 136.9 (Cq), 131.6 (CH),
129.8 (CH), 128.3 (CH), 128.1 (Cq), 123.2 (CH), 116.0 (CH), 113.9
(CH ), 36.3 (CH ), 36.2 (CH ) ppm. IR (CHCl ): ν = 3440, 1747,
˜
2
2
2
3
1650 cm–1. HRMS (ESI): calcd. for C39H34N2NaO6 [M + Na]+
649.2315; found 649.2305.
(CH), 80.8 (CH), 71.5 (CH), 61.6 (CH), 55.3 (CH3), 40.6 (CH2), Supporting Information (see footnote on the first page of this arti-
36.3 (CH ) ppm. IR (CHCl ): ν = 3436, 1749, 1644 cm–1. HRMS cle): Compound characterization data and experimental procedures
˜
2
3
(ESI): calcd. for C46H41N2O8 [M + H]+ 749.2863; found 749.2869.
for compounds 2a–g, 3a, 3b, 4c–i, 5a–k, 6b, 6d, 6e, 6g, 7a–d, 9a,
9b, and 10a–c, in addition to copies of the NMR spectra of all new
compounds.
Bis(tricyclic) β-Lactam (–)-12a: From bis(allenyne) (+)-10a (20 mg,
0.03 mmol). Chromatography (hexanes/ethyl acetate, 1:1) of the
residue gave compound (–)-12a (9 mg, 45%) as a colorless oil.
[α]2D0 = –263.4 (c = 0.1, CHCl3). 1H NMR (300 MHz, CDCl3,
25 °C): δ = 7.40 (m, 9 H, Ar-H), 7.17 (d, J = 7.8 Hz, 2 H, Ar-H),
7.09 (t, J = 7.3 Hz, 1 H, Ar-H), 6.91 (d, J = 9.8 Hz, 2 H, Ar-H),
5.31 (d, J = 3.7 Hz, 2 H, 2 CH), 4.94 and 4.83 (br. s, each 1 H, 2
CHOH), 4.70 (m, 2 H, NCHH, NCHH), 4.59 (d, J = 3.7 Hz, 1 H,
CH), 4.41 (d, J = 4.7 Hz, 1 H, CH), 4.23 (d, J = 4.6 Hz, 1 H, CH),
4.26 (m, 2 H, NCHH, NCHH), 3.84 (s, 3 H, OCH3), 3.69 (s, 3 H,
OCH3), 3.34 (m, 2 H, CHH, CHH), 3.09 (m, 2 H, CHH, CHH)
ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 166.8 (NC=O), 165.1
(NC=O), 158.9 (Cq), 157.0 (Cq), 140.9 (Cq), 139.8 (Cq), 139.3
(Cq), 138.4 (Cq), 138.3 (Cq), 137.3 (Cq), 136.9 (Cq), 132.9 (Cq),
129.8 (CH), 128.5 (CH), 128.3 (CH), 127.2 (CH), 127.0 (CH), 123.2
(CH), 116.0 (CH), 113.9 (CH), 83.5 (CH), 80.9 (CH), 71.7 (CH),
71.6 (CH), 61.6 (CH), 61.3 (CH3), 59.8 (CH3), 55.3 (CH), 40.6
Acknowledgments
We would like to thank the Dirección General de Investigación –
Ministerio de Ciencia e Innovación (DGI-MICINN) (Project
CTQ2009-09318), Universidad Complutense-Banco Santander
(UCM-BSCH) (Grant GR58/08), and Comunidad Autónoma de
Madrid (CAM) (Project S2009/PPQ-1752) for financial support.
C.A. and G.G.C. thank the MICINN for a Ramón y Cajal grant
co-financed by the European Social Fund and a predoctoral grant,
respectively.
[1] For recent reviews, see: a) V. M. Dembitsky, J. Nat. Med. 2008,
62, 1; b) Z. Rappoport, J. F. Liebman (Eds.), The Chemistry of
Cyclobutanes, John Wiley & Sons, Ltd., Chichester, UK, 2005,
vol. 1, pp. 357–440; c) E. Lee-Ruff, G. Mladenova, Chem. Rev.
2003, 103, 1449; d) J. C. Namyslo, D. Kaufmann, Chem. Rev.
2003, 103, 1485; e) A. K. Sadana, R. K. Saini, W. E. Billups,
Chem. Rev. 2003, 103, 1539; for a selected reference, see: f)
J. M. Um, H. Xu, K. N. Houk, W. Tang, J. Am. Chem. Soc.
2009, 131, 6664.
[2] For a review on the [2+2] cycloaddition chemistry of allenes,
see: a) B. Alcaide, P. Almendros, C. Aragoncillo, Chem. Soc.
Rev. 2010, 39, 783; for allene/alkyne [2+2] cycloadditions, see:
b) D. J. Pasto, W. Kong, J. Org. Chem. 1988, 53, 4807; c) D. J.
Pasto, K. D. Sugi, J. Org. Chem. 1992, 57, 1146; d) Q. Shen,
G. B. Hammond, J. Am. Chem. Soc. 2002, 124, 6534; e) Y. Hor-
ino, M. Kimura, S. Tanaka, T. Okajima, Y. Tamaru, Chem.
Eur. J. 2003, 9, 2419; f) Y. Yang, J. L. Petersen, K. K. Wang, J.
Org. Chem. 2003, 68, 5832; g) H. Ohno, T. Mizutani, Y. Fado,
K. Miyamura, T. Tanaka, Angew. Chem. Int. Ed. 2005, 44,
5113; h) K. M. Brummond, D. Chen, Org. Lett. 2005, 7, 3473;
i) C. H. Oh, A. K. Gupta, D. I. Park, N. Kim, Chem. Commun.
2005, 5670; j) C. Mukai, Y. Hara, Y. Miyashita, F. Inagaki, J.
Org. Chem. 2007, 72, 4454; k) X. Jiang, S. Ma, Tetrahedron
2007, 63, 7589; l) T. V. Ovaska, R. E. Kyne, Tetrahedron Lett.
2008, 49, 376; m) N. Saito, Y. Tanaka, Y. Sato, Org. Lett. 2009,
11, 4124; n) M. R. Siebert, J. M. Osbourn, K. M. Brummond,
D. J. Tantillo, J. Am. Chem. Soc. 2010, 132, 11952.
(CH ), 40.4 (CH ), 36.3 (CH ) ppm. IR (CHCl ): ν = 3434, 1746,
˜
2
2
2
3
1648 cm–1. HRMS (ESI): calcd. for C40H37N2O7 [M + H]+
657.2601; found 657.2607.
Bis(tricyclic) β-Lactam (–)-12b: From bis(allenyne) (+)-10b (30 mg,
0.04 mmol). Chromatography (hexanes/ethyl acetate, 1:1) of the
residue gave compound (–)-12b (16 mg, 53%) as a yellow oil. [α]2D0
1
= –22.3 (c = 1.0, CHCl3). H NMR (300 MHz, CDCl3, 25 °C): δ
= 7.45 (m, 3 H, Ar-H), 7.34 (m, 2 H, Ar-H), 7.17 (m, 3 H, Ar-H),
6.90 (m, 5 H, Ar-H), 5.31 (d, J = 5.7 Hz, 1 H, CH), 4.93 and 4.80
(br. s, each 1 H, 2 CHOH), 4.73 (m, 2 H, NCHH, NCHH), 4.59
(d, J = 4.1 Hz, 1 H, CH), 4.41 (d, J = 4.8 Hz, 1 H, CH), 4.25 (m,
2 H, NCHH, NCHH), 4.21 (d, J = 4.8 Hz, 1 H, CH), 3.84 (s, 3 H,
CH3), 3.83 (s, 3 H, CH3), 3.69 (s, 3 H, CH3), 3.33 (m, 2 H, CHH,
CHH), 3.14 (m, 2 H, CHH, CHH) ppm. 13C NMR (75 MHz,
CDCl3, 25 °C): δ = 166.6 (NC=O), 165.2 (NC=O), 159.0 (Cq),
158.9 (Cq), 157.1 (Cq), 139.9 (Cq), 139.7 (Cq), 138.5 (Cq), 137.9
(Cq), 136.9 (Cq), 136.6 (Cq), 131.8 (Cq), 131.6 (Cq), 129.8 (CH),
128.3 (CH), 128.1 (Cq), 127.9 (Cq), 123.2 (CH), 116.1 (CH), 114.0
(CH), 113.9 (CH), 83.5 (CH), 80.9 (CH), 71.7 (CH), 71.6 (CH),
61.7 (CH), 61.2 (CH), 59.8 (CH), 40.6 (CH2), 40.4 (CH2), 36.3
(CH ) ppm. IR (CHCl ): ν = 3435, 1748, 1646 cm–1. HRMS (ESI):
˜
2
3
calcd. for C41H39N2O8 [M + H]+ 687.2706; found 687.2701.
[3] For selected reviews and leading papers, see: a) J. Mulchande,
R. Oliveira, M. Carrasco, L. Gouveia, R. C. Guedes, J. Iley, R.
Moreira, J. Med. Chem. 2010, 53, 241; b) B. Alcaide, P. Al-
Bis(tricyclic) β-Lactam (+)-12c: From bis(allenyne) (+)-10c (48 mg,
0.08 mmol). Chromatography (hexanes/ethyl acetate, 1:2) of the
Eur. J. Org. Chem. 2011, 364–370
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369

B. Alcaide, P. Almendros, C. Aragoncillo, G. Gómez-Campillos
FULL PAPER
mendros, C. Aragoncillo, Chem. Rev. 2007, 107, 4437; c) F.
Von Nussbaum, M. Brands, B. Hinzen, S. Weigan, D. Häbich,
Angew. Chem. Int. Ed. 2006, 45, 5072; Angew. Chem. 2006, 118,
5194; d) J. D. Rothstein, S. Patel, M. R. Regan, C. Haenggeli,
Y. H. Huang, D. E. Bergles, L. Jin, M. D. Hoberg, S. Vidensky,
D. S. Chung, S. V. Toan, L. I. Bruijn, Z.-z. Su, P. Gupta, P. B.
Fisher, Nature 2005, 433, 73; e) L. Kvaerno, T. Ritter, M.
Werder, H. Hauser, E. M. Carreira, Angew. Chem. Int. Ed.
2004, 43, 4653; Angew. Chem. 2004, 116, 4753; f) D. A. Burnett,
Curr. Med. Chem. 2004, 11, 1873; g) B. Alcaide, P. Almendros,
Curr. Med. Chem. 2004, 11, 1921; h) G. Veinberg, M. Vorona,
I. Shestakova, I. Kanepe, E. Lukevics, Curr. Med. Chem. 2003,
10, 1741; i) D. Niccolai, L. Tarsi, R. J. Thomas, Chem. Com-
mun. 1997, 2333; j) R. B. Morin, M. Gorman (Eds.), Chemistry
Chem. 2007, 119, 6804; g) B. Alcaide, P. Almendros, T. Martí-
nez del Campo, Angew. Chem. 2006, 118, 4613; Angew. Chem.
Int. Ed. 2006, 45, 4501.
[6] For a report on the thermal [2+2] cyclization of enallenes, see:
a) B. Alcaide, P. Almendros, C. Aragoncillo, Org. Lett. 2003,
5, 3795; b) B. Alcaide, P. Almendros, C. Aragoncillo, M. C.
Redondo, M. R. Torres, Chem. Eur. J. 2006, 12, 1539.
[7] a) B. Alcaide, P. Almendros, C. Aragoncillo, Chem. Commun.
1999, 1913; b) B. Alcaide, P. Almendros, C. Aragoncillo, J. Org.
Chem. 2001, 66, 1612; c) B. Alcaide, P. Almendros, J. M.
Alonso, M. F. Aly, C. Pardo, E. Sáez, M. R. Torres, J. Org.
Chem. 2002, 67, 7004.
[8] B. Alcaide, P. Almendros, N. Rodríguez-Salgado, J. Org. Chem.
2000, 65, 3310.
and Biology of β-Lactam Antibiotics, Academic, New York, [9] B. Alcaide, P. Almendros, C. Aragoncillo, Chem. Eur. J. 2002,
1982, vols. 1–3.
8, 1719.
[4] Tricyclic β-lactam antibiotics that are generally referred to as
trinems are a new class of synthetic antibacterial agents featur-
ing good resistance to β-lactamases and dehydropeptidases: a)
O. Kanno, I. Kawamoto, Tetrahedron 2000, 56, 5639; b) S.
Hanessian, B. Reddy, Tetrahedron 1999, 55, 3427; c) C. Ghiron,
T. Rossi “The Chemistry of Trinems” in Targets in Heterocyclic
Systems-Chemistry and Properties (Eds.: O. A. Attanasi, D.
Spinelli), Societa Chimica Italiana, Rome, 1997, vol. 1, pp.
161–186; for a review on tricyclic β-lactams, see: d) B. Alcaide,
P. Almendros, Curr. Org. Chem. 2002, 6, 245.
[5] See, for instance: a) B. Alcaide, P. Almendros, A. Luna, M. R.
Torres, Adv. Synth. Catal. 2010, 352, 621; b) B. Alcaide, P. Al-
mendros, T. Martínez del Campo, M. T. Quirós, Chem. Eur. J.
2009, 15, 3344; c) B. Alcaide, P. Almendros, R. Carrascosa, T.
Martínez del Campo, Chem. Eur. J. 2009, 15, 2496; d) B. Al-
caide, P. Almendros, T. Martínez del Campo, E. Soriano, J. L.
Marco-Contelles, Chem. Eur. J. 2009, 15, 1901; e) B. Alcaide,
P. Almendros, R. Carrascosa, M. C. Redondo, Chem. Eur. J.
2008, 14, 637; f) B. Alcaide, P. Almendros, T. Martí-
nez del Campo, Angew. Chem. Int. Ed. 2007, 46, 6684; Angew.
[10] J. E. Baldwin, J. Chem. Soc., Chem. Commun. 1976, 734.
[11] a) C. Glaser, Ber. Dtsch. Chem. Ges. 1869, 2, 422; b) G. Eglin-
ton, A. R. Galbrait, Chem. Ind. (London) 1956, 737; c) A. S.
Hay, J. Org. Chem. 1962, 27, 3320.
[12] a) P. Cadiot, W. Chodkiewicz in Chemistry of Acetylenes (Ed.:
H. G. Viehe), Marcel Dekker, New York, 1969, pp. 597; b) S.
Kim, Angew. Chem. 2009, 121, 7876; Angew. Chem. Int. Ed.
2009, 48, 7740.
[13] For a report describing that tanikolide dimer is a more potent
inhibitor of cytoplasmic proteins than its monomer, see: a) M.
Gutiérrez, E. H. Andrianasolo, W. K. Shin, D. E. Goeger, A.
Yokochi, J. Schemies, M. Jung, D. France, S. Cornell-Kennon,
E. Lee, W. H. Gerwick, J. Org. Chem. 2009, 74, 5267; similarly,
the increased antibacterial activity of β-lactam heterodimers in
comparison with their monomeric components has been re-
ported: b) D. D. Long, J. B. Aggen, B. G. Christensen, J. K.
Judice, S. S. Hegde, K. Kaniga, K. M. Krause, M. S. Linsell,
E. J. Moran, J. L. Pace, J. Antibiot. 2008, 61, 595.
Received: September 1, 2010
Published Online: November 24, 2010
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