A versatile and stereoselective synthesis of fnnctionalized cyclobutenes

Article abstract of DOI:10.1002/anie.201000911

(Figure Presented) Square flat: A new atom-economical method for the synthesis of functionalized cyclobutenes has been developed. This versatile sequence hinges upon a unique combination of an elegant photochemical isomerization and a palladium-catalyzed

Full text of DOI:10.1002/anie.201000911

Communications
DOI: 10.1002/anie.201000911
Small-Ring Systems
AVersatile and Stereoselective Synthesis of Functionalized
Cyclobutenes**
Frꢀdꢀric Frꢀbault, Marco Luparia, Maria Teresa Oliveira, Richard Goddard, and Nuno Maulide*
All-carbon four-membered rings are incorporated in a high
number of naturally occurring and/or biologically active
substances (Scheme 1),[1] and their preparation has been an
ubiquitous topic in organic synthesis ever since chemists
realized the potential associated with their inherent ring
Scheme 1. Structures of selected natural products containing cyclo-
Scheme 2. Photochemical approaches to the synthesis of cyclobutenes.
butane and cyclobutene units.[4]
directly connected to the four-membered ring highlights a
pressing need for more flexible and stereoselective routes to
substituted cyclobutenes.
strain. Cyclobutanones and cyclobutenones are arguably the
most readily available derivatives of cyclobutane, and the
ones that have been most often studied.[2] In contrast,
stereoselective and efficient methods for the preparation of
cyclobutane and cyclobutene derivatives are comparatively
scarce.[3] Indeed, cyclobutenes are especially attractive build-
ing blocks owing to the synthetic versatility associated with
the presence of the additional carbon–carbon double bond in
the four-membered ring.[3]
The photocycloaddition of maleic anhydride to acetylene
is probably a benchmark of cyclobutene synthesis (Sche-
me 2a).[3a,5] In spite of the numerous advances reported in the
desymmetrization of the adduct 1 (and analogues) through
ring-opening reactions,[6] the somewhat low synthetic versa-
tility of products bearing two carboxylic acid derivatives
When we considered such routes, our interest was piqued
by the 40-year-old, yet little explored, photoisomerization of
2-pyrone (2) reported to generate lactone 3 (Scheme 2b).[7a]
Compound 3 is known to be a sensitive, unstable, and
potentially explosive substance[7a,b] which, perhaps unsurpris-
ingly remained overlooked as a potential starting material for
further elaboration.[7] We were lured by its appeal as a
promising, versatile starting material for a variety of chemical
transformations. Herein we describe the first catalytic,
stereoselective transformations of 3 that suggest a versatile
synthesis of functionalized cyclobutenes in only two oper-
ations from 2-pyrone.
In our hands, the photochemical isomerization of readily
available 2 to give 3 proceeded in quantitative yield. Stock
solutions of 3 in diethyl ether with concentrations in the range
of 0.1 to 0.2m could be stored and routinely handled without
special precautions.[8] Initial attempts at metal-promoted
functionalization of 3 quickly revealed that its strained allylic
lactone moiety responded productively to palladium cataly-
sis.[9] After optimization,[10] we eventually found that treat-
ment of 3 with sodium dimethylmalonate in the presence of
5 mol% [Pd(PPh3)4] led to a nearly quantitative yield of the
cis-cyclobutene carboxylic acid 4a as a single diastereomer
(Scheme 3).[11]
[*] Dr. F. Frꢀbault,[+] Dr. M. Luparia,[+] M. T. Oliveira, Dr. R. Goddard,
Dr. N. Maulide
Max-Planck-Institut fꢁr Kohlenforschung
Kaiser-Wilhelm-Platz 1, 45470 Mꢁlheim an der Ruhr (Germany)
Fax: (+49)208-306-2999
E-mail: maulide@mpi-muelheim.mpg.de
Homepage: http://www.kofo.mpg.de/maulide
[+] These authors contributed equally.
[**] We are grateful to the Max Planck Society and the Max-Planck-
Institut fꢁr Kohlenforschung for generous funding of our research
programs. Invaluable assistance from our HPLC, NMR, and X-ray
Departments is acknowledged. We thank Dr. W. Klotzbꢁcher (MPI
Mꢁlheim) for a donation of photochemical equipment, U. Specht
for assistance with photochemical reactions, and the ANKA
synchrotron facility, Karlsruhe, for beam time.
Encouraged by what essentially amounts to a stereose-
lective synthesis of a highly functionalized cyclobutene
derivative in only two steps, we investigated further the
range of nucleophiles that can be employed in this process
(Table 1). For ease of purification and analytical purposes,
most of the crude acids 4 were routinely converted into the
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201000911.
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of azlactone 6a led to the formation of a new product which
we surmised to be the alkylated acid A. However, single-
crystal X-ray analysis of this compound showed it to be the
rearranged azabicycle 7a.[11] The putative product A appears
to undergo rupture of the azlactone moiety followed by an
unusually facile cyclization to the lactam 7a (Scheme 4). To
our knowledge, this type of rearrangement is unprecedented
in the chemistry of azlactones.[13]
Scheme 3. First result on the catalytic functionalization of lactone 3.
Table 1: Scope of the catalytic alkylation of lactone 3.[a]
Entry
R
R’
EWG
Product
Yield [%][b]
1
2
3
4
5
6
7
8
Me
Bn
tBu
Et
H
H
H
Me
Et
nBu
Bn
allyl
CO2Me
CO2Bn
CO2tBu
CO2Et
4a
4b
4c
5d
4e
5 f
5g
5h
5i
[92]
[47]
[42]
80
[90]
74
83
76
59
Scheme 4. Alkylation of lactone 3 with azlactone 6a and unexpected
rearrangement.
9
Me
CH2C6H4(4-NO2)
CO2Me
ꢁ
10
11
12
(CH2)2CH CH
CH2CO2Et
H
5j
5k
5l
88
Et
Me
CO2Et
CONPh2
51
An additional intriguing aspect was the very high
diastereoselectivity of this reaction. Careful analysis of
crude reaction mixtures of 7a revealed the presence of only
small amounts (typically ꢀ 10%) of the lactam epimeric at C4
(Scheme 4). Remarkably, this constitutes a rare case of high
double diastereoselectivity using azlactones, in the absence of
external chiral ligands (vide infra).[14]
46[c]
[a] All reactions were conducted on a 0.1 or 0.2 mmol scale, with 5 mol%
[Pd(PPh3)4], 2.0 equiv NaH, and 2.2 equiv nucleophile at 08C, unless
noted otherwise. [b] Yields of pure isolated products. Yields in brackets
correspond to analytically pure crude carboxylic acids 4. [c] Compound 5l
was obtained as a single diastereoisomer after methylation.[8]
A number of trends emerged upon inspection of the
substrate scope (Table 2).[10] Interestingly, the aromatic por-
tion of the incoming azlactone nucleophile played a signifi-
cant role in this reaction (Table 2, entries 1 to 4); nearly 10%
corresponding methyl esters 5 using thionyl chloride in
methanol. As can be seen from Table 1, and in spite of the
high instability of lactone 3, a variety of active methylene
derivatives perform competently as nucleophiles in this
reaction. The electron-withdrawing substituents could be
varied in this process (Table 1, entries 1–3 and 12), and
substituted nucleophiles smoothly led to all-carbon quater-
nary centers (Table 1, entries 4–11). Importantly, alkyl,
benzyl, acetate, allyl, and homopropargyl groups were well
tolerated. Furthermore, high diastereoselectivity could be
obtained when the carbonyl functionalities of the nucleophile
were not identical (Table 1, entry 12).
Table 2: Scope of the catalytic synthesis of azabicycles 7.[a]
Entry Azlactone Ar
R
Product Yield [%] (d.r.)[b]
The high atom economy of this reaction sequence
(starting from 2-pyrone (2)) translates into a significant
increase of molecular complexity employing only the simplest
of starting materials, and stimulated us to seek additional
opportunities. In line with our desire to target biologically
relevant substructures, we became intrigued by the possibility
of generating cyclobutene amino acid derivatives. Indeed,
much interest has been recently devoted to the biological
potential of constrained amino acids.[12] It appeared to us that
the use of azlactones as nucleophiles in this process might lead
to elaborated amino acid scaffolds with interesting properties.
In the event, exposure of lactone 3 to conditions
analogous to those listed in Scheme 3, but in the presence
1
2
3
4
5
6
7
8
9
10
6a
6b
6c
6d
6e
6 f
6g
6h
6i
Ph
Me
7a
7b
7c
7d
7e
7 f
57 (90:10)
37 (90:10)
45 (91:9)
68 (93:7)
26 (>95:5)
46 (95:5)
54 (93:7)
57 (94:6)
47 (88:12)
56 (90:10)
(4-OMe)-C6H4
(3,5-CF3)-C6H3
(4-NO2)-C6H4
Ph
Bn
(4-NO2)-C6H4 Bn
Et
Bu
7g
7h
(CH2)2Ph 7i
allyl 7j
6j
[a] All reactions were conducted in a 0.2 mmol scale, with 5 mol%
[Pd(PPh3)4], 2.0 equiv NEt3, and 2.25 equiv 6 at 08C, unless noted
otherwise. [b] Yields of isolated diastereomerically pure products; d.r.
values refer to the crude reaction mixture.
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5673

Communications
increments in yield were observed when progressing from
Thus, ring-opening metathesis/cross-metathesis[17] of azabi-
cycle 11 under an atmosphere of ethylene (1 atm) promoted
by Grubbsꢀ second-generation catalyst afforded the diaster-
eomerially pure pyrrolidinone 12, whose structure is reminis-
cent of kainic and domoic acid derivatives.[18] In another
sequence, a two-step halolactonization of triester 5a led to
compound 13, which embodies the core structure of pestalo-
tiopsin A.[19] It is testament to the power of this approach that
synthetically relevant compounds can be derived from 2-
pyrone in only three straightforward synthetic manipulations.
Finally, initial studies aimed at developing an asymmetric
variant provided encouraging results (Scheme 6). The simple
replacement of the previously employed palladium catalyst
donating (p-OMe) to inductive withdrawing (p-CF3), neutral
(H), and strongly withdrawing (p-NO2) substituents. That this
was not simply a conversion effect could be seen by NMR
analysis of the crude mixtures: considerably fewer by-
products were observed when the p-nitroazlactone 6d was
employed. This effect[15] was also apparent in other substrates
(cf. Table 2, entries 5 and 6, for example), and we opted for
the nitrophenyl appendage in subsequent studies. Different
alkyl, allyl, and benzyl moieties as the R group in 6 were
compatible with this transformation (Table 2, entries 6–10).
The adducts formed through this simple reaction
sequence proved amenable to a variety of transformations,
which exploited the latent reactivity of the functional groups
generated (Scheme 5). For instance, the strained double bond
Scheme 6. Preliminary results on asymmetric alkylations of lactone 3.
The absolute configuration of the major enantiomer of (À)-14 and (+)-
15 was not determined. EDCl=1-ethyl-3-(3-dimethylaminopropyl)car-
bodiimide.
system with a mixture of the dimeric [{Pd(C3H5)Cl}2] and the
Trost ligand (R,R)-L1, without any change in reaction
conditions, led to product (À)-14 (isolated as the benzamide
derivative) in a 89.5:10.5 enantiomer ratio[20] (Scheme 6; the
absolute configuration of the major enantiomer was not
determined). Transposing this to the azlactone case using
ligand (R,R)-L2 led to azabicycle (+)-15 in an impressive 97:3
enantiomer ratio. Interestingly, the powerful asymmetric
induction of ligand L2 strongly biased the inherently high
diastereoselectivity of the racemic process (cf. Scheme 4 and
Table 2), and a nearly 2:1 diastereomer ratio of epimers at C4
was obtained (Scheme 6, major diastereomer depicted;
absolute configuration of the major enantiomer not deter-
mined). The origin of such an effect is not clear at present, but
the prospect of weakening or even overriding the innate
diastereopreference of the coupling between lactone 3 and
nucleophiles through the choice of an appropriate ligand is
particularly exciting and is being studied further.
Scheme 5. Functionalization of the adducts obtained. DCM=dichloro-
methane, MTBE=methyl tert-butyl ether, NIS=N-iodosuccinimide,
TFA=trifluoroacetic acid.
in cyclobutene 5d could be easily dihydroxylated, affording
the tetrasubstituted cyclobutane 10 in good yield with
complete control of all four stereogenic centers. Aiming at
biologically relevant scaffolds, the amide derivative
8
smoothly underwent Hofmann rearrangement to give the
novel constrained, fully protected cyclobutene-g-amino acid
9.[16]
Other manipulations further showcase the synthetic
advantage derived from the cyclobutene double bond and
hint at potential applications of this method in total synthesis.
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10773; e) R. Alibꢃs, P. de March, M. Figueredo, J. Font, M.
In summary, we have developed a new and concise
synthesis of functionalized cyclobutenes. To achieve this goal,
palladium catalysis was decisive in taming the instability of
lactone 3. The overall process reported here combines the
efficiency of clean, highly efficient photochemical reactions
with the powerful selectivity that can be imparted by metal
catalysis and should find broad applications in synthesis. That
this sequence of events proceeds with excellent atom
economy starting from cheap and readily available, achiral
“flat” pyrones to produce versatile added-value products is
perhaps the most striking consequence of such a combination.
Further developments of this methodology and related
sequences that harness the potential of lactone 3 and its
derivatives, as well as applications to the total synthesis of
biologically relevant targets are underway in our laboratories.
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[8] For details, see the Supporting Information.
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Received: February 12, 2010
Revised: March 12, 2010
Published online: July 13, 2010
Keywords: azlactones · cyclobutenes · palladium ·
.
photochemistry · stereoselective reactions
[10] See the Supporting Information.
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