Expanding the scope of Enantioselective FerroPHANE-promoted [3+2] annulations with α,β-unsaturated ketones

Article abstract of DOI:10.1002/chem.200901893

The planar chiral 2-phospha [3]ferrocenophane I has been shown to be the first efficient nucleo- philic organocatalyst for the enantiose- lective synthesis of cyclopentenyl- phosphonates, through [3+2] cycliza- tions between diethyl allenylphospho- nate a

Full text of DOI:10.1002/chem.200901893

FULL PAPER
DOI: 10.1002/chem.200901893
Expanding the Scope of Enantioselective FerroPHANE-Promoted [3+2]
Annulations with a,b-Unsaturated Ketones
Nathalie Pinto,[a] Mathilde Neel,[a] Armen Panossian,[a] Pascal Retailleau,[a]
Gilles Frison,[b] Arnaud Voituriez,[a] and Angela Marinetti*[a]
Abstract: The planar chiral 2-phos-
pha[3]ferrocenophane has been
deneacetone and analogous bis-enones,
leading to functionalised cyclopentenes
with either monocyclic or spirocyclic
structures (ee 84–95%). It has been
shown that the residual enone func-
tions in the resulting cyclopentenes can
be involved in subsequent cyclization
steps to afford unprecedented C2-sym-
metric bis-cyclopentenylketones. In
order to provide insight into the behav-
iour of FerroPHANE I as a chiral cata-
lyst in [3+2] cyclisations, the energeti-
cally most favoured isomers of the key
phosphine-allene adduct have been cal-
culated by DFT methods. Factors likely
to control the chiral induction process
are highlighted.
I
shown to be the first efficient nucleo-
philic organocatalyst for the enantiose-
lective synthesis of cyclopentenyl-
phosphonates, through [3+2] cycliza-
tions between diethyl allenylphospho-
nate and a,b-unsaturated ketones. The
same catalyst has also been applied to
the highly enantioselective [3+2] cycli-
zations of allenic esters with dibenzyli-
Keywords: allenyl phosphonates ·
cyclization
·
enantioselectivity
·
organocatalysis · spiro compounds
Introduction
Since then, intensive efforts and some significant achieve-
ments have been made, by taking advantage of either
known[6] or specifically designed chiral nucleophilic phos-
phines.[7]
Phosphine organocatalysis is currently a rapidly expanding
field affording an impressive number of new methods for
the formation of carbon-carbon and carbon-heteroatom
bonds from easily available starting materials.[1] It notably
represents a privileged tool for the construction of cyclic
compounds in single-step fashion through the use of simple
allenes or alkynes and electron-poor olefins or imines as
starting materials.[2] Surprisingly, however, the fascinating
field of asymmetric phosphine organocatalysis is currently
only at a very early stage of development.[3] It was only in
the late 1990s that the first successful attempts directed to-
wards this challenging target appeared in the literature,
thanks to the pioneering work of Vedejs[4] and Zhang.[5]
Our recent contributions to the field of asymmetric phos-
phine organocatalysis have included the development of
new applications of chiral phosphines,[8] as well as the design
of planar chiral 2-phospha[3]ferrocenophanes as new cyclic
scaffolds for phosphorus-based catalysts.[9] From these last
studies, the trimethylsilyl-substituted, P-cyclohexyl-ferroce-
nophane I (called FerroPHANE) has been highlighted as a
highly efficient promoter for enantioselective cyclizations of
allenic esters and both unsaturated esters and ketones
(Scheme 1).
Now, taking advantage of the excellent catalytic proper-
ties of the new phosphine I, we intend to expand the current
range of organocatalytic enantioselective processes further.
In this paper we report the most recent results of our inves-
tigations into the catalytic use of FerroPHANE I in [3+2]
cyclizations, as well as the first attempts to elucidate the
mechanism of chiral induction by DFT studies.
[a] N. Pinto, M. Neel, Dr. A. Panossian, Dr. P. Retailleau,
Dr. A. Voituriez, Dr. A. Marinetti
Centre de Recherche de Gif
Institut de Chimie des Substances Naturelles—CNRS UPR 2301
1, av. de la Terrasse, 91198 Gif-sur-Yvette Cedex (France)
Fax : (+33)169-07-7247
E-mail: angela.marinetti@icsn.cnrs-gif.fr
[b] Dr. G. Frison
Laboratoire des Mꢀcanismes Rꢀactionnels—CNRS UMR 7651
Ecole Polytechnique, Dꢀpartement de Chimie
91128 Palaiseau Cedex (France)
Results and Discussion
Enantioselective annulations on allenylphosphonates: The
first catalytic application of FerroPHANE I that we would
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200901893.
Chem. Eur. J. 2010, 16, 1033 – 1045
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1033

Table 1. Enantioselective [3+2] cyclizations between allenylphosphonate
1 and enone 2a.
Entry
PR3
3a/4
Yield of 3a (conv.)[a]
ee[b]
1
2
3
4
5
6
7
8
(R)-BINAP
A
4:96
– (22)
– (100)
– (74)
n.d.
n.d.
n.d.
8
81
90
10:90
19:81
25:75
12:88
95:5
N
(S)-Me-BPE
(S)-tBu-Binepine
N
<10 (100)[c]
~10 (100)
80 (100)
49 (56)[d]
30 (40)[e]
Scheme 1. Enantioselective [3+2] cyclizations promoted by Ferro-
PHANE I.
N
95:5
82:18
90
93
N
[a] For an allene/enone ratio of 1:2. [b] By chiral HPLC. [c] At a 30%
catalyst loading. [d] At a 5 mol% catalyst loading. [e] Reaction per-
formed at 1008C.
like to present here is its convenient use in [3+2] cycliza-
tions on allenylphosphonates, leading to the highly enantio-
selective synthesis of functionalised cyclopentenylphospho-
nates.
cause alkyne 4 was also the major product in this case.
Diop, PhanePhos and Et-FerroTANE did not afford active
catalysts.
The continuing search for synthetic approaches to phos-
phonates and phosphonic acids relates both to their involve-
ment in synthetically important reactions and to their appli-
cations in medicine and other fields.[10] Common and suita-
ble methods for the synthesis of phosphonates involve either
formation of the carbon-phosphorus bond or modification
of the carbon skeleton of a simple, easily available phospho-
nate to generate new species of increased complexity. So far
only a few examples of phosphine-promoted organocatalytic
transformations of phosphonates and other phosphorus-
functionalised substrates have been reported,[11,12] and none
of them has made use of allenylphosphonates as starting ma-
terials, despite the wide uses of the analogous allenic esters
in organocatalysed reactions. Our initial investigations[8c]
have shown that allenic phosphonates can serve as readily
available[13] and inexpensive substrates for phosphine-pro-
moted organocatalytic cyclization reactions. Attempts to
perform enantioselective cyclizations through the use of
chiral nucleophilic phosphines, such as (S)-tBu-Binepine—
one of the most prominent catalysts for enantioselective cyc-
lization reactions[6a,b,8d]—were hampered, however, by the
very low reactivity of allenylphosphonates, and the low con-
version rates dramatically decreased the usefulness of these
reactions. Gratifyingly, these limitations have been over-
come by the use of FerroPHANE I as the catalyst.
In relation to all other catalysts tested so far, Ferro-
PHANE I displayed an excellent reactivity profile, affording
the desired cyclopentene 3a as the major product. The
alkyne by-product 4 was formed in only <5% amount when
optimised conditions were applied; these include the use of
a twofold excess of enone 2a, use of toluene as the solvent,
a 0.3m concentration of the reactants and heating at 1208C
for 24 h (entry 6). Slightly lower 3a/4 ratios were obtained
in reactions performed in toluene at 1008C (entry 8).
The high chemoselectivity of FerroPHANE in these reac-
tions, in terms of the cyclopentene/alkyne ratio, has so far
hardly been explained. From the mechanism postulated for
analogous reactions with allenic esters,[2c,14] the first key step
of the catalytic cycle leading to 3a should be the addition of
the nucleophilic phosphine to the allenic substrate 1 to give
the zwitterionic intermediate A (Scheme 2). The isomeriza-
Scheme 2. Key intermediate for the phosphine-promoted transformations
of allenylphosphonates.
In a first series of experiments, (S,S)-FerroPHANE I was
used to promote cyclization reactions between diethyl
propa-2,3-dienylphosphonate (1) and 3-(1-naphthyl)-1-phe-
nylpropenone (2a). For purposes of comparison, (S)-tBu-Bi-
nepine and some commercially available chiral phosphines
were also evaluated. Representative results are given in
Table 1.
BINAP, Me-DuPHOS, DIPAMP, Me-BPE and tBu-Bine-
pine converted 1 mainly into the isomeric propynylphospho-
nate 4. With tBu-Binepine an enantiomeric excess of 81%
was measured, but the isolated yield of 3a was very low, be-
tion process leading to the propynylphosphonate 4 might
proceed via the same intermediate through intermolecular
proton exchange reactions, in which A would behave as a
strong base.[15,16] The high efficiency of FerroPHANE I in
terms of product selectivity is therefore probably the result
of an increased nucleophilicity of the intermediate phos-
phine-allene adduct, orienting the reaction course predomi-
nantly to the desired cyclization product 3a.
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ACHTUNGTRENNUNG[3+2] Annulations with a,b-Unsaturated Ketones
FULL PAPER
FerroPHANE I also proved to be especially robust and
Enantioselective annulations on bis-enones: [3+2] Cycliza-
tions between allenoates and divinyl ketones were next con-
sidered as suitable applications for FerroPHANE I.
enantioselective as a catalyst in this reaction: an enantio-
meric excess as high as 90% was obtained, although pro-
longed heating at 1208C was required for the reaction to
take place with good conversion rates and chemoselectivity
(entry 6 in Table 1). A reduction in the catalyst loading to
5% decreases the conversion rate, although the same levels
of enantioselectivity are retained (entry 7).
Further experiments to evaluate the scope of the above
cyclization reactions were then conducted, by variation of
the enone substrates 2 (Table 2). With enones 2b–l the cor-
responding cyclopentenes 3 were obtained as the major iso-
mers, with very high regio- and diastereoselectivities (only
trace amounts of other isomers were observed). The cycliza-
tion reactions take place by attack of the allene g-carbon on
the enone in the Michael-type addition step. The trans ste-
reochemistry of the enone is retained in the final product.
Phosphine-promoted [3+2] annulations between allenic
esters and enones are widely documented as elegant and ef-
[2h,k,q,6b,e]
À
ficient protocols for carbon carbon bond formation.
Nevertheless, the use of bis-enone substrates—that is, diben-
zylidene acetone and analogues—has been barely men-
tioned in the literature. The only known examples of enan-
tioselective cyclizations on cyclic or acyclic dienones have
been reported by Fu, with use of tBu-Binepine as the chiral
promoter (four examples, with ee values of between 73 and
93%).[6b] With respect to simple enones, the peculiar advant-
age of these substrates is to give access to cyclopentenes
that each contain a residual, potentially reactive enone func-
tion. An attractive target would therefore be first to build a
cyclopentene ring through organocatalytic, enantioselective
cyclizations and then to perform stereocontrolled transfor-
mations of the residual double bond. This strategy is typified
here by a two-step sequence involving two successive orga-
nocatalysed cyclizations and FerroPHANE as the chiral aux-
iliary.
Table 2. Synthesis of cyclopentenylphosphonates 3 by FerroPHANE-cat-
alysed annulations.
At the outset of our studies, investigations were carried
out on cyclizations between buta-2,3-dienoates and dibenzy-
lidene acetone (dba) as the model substrate, in the presence
of FerroPHANE (Table 3). In principle, cyclizations be-
tween allenoates and a,b-unsaturated ketones might afford
both the a-addition products (from attack of the allene a-
carbon on the enone) and the g-addition products: that is, 4-
acyl-5-arylcyclopent-1-enecarboxylates and 5-acyl-4-arylcy-
clo-pent-1-enecarboxylates, respectively.[7d,14a] We had previ-
ously noticed that FerroPHANE I converts simple enones
mainly into the g-addition products.[9a] This is also the case
with reactions involving dba and butadienoates 5a–c, in
which almost perfect regioselectivity in favour of 7 has been
ascertained by NMR analysis of the crude reaction mixtures
(>20:1 ratios of regioisomers[18]).
Entry
R1
R2
Product
Yield [%]
ee [%]
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
3b
3c
3d
3e
3 f
3g
3h
3i
78
80
68
83
77
87
28
73
60
80
85
90
91
86
88
91
90
84
90
84
83
45
4-MeOC6H4
4-NO2C6H4
2-naphthyl
2-furyl
3-quinolyl
C5H11C C
Ph
Ph
Ph
Ph
ꢀ
4-MeOC6H4
4-NO2C6H4
2-furyl
Me
9
10
11
3j
3k
3l
Conditions: allene/enone 1:2 ratio.
Several reactants and reaction parameters were screened
in order to find optimal conditions with respect both to con-
version rates and to enantioselectivity. The best solvent
proved to be toluene, in which the expected cyclopentene
7a was obtained in 90% yield and 92% ee (entry 3 vs. 1 and
2).[19] A reduction in the temperature to 08C dramatically
decreased the yield, but no significant increase in the enan-
tioselectivity level was observed (93% ee, entry 4).
The replacement of ethyl buta-2,3-dienoate (5a) with
three-atom synthons bearing bulkier ester groups—that is
cyclohexyl (5b) or benzyl groups (5c)—led to cyclopentenes
7b and 7c with comparable enantiomeric excesses but in
lower isolated yields (entries 5 and 6).
Because alkynes might represent more convenient starting
materials than allenes, the possible use of ethyl but-2-ynoate
was also checked. The reaction afforded the desired cyclo-
pentene 7a, but required a much higher reaction tempera-
ture (1208C, 80% yield after 24 h), with a concomitant de-
crease in the enantiomeric excess to 85% (entry 7).
As shown in Table 2, the reactions can give good yields
and enantiomeric excesses of over 86% for enones bearing
substituted aryl or heteroaryl groups on the double bond
(entries 1–6). The 1-heptynoyl-substituted enone 2h displays
lower reactivity, but the annulation reaction retains a good
level of enantiocontrol, with an 84% ee. The reaction also
tolerates substituted aryl groups as the carbonyl substituents
(entries 8–10), whereas both conversion rates and enantiose-
lectivity decrease when benzylidene acetone is used as the
enone substrate (entry 11).
The results above highlight FerroPHANE I as the first
synthetically useful phosphine catalyst for enantioselective
annulations on allenylphosphonates. These reactions, taking
place with excellent control over chemo-, regio- and stereo-
selectivity, open the way to the development of new families
of cyclic enantioenriched vinylphosphonates, a well-known
useful class of intermediates for organophosphorus chemis-
try and organic synthesis.[17]
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1035

A. Marinetti et al.
Table 3. ACHTUNGTRENNUNG[3+2] Cyclizations between dibenzylideneacetone and buta-2,3-dienoates promoted by FerroPHANE
I.
2,6-dichlorophenyl) was isolat-
ed, because of the lower reac-
tivity of the hindered ortho-di-
chlorophenyl-substituted dou-
ble bond.[20] However, a mix-
ture of two annulation products
in a 1.7:1 ratio and in a com-
bined yield of 87% was ob-
tained from the reaction be-
tween enone 6h and ethyl buta-
2,3-dienoate (entry 5).
The five-membered cyclic
enones 8a–d, containing exocy-
clic double bonds, also undergo
[3+2] annulations with ethyl
buta-2,3-dienoate (5a) to afford
spirocyclic products containing
quaternary stereocentres (10a–
d). The spirocyclopentanones
Subst.
R
Solvent
Conditions[a]
Prod.
Yield (conv.) [%]
ee [%][b]
1
2
3
4
5
6
7
5a
5a
5a
5a
5b
5c
Et
Et
Et
Et
Cy
Bn
CH2Cl2
acetone
toluene
toluene
toluene
toluene
toluene
RT, 16 h
RT, 40 h
RT, 24 h
08C, 60 h
RT, 24 h
RT, 24 h
1208C, 24 h
7a
7a
7a
7a
7b
7c
7a
80 (100)
26 (28)
88
90
92
93
92
91
85
90 (100)
13 (20)
28 (80)[c]
70 (100)
80 (100)
ꢀ
MeC CCO2Et
[a] Allene/enone ratio 2:1. [b] By HPLC. The configurations of the final products were assigned on the basis
of the X-ray diffraction studies presented below. [c] Low yields are due to difficulties in separation of the final
product from the starting enone.
After this optimization process, ethyl buta-2,3-dienoate
was retained as the preferred reactant for further experi-
ments with a range of enone substrates. The conditions of
entry 3 in Table 3 were applied to reactions between 5a and
the acyclic and cyclic dienones 6d–h, 8a–e and 9 (Table 4).
The acyclic dienones 6d–h, bearing substituted aryl and
heteroaryl substituents, afforded cyclopentenes 7d–h with
good yields, high regioselectivities (>20:1 regioisomer
ratios) and uniformly high enantiomeric excesses (92–
95% ee). With dissymmetric substrates, the annulation reac-
tion can take place on both olefinic functions. High product
selectivity was observed when starting from the disymmetric
enone 6g bearing a phenyl and a 2,6-dichlorophenyl sub-
stituent (entry 4). Only cyclopentene 7g (Ar1 =Ph, Ar2 =
10a–d were obtained in moderate to good yields and high
enantiomeric excesses (84–92%, entries 6–9), although the
electron-rich 4-methoxyphenyl-substituted enone 8e failed
to react under the given conditions (entry 10). The six-mem-
bered cyclic enone 9 afforded the expected annulation prod-
uct 11 in 85% ee and 35% yield.
The above results demonstrate that, overall, Ferro-
PHANE I performs as well as the previously used tBu-Bine-
pine catalyst[6b] in cyclizations on enones containing exocy-
clic double bonds and allows the scope of these cyclizations
to be extended to a few additional substrates. These reac-
tions represent a valuable strategy for the enantioselective
construction of quaternary stereogenic centres at the cross-
points of spirocyclic derivatives.
With the cyclopentenes 7 now available with high regio-
and enantioselectivities through the use of FerroPHANE as
the catalyst, it seemed worthwhile to use them as substrates
for subsequent reactions on the remaining enone function.
With this in mind, we attempted a second phosphine-pro-
moted cyclization with cyclopentene 7a by treating this
compound with an excess of ethyl buta-2,3-dienoate in the
presence of achiral phosphines. PPh3 was found to promote
the desired cyclization reaction suitably at room tempera-
ture (Scheme 3). The product, isolated in 66% yield, consist-
ed mainly (over 95%) of the bis-cyclopentenyl ketone 12a.
Minor amounts of other isomers were also observed in the
crude reaction mixture. The stereochemistry of 12a was es-
tablished by single-crystal X-ray analysis. As shown by the
ORTEP drawing in Figure 1, 12a is the C2-symmetric, chiral
stereoisomer, with the C=O bond lying along the C2 symme-
try axis.
The good diastereoselectivities of reactions promoted by
PPh3 mean that effective stereochemical control of the
second cyclization reaction is effected by the first formed cy-
clopentene unit.
Other enantiomerically enriched bis-cyclopentenyl ke-
tones 12 could be accessed by the same two-step procedure:
after the production of the cyclopentenyl ketones 7d–f from
Table 4. ACHTUNGTRENNUNG[3+2] Cyclizations of dienones 6d–h, 8a–e and 9 with ethyl
buta-2,3-dienoate (5a) promoted by (S,S)-FerroPHANE I: reactants and
products.
Entry Subst. Ar1
Ar2
Product Yield [%] ee [%]
1
2
3
4
5
6
7
8
6d[a]
6e[a]
6 f[a]
6g[a]
6h[a]
8a[d]
8b[d]
8c[d]
8d[d]
8e[d]
9[d]
4-ClC6H4
4-MeC6H4
2-thienyl
Ph
Ph
Ph
4-ClC6H4
4-BrC6H4
2-furyl
4-MeOC6H4
Ph
4-ClC6H4
4-MeC6H4
2-thienyl
7d
7e
7 f
67
92
93
93
92
92/95
85
87
92
84
80
60[b]
55[b]
2,6-Cl2C6H3 7g
4-MeOC6H4 7h+7h’ 55[c]/32
10a
10b
10c
10d
10e
11
84
90
85
53
<10
35
9
10
11
n.d.
85
[a] Conditions: toluene, RT, 24 h, under argon, ethyl butadienoate/enone
ratio 2:1, 0.3m concentration of enone, FerroPHANE 10 mol%.
I
[b] Contains about 10% of a side product, presumably the a-addition
product. [c] Ar1 =Ph for the major regioisomer. [d] Reactions performed
at 408C for 18 h. These substrates are poorly soluble in toluene at RT
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ACHTUNGTRENNUNG[3+2] Annulations with a,b-Unsaturated Ketones
FULL PAPER
A “one-pot” process can be applied to these cyclizations,
avoiding isolation of the intermediate cyclopentenes 7, pro-
vided that total conversions of the starting bis-enones 6 into
compounds 7 are achieved in the first FerroPHANE-cata-
lysed annulations. Subsequent addition of PPh3 to the reac-
tion mixtures then allows the second annulation steps to be
performed (Note: FerroPHANE itself does not promote the
second cyclization steps at room temperature). This last pro-
cedure is especially convenient for unsymmetric enones,
from which the first cyclization step takes place with low
chemoselectivity. A representative example is the synthesis
of compound 12g (Scheme 4).
Scheme 3. ACHTUNGTRENNUNG[3+2] annulation with the 5-cinnamoylcyclopentene (7a).
Scheme 4. One-pot synthesis of the unsymmetric bis(cyclopentenyl)
ketone 12g.
Figure 1. X-ray crystal structure of compound 12a. Hydrogen atoms have
been omitted for clarity.
The above experiments simply reveal that the chiral cyclic
moieties of 7 may effect efficient stereocontrol in reactions
involving the enone functions. In the targeted organocatalyt-
ic cyclizations two additional stereogenic centres are gener-
ated with good diastereoselectivity. As an extension of this
work, other relevant transformations of the same enone
functions might be considered, with the aim of taking ad-
vantage of possible high levels of diastereocontrol.
As a very preliminary investigation, we performed the re-
duction of the carbonyl function of 7a into the correspond-
ing alcohol. Reductions either with NaBH4 or with NaBH4/
CeCl3 mixtures take place with a quite good diastereoselec-
tivity (80:20 diastereomer ratio) and afford opposite epimers
as the major products. Although they could not be made
fully diastereoselective, these reductions suggest that some
stereocontrol can be exerted by the chiral cyclopentenyl
moiety of 7 in reactions other than the organocatalytic
[3+2] cyclizations of Scheme 3.
the corresponding bis-enones 6 under FerroPHANE cataly-
sis conditions, PPh3 was used to promote the second cycliza-
tions on the residual double bonds in compounds 7. The ex-
pected compounds 12d–f (Table 5) were isolated in about
50% yields as ~9:1 mixtures of isomers. The major isomers
were fully characterised.
Table 5. Enantiomerically enriched bis(cyclopentenyl)ketones obtained
through diastereoselective PPh3-promoted cyclizations on the enone
functions of compounds 7.
Entry
Substrate (ee)
Ar
Product[a]
Yield [%]
In summary, the above results open promising perspec-
tives for the stereoselective synthesis of variously functional-
ised chiral cyclopentenes. The synthetically challenging bis-
cyclopentenyl ketones 12 are available through a simple
two-step sequence involving a FerroPHANE-promoted or-
ganocatalytic process as the enantioselective step.
1
2
3
4
7d (92)
7e (93)
7 f (93)
7a (92)
4-ClC6H4
4-MeC6H4
2-thienyl
Ph
12d
12e
12 f
13[b]
48
53
50
58
[a] Conditions: H2C=C=CHCO2Et (3 equiv), PPh3 10 mol%, toluene, RT,
ꢀ
18 h. [b] MeC CCO2Men* (3 equiv), PPh3 10 mol%, toluene, RT, 24 h.
Sense of chiral induction and a tentative interpretation
based on DFT studies: Both from our previous work and
from the above studies, it appears that (S,S)-FerroPHANE I
is an efficient and highly enantioselective catalyst for [3+2]
annulations between electron-poor allenes (allenic esters or
phosphonates) and olefinic double bonds activated by elec-
tron-withdrawing groups (acrylates, fumarates and various
enones). The sense of chiral induction of FerroPHANE-pro-
moted cyclizations has been established previously for the
The dissymmetric bis-cyclopentenylketone 13 could also
be obtained by treatment of 7a with d-menthyl but-2-ynoate
at room temperature, with PPh3 (10 mol%) as the catalyst.
Good diastereoselectivity was also observed in this case,
with a d.r. of 90%. The double bonds in the spirocyclic
enones 10a and 11 failed to undergo cyclization with ethyl
buta-2,3-dienoate in the presence of PPh3, either under the
above conditions or at higher temperature.
Chem. Eur. J. 2010, 16, 1033 – 1045
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1037

A. Marinetti et al.
a-addition product 14 obtained from ethyl buta-2,3-dienoate
and ethyl acrylate (Scheme 5). In this case, the S-configured
FerroPHANE gives an S-configured cyclopentene 14.
Scheme 5. Stereochemical course of the a-addition between ethyl buta-
2,3-dienoate and ethyl acrylate.
With regard to the stereochemical outcomes of [3+2] an-
nulations on enone derivatives that proceed by g-addition,
assignment has so far been achieved only for the cyclization
product obtained from chalcone, based on [a]D values by
comparison with literature data.[6b,9b] In order to ascertain
the stereochemical courses of the cyclization reactions in-
volving bis-enones, as well as to confirm the previous assign-
ments, we unambiguously determined the configuration of a
representative g-addition product through X-ray studies, as
shown below.
Figure 2. ORTEP drawing for compound 16.
This assignment is fully consistent with the sense of chiral
induction of (S,S)-FerroPHANE-promoted annulations on
simple chalcones.
With the above assignment of configuration to hand, DFT
analysis of some key reaction intermediates was envisioned
with the aim of providing an explanation of the chiral induc-
tion process.
ACHTUNGTRENNUNG(S,S)-FerroPHANE I was used to promote the [3+2] an-
nulation between d-menthyl but-2-ynoate (15) and dba
(Scheme 6). The reaction delivered the expected cyclopen-
tene 7j with a diastereomeric ratio of 95:5, in a phosphine-
controlled process.[21] To obtain crystals suitable for X-ray
diffraction studies, the cyclopentenylketone 7j was convert-
ed into the corresponding hydrazone 16.
According to the widely accepted mechanistic proposal
(Scheme 7),[14,22] the catalytic cycle of the above [3+2] annu-
lations starts with the addition of the nucleophilic phosphine
on the b-carbon atom of the allenic substrate to give the
zwitterionic phosphonium salt A. The anionic allylic moiety
of A may then add to an unsaturated electron-poor sub-
strate through either its a- or its g-carbon atom. Because g-
addition takes place selectively in the FerroPHANE-pro-
moted annulations between allenes and enones, only the g-
adduct B is considered in Scheme 7.
Scheme 6. ACHTUNGTRENNUNG[3+2] cyclization between dba and d-menthyl but-2-ynoate
(15).
The X-ray crystal structure of 16 (Figure 2) unambiguous-
ly shows that the major diastereomer obtained from the S,S-
configured FerroPHANE has a 4S,5R configuration in the
chiral cyclopentene ring.
Scheme 7. Postulated mechanism for phosphine-promoted [3+2] cycliza-
tions between allenes and enones.
1038
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Chem. Eur. J. 2010, 16, 1033 – 1045

ACHTUNGTRENNUNG[3+2] Annulations with a,b-Unsaturated Ketones
FULL PAPER
The zwitterionic intermediate A is likely to be a key inter-
Isomer A-3 was calculated to be the most stable form;
steric hindrance between the TMS group and the ester func-
tion induces destabilization of A-1 by +20 kJmolÀ1 relative
to A-3, whereas in A-2 an energy difference of +12 kJmolÀ1
is induced by the close proximity between the methylene
group and the ferrocene scaffold. These main destabilising
interactions are indicated in Figure 4 by black arrows. It
should be noted here that structures A-2 and A-3 are epi-
meric forms in which the phosphorus centres display oppo-
site configurations. They would have an enantiomeric rela-
tionship and would therefore be energetically equivalent for
phosphines with achiral ferrocene scaffolds.
mediate, its three-dimensional arrangement potentially play-
ing an essential role in the stereochemical control of the cyc-
lization reaction.[23] On the basis of this working hypothesis,
we focused our attention on this intermediate for P=(S,S)-
FerroPHANE I as a key for understanding the catalytic be-
haviour of the chiral phosphine.
The geometric features of FerroPHANE I, of the simpli-
fied analogue Ib (in which the TMS and Cy groups have
been substituted by a hydrogen atom and a methyl group,
respectively) and their phosphine-allene adducts A were
studied by quantum chemical calculations with the aid of
the TURBOMOLE program and density functional meth-
ods (marij-BP86/def2-SVP level of calculation; see the Sup-
porting Information for the calculated conformations and
energy values). The resulting structural parameters for Fer-
roPHANE I are in good agreement with the previously re-
ported X-ray data (Figure 3).[9a]
Figure 4. Optimised geometries of the zwitterionic intermediates A for
PR3 =(S,S)-FerroPHANE.
With regard to the second step of the catalytic cycle, we
may reasonably assume that the three isomeric intermedi-
ates A add to the enone with comparable reaction rates. If
this is the case, the major stereoisomer of the final product
should be formed from A-3. In this isomer, only one face of
the unsaturated enolate—that is, the bottom face in
Scheme 8—is reasonably accessible to the enone reactant,
the upper face being hindered by the ferrocenyl-TMS group.
Figure 3. Optimized structures of phosphines I and Ib at the marij-BP86/
def2-SVP level. Selected distances in ꢂ (X-ray values in parentheses).
An enlarged colour figure is given in the Supporting Information.
The corresponding phosphine-allene adduct A was con-
structed analogously, by starting from the calculated struc-
ture of FerroPHANE I. It was found that the most stable
structure involves the enolate form of the ester function and
a stabilizing dipolar P+···OÀ interaction (Figure 4). These re-
sults corroborate the previous findings of Dudding[14b] and
Yu[14c] relating to the analogous PMe3 adducts.[24] The phos-
phorus atom displays a distorted tetrahedral coordination,
approaching a trigonal bipyramid geometry as a result of
the P+···OÀ interaction. Energy minima were found for
three isomeric forms in which the P···O bond lies along
either the P–CCyclohexyl axis (A-1) or the P–Cferrocene axes (A-2
and A-3).
Scheme 8. Postulated approach of the enone to the zwitterionic inter-
mediate A-3.
Chem. Eur. J. 2010, 16, 1033 – 1045
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1039

A. Marinetti et al.
Perkin–Elmer FT-IR spectrophotometer. High-resolution mass spectra
(HRMS-ESI) were obtained with LCT Waters equipment. Optical rota-
tions were determined with a JASCO P-1010 polarimeter. HPLC was
performed at a column temperature of 308C with a Waters 2695 Separa-
tions Module fitted with a diode array UV detector. Data are reported as
follows: column type, eluent, flow rate, retention time. Substrates 2, 6, 8
and 9 were prepared by known procedures.[6b]
The enone might then approach the allene-phosphine
adduct with either the Ph or the carbonyl group oriented
toward the bulky phosphine. The preferred 4S,5R-configured
product should then result from the approach shown in
Scheme 8, which would allow the phenyl substituent to be in
the less hindered region. The lower steric hindrance of the
carbonyl function, relative to the aryl group, might account
for this preferred orientation, but energetically favourable
P–OCOR interactions might also favour this approach.[14b]
In other words, according to the tentative model above,
the planar chiral arrangement of the phosphine allows dis-
crimination of the upper and bottom face of the allenoate
(that is to say, it induces energy difference between A-3 and
A-2) and dictates attack of the olefin from the bottom face.
The relative steric hindrance of the enone substituents then
determines the sense of addition and the preferred configu-
ration.
The same model might also account for the observed ste-
reochemical outcome of the a-addition process shown in
Scheme 5. In this case, the pathway leading to the major S
enantiomer of 14 would involve approach of the olefin to
the phosphine-allene adduct so as to minimise the destabi-
lizing steric interactions between the phosphine and the ac-
rylate ester group.
Representative procedure for the asymmetric [3+2] annulations of di-
AHCTUNGERTGeNNUN thyl propa-1,2-dienylphosphonate with enones 2 (Tables 1 and 2)—syn-
thesis of diethyl 5-benzoyl-4-(naphthalen-1-yl)cyclopent-1-enylphospho-
nate (3a, entry 6 in Table 1): Degassed toluene (0.5 mL) was added
under argon to a mixture of enone 2a (77 mg, 0.30 mmol), diethyl propa-
1,2-dienylphosphonate (1, 26 mg, 0.15 mmol) and FerroPHANE
I
(7.1 mg, 0.015 mmol). The mixture was heated at 1208C for 24 h in a
sealed tube. The solvent and small amounts of the side product 4 were re-
moved in vacuo. The final product was purified by flash chromatography
on silica gel with an EtOAc/heptane 80:20 mixture (Rf =0.4) Compound
3a was obtained in 80% yield (52 mg) and 90% ee. [a]2D5 =+8 (c=0.6,
CHCl3). NMR data for this compound have been reported in ref. [8c].
HRMS (ESI): m/z: calcd for C26H27NaO4P [M+Na]+: 457.1545; found:
457.1540. The enantiomeric excess was measured by HPLC analysis:
Daicel CHIRACEL IC column, iPrOH/n-heptane (5%), 1 mLminÀ1
,
285 nm, retention times: 89.3 min (minor) and 96.2 min (major).
Diethyl 5-benzoyl-4-phenylcyclopent-1-enylphosphonate (3b): Com-
pound 3b was obtained in 78% yield and 90% ee after purification with
EtOAc/heptanes (70%, Rf =0.3). [a]2D5 =+10 (c=0.8, CHCl3). NMR data
for this compound have been reported in ref. [8c]. HRMS (ESI): m/z:
calcd for C22H25NaO4P [M+Na]+: 407.1388; found: 407.1390; HPLC
analysis: Daicel CHIRACEL IC column, iPrOH/n-heptane (10%),
The above computations thus afford a reasonable heuris-
tic model for the chiral discrimination operated by (S,S)-Fer-
roPHANE I.
1 mLminÀ1
(major).
,
271 nm, retention times: 26.8 min (minor) and 32.3 min
Diethyl
5-benzoyl-4-(4-methoxyphenyl)cyclopent-1-enylphosphonate
(3c): Compound 3c was obtained in 80% yield and 91% ee after purifi-
cation on a silica gel column with EtOAc/heptanes (80%, Rf =0.2).
[a]2D5 =+20 (c=1.2, CHCl3). NMR data for this compound have been re-
ported in ref. [8c]. HRMS (ESI): m/z: calcd for C23H27NaO5P [M+Na]+:
437.1494; found: 437.1492; HPLC analysis: Daicel CHIRACEL IC
column, iPrOH/n-heptane (20%), 1 mLminÀ1, 231 nm, retention times:
40.8 min (minor) and 52.3 min (major).
Conclusions
This work affords new evidence for the high efficiency of
FerroPHANE I in the enantioselective [3+2] cyclizations of
electron-poor allenes and enones. In particular, these reac-
tions have been extended to allenic phosphonates and to
dba derivatives. Unprecedented bis-cyclopentenyl scaffolds
with four stereocentres have been created through sequen-
ces of two successive organocatalysed cyclizations.
A tentative interpretation of the chiral induction exerted
by FerroPHANE I in the cyclization reactions involving al-
lenic esters and enones has been afforded by modelling of
the energetically most favoured isomers of the key phos-
phine-allene adduct.
Diethyl 5-benzoyl-4-(4-nitrophenyl)cyclopent-1-enylphosphonate (3d):
Compound 3d was obtained in 68% yield and 86% ee after purification
with EtOAc/heptanes (80%, Rf =0.2). [a]2D5 =+2.5 (c=0.5, CHCl3). NMR
data for this compound have been reported in ref. [8c]. HRMS (ESI):
m/z: calcd for C22H24NNaO6P [M+Na]+: 452.1239; found: 452.1246;
HPLC analysis: Daicel CHIRACEL IC column, iPrOH/n-heptane
(20%), 1 mLminÀ1
85.5 min (major).
, 205 nm, retention times: 70.7 min (minor) and
Diethyl 5-benzoyl-4-(naphthalen-2-yl)cyclopent-1-enylphosphonate (3e):
Compound 3e was obtained in 83% yield and 88% ee after column chro-
matography with EtOAc/heptanes (80%, Rf =0.25); [a]2D5 =+41 (c=0.3,
CHCl3); 1H NMR (500 MHz, CDCl3): d=7.90 (d, J=7.7 Hz, 2H), 7.83
(d, J=8.3 Hz, 2H), 7.76 (d, J=8.1 Hz, 1H), 7.62 (s, 1H), 7.54 (t, J=
7.3 Hz, 1H), 7.50–7.45 (m, 2H), 7.45–7.35 (m, 3H), 7.08 (d, J=11.2 Hz,
1H), 4.96 (brs, 1H), 4.10–3.95 (m, 4H), 3.95–3.90 (m, 1H), 3.40–3.30 (m,
1H), 2.82 (d, J=19.0 Hz, 1H), 1.20 ppm (t, J=6.5 Hz, 6H); 13C NMR
(75 MHz, CDCl3): d=200.0 (C), 150.8 (d, JC,P =13.9 Hz, CH), 142.3 (C),
136.7 (C), 133.6 (C), 133.4 (CH), 132.6 (C), 132.4 (d, JC,P =191.4 Hz, C),
129.1 (CH), 128.9 (2ꢃCH), 128.6 (2ꢃCH), 127.8 (CH), 127.7 (CH), 126.4
(CH), 125.9 (CH), 125.3 (CH), 125.0 (CH), 62.1 (d, JC,P =5.1 Hz, CH2),
Further applications of FerroPHANE I in organocatalytic
processes are currently under study.
Experimental Section
General methods: All reactions were run under inert atmosphere
(argon), by standard techniques for manipulation of air-sensitive com-
pounds. All glassware was stored in the oven and/or was flame-dried
prior to use. Anhydrous solvents were obtained by filtration through
drying columns (THF, Et2O, CH2Cl2). All reagents and solvents were of
commercial quality and were used without further purification. Flash
column chromatography was performed with 40–63 mesh silica. Nuclear
magnetic resonance spectra (1H, 13C, 31P) were recorded with Brucker
61.7 (d, JC,P =5.9 Hz, CH2), 61.3 (d, JC,P =12.8 Hz, CH), 49.7 (d, JC,P
10.5 Hz, CH), 43.0 (d, JC,P =19.2 Hz, CH2), 16.3 (d, JC,P =6.4 Hz, CH3),
16.2 ppm (d,
C,P =6.9 Hz, CH3); 31P NMR (121 MHz, CDCl3): d=
=
J
14.2 ppm; IR: n˜max =2982, 2355, 1662, 1590, 1573, 1449, 1332, 1207, 1023,
967, 852, 739 cmÀ1; HRMS (ESI): m/z: calcd for C26H27NaO4P [M+Na]+:
457.1545; found: 457.1569; HPLC analysis: Daicel CHIRACEL IC
column, iPrOH/n-heptane (20%), 1 mLminÀ1, 226 nm, retention times:
26.3 min (minor) and 39.6 min (major).
AV 500 or AV 300 spectrometers. IR spectra were recorded with
a
1040
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ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 1033 – 1045

ACHTUNGTRENNUNG[3+2] Annulations with a,b-Unsaturated Ketones
FULL PAPER
Diethyl 5-benzoyl-4-(furan-2-yl)cyclopent-1-enylphosphonate (3 f): Com-
pound 3 f was obtained in 77% yield and 91% ee after purification with
EtOAc/heptanes (80%, Rf =0.2). [a]2D5 =+67 (c=0.35, CHCl3). NMR
data for this compound have been reported in ref. [8c]. HRMS (ESI): m/
z: calcd for C20H23NaO5P [M+Na]+: 397.1181; found: 397.1176; HPLC
analysis: Daicel CHIRACEL IC column, iPrOH/n-heptane (20%),
2854, 2361, 1726, 1688, 1602, 1524, 1344, 1246, 1208, 1021, 964, 832, 750,
699 cmÀ1
;
HRMS (ESI): m/z: calcd for C22H24NNaO6P [M+Na]+
452.1239; found: 452.1237; HPLC analysis: Daicel CHIRACEL IC
column, iPrOH/n-heptane (20%), 1 mLminÀ1, 264 nm, retention times:
48.0 min (major) and 64.7 min (minor). Slow degradation of samples
stored under argon at À208C has been observed.
1 mLminÀ1
(major).
, 251 nm, retention times: 27.5 min (minor) and 31.0 min
Diethyl 5-(furan-2-carbonyl)-4-phenylcyclopent-1-enylphosphonate (3k):
Compound 3k was obtained in 80% yield and 83% ee after purification
by column chromatography with EtOAc/heptanes (80%, Rf =0.17);
[a]2D5 =+37 (c=0.6, CHCl3); 1H NMR (300 MHz, CDCl3): d=7.39 (s,
1H), 7.15–6.95 (m, 5H), 6.95–6.90 (m, 1H), 6.80 (dm, J=11.0 Hz, 1H),
6.30–6.25 (m, 1H), 4.40–4.35 (m, 1H), 3.90–3.70 (m, 4H), 3.65–3.55 (m,
1H), 3.04 (dm, J=19.8, 1H), 2.51 (dm, J=18.4 Hz, 1H), 1.10–0.95 ppm
Diethyl 5-benzoyl-4-(quinolin-3-yl)cyclopent-1-enylphosphonate (3g):
Compound 3g was obtained in 87% yield and 90% ee. Rf =0.15 in
EtOAc/heptanes (80%); [a]2D5 =+180 (c=0.6, CHCl3); 1H NMR
(300 MHz, CDCl3): d=8.79 (d, J=2.3 Hz, 1H), 8.1 Hz (d, J=8.5 Hz,
1H), 7.98–7.88 (m, 3H), 7.80–7.66 (m, 2H), 7.59–7.51 (m, 2H), 7.41 (t,
J=8.1 Hz, 2H), 7.07 (dm, J=11.0 Hz, 1H), 4.96 (brs, 1H), 4.10–3.90 (m,
5H), 3.38 (dm, J=17.7 Hz, 1H), 2.81 (dm, J=18.4 Hz, 1H), 1.25–
1.10 ppm (m, 6H); 13C NMR (75 MHz, CDCl3): d=198.4, 149.4, 149.3 (d,
(m, 6H); 13C NMR (300 MHz, CDCl3): d=188.2, 152.3, 150.9 (d, JC,P
=
13.7 Hz), 147.2, 144.6, 131.4 (d, J=191.0 Hz), 128.8, 126.9, 126.7, 118.9,
112.3, 62.1 (d, JC,P =4.8 Hz), 61.9 (d, JC,P =13.2 Hz), 61.6 (d, JC,P =5.7 Hz),
49.1 (d, JC,P =10.3 Hz), 42.7 (d, JC,P =19.6 Hz), 16.2 (d, JC,P =6.9 Hz),
16.1 ppm (d, JC,P =6.9 Hz); 31P NMR (121 MHz, CDCl3): d=14.2 ppm;
J
C,P =14.2 Hz), 146.5, 136.5, 135.5, 132.6, 131.3 (d, JC,P =193.0 Hz), 128.4,
128.3, 127.9, 127.8, 127.4, 127.1, 126.7, 126.1, 61.2 (d, JC,P =5.3 Hz), 60.8
(d, JC,P =6.0 Hz), 59.8 (d, JC,P =13.2 Hz), 46.0 (d, JC,P =10.5 Hz), 41.6 (d,
IR: n˜max =2926, 2359, 1672, 1566, 1465, 1393, 1245, 1023, 969, 763 cmÀ1
;
HRMS (ESI): m/z: calcd for C20H23NaO5P [M+Na]+: 397.1181; found:
397.1187; HPLC analysis: Daicel CHIRACEL IC column, iPrOH/n-hep-
tane (20%), 1 mLminÀ1, 216 nm, retention times: 79.9 min (major) and
92.8 min (minor).
J
C,P =20.2 Hz, C3), 15.3 (d, JC,P =6.5 Hz), 15.1 ppm (d, JC,P =7.0 Hz);
31P NMR (121 MHz, CDCl3): d=13.6 ppm; IR: n˜max =2928, 1678, 1596,
1579, 1493, 1447, 1244, 1048, 1024, 966, 838, 788, 752 cmÀ1; HRMS (ESI):
m/z: calcd for C25H26NNaO4P [M+Na]+: 458.1497; found: 458.1500;
HPLC analysis: Daicel CHIRACEL IC column, EtOH/n-heptane (10%),
Diethyl 5-acetyl-4-phenylcyclopent-1-enylphosphonate (3l): Compound
3l was obtained in 85% yield and 45% ee after column chromatography
with EtOAc/heptanes (80%) as the eluent (Rf =0.3); [a]2D5 =+72 (c=0.3,
CHCl3). NMR data for this compound have been reported in ref. [8c].
HRMS (ESI): m/z: calcd for C17H23NaO4P [M+Na]+: 345.1232; found:
345.1241; HPLC analysis: Daicel CHIRACEL IC column, EtOH/n-hep-
tane (20%), 1 mLminÀ1, 210 nm, retention times: 9.0 min (minor) and
10.3 min (major).
1 mLminÀ1
(major).
, 240 nm, retention times: 30.8 min (minor) and 36.9 min
Diethyl 5-benzoyl-4-(hept-1-ynyl)cyclopent-1-enylphosphonate (3h):
Compound 3h was obtained in 28% yield and 84% ee. Rf =0.3 in
EtOAc/heptanes (80%); [a]2D5 =+86 (c=0.5, CHCl3); 1H NMR
(300 MHz, CDCl3): d=8.12–8.06 (m, 1H), 7.64–7.46 (m, 4H), 6.88 (dm,
J=10.8 Hz, 1H), 4.85 (s, 1H), 4.04–4.86 (m, 4H), 3.42–3.33 (m, 1H),
3.13–3.00 (m, 1H), 2.67 (dm, J=17.5, 1H), 2.14 (m, 1H),1.52–1.40 (m,
2H), 1.40–1.25 (m, 4H), 1.18 (m, 6H), 0.91–0.85 ppm (m, 3H); 13C NMR
(125 MHz, CDCl3): d=199.7, 150.0 (d, JC,P =13.0 Hz), 137.3, 133.7, 131.8
(d, JC,P =191.6 Hz), 129.0, 128.7, 82.6, 81.9, 62.1 (d, JC,P =5.0 Hz), 61.8 (d,
Representative procedures for the asymmetric [3+2] annulations on
enones 6, 8 and 9 (Tables 3 and 4 and Scheme 6)
a) Synthesis of the cyclopentenylcarboxylates 7
Ethyl (4S,5R,E)-5-cinnamoyl-4-phenylcyclopent-1-enylcarboxylate (7a,
Table 3, entry 3): Ethyl buta-2,3-dienoate (35 mL, 0.3 mmol) was added to
J
J
C,P =5.2 Hz), 60.5 (d, JC,P =13.0 Hz), 42.1 (d, JC,P =19.6 Hz), 35.3 (d,
C,P =11.3 Hz), 31.2, 28.7, 22.3, 18.8, 16.2 (dd, JC,P =6.2, 6.1 Hz), 14.1 ppm;
a
mixture of dba (35 mg, 0.15 mmol) and FerroPHANE I (7.1 mg,
31P NMR (121 MHz, CDCl3): d=14.7 ppm; IR: n˜max =2926, 2855, 1682,
1597, 1448, 1248, 1051, 1023, 969 cmÀ1; HRMS (ESI): m/z: calcd for
C23H31NaO4P [M+Na]+: 425.1858; found: 425.1852; HPLC analysis:
0.015 mmol) in degassed toluene (0.5 mL). The mixture was stirred at
room temperature for 24 h. After evaporation of the solvent, the final
product was purified by chromatography on silica gel with AcOEt/hep-
tane (10%) as the eluent (Rf =0.25). Compound 7a was obtained as a
pale yellow solid, in 90% yield (47 mg) and 92% ee. [a]2D4 =+190 (c=0.5,
CHCl3). NMR data for this compound have been reported in ref. [6b].
HRMS (ESI): m/z: calcd for C23H22NaO3 [M+Na]+: 369.1467; found:
369.1475; HPLC analysis: Daicel CHIRACEL OD, iPrOH/n-heptane
Daicel CHIRACEL IC column, iPrOH/n-heptane (20%), 1 mLminÀ1
,
248 nm, retention times: 16.6 min (minor) and 18.3 min (major).
Diethyl 5-(4-methoxybenzoyl)-4-phenylcyclopent-1-enylphosphonate (3i):
Compound 3i was obtained in 73% yield and 90% ee. Rf =0.23 in
EtOAc/heptanes (80%); [a]2D5 =+41 (c=0.8, CHCl3); 1H NMR
(300 MHz, CDCl3): d=7.88 (d, J=8.8 Hz, 2H), 7.35–7.10 (m, 5H), 6.99
(dm, J=10.9 Hz, 1H), 6.88 (d, J=8.4 Hz, 2H), 4.81 (brs, 1H), 4.05–3.92
(m, 4H), 3.85 (s, 3H), 3.80–3.65 (m, 1H), 3.26 (dm, J=18.0 Hz, 1H), 2.70
(dm, J=18.0 Hz, 1H), 1.19 ppm (t, J=7.9 Hz, 6H); 13C NMR (75 MHz,
CDCl3): d=198.5, 163.8, 150.6 (d, JC,P =13.8 Hz), 145.2, 133.4, 130.9,
(5%), 1 mLminÀ1
49.8 min (minor).
, 290 nm, retention times: 11.9 min (major) and
Cyclohexyl (4S,5R,E)-5-cinnamoyl-4-phenylcyclopent-1-enecarboxylate
(7b): Compound 7b was obtained in 28% yield and 92% ee, >20:1 regio-
selectivity, after chromatography (Rf =0.3 in EtOAc/heptanes 10%);
[a]2D4 =+105 (c=1, CHCl3); 1H NMR (300 MHz, CDCl3): d=7.30–7.00
(m, 11H), 6.85 (m, 1H), 6.55 (d, J=16.2 Hz, 1H), 4.60 (m, 1H), 4.17 (m,
1H), 3.40 (dt, J=9.0, 6.0 Hz, 1H), 2.96 (ddt, J=18.6, 9.0, 2.7 Hz, 1H),
2.53 (ddt, J=18.9, 6.0, 2.4 Hz, 1H), 1.70–1.00 ppm (m, 10H); 13C NMR
(75 MHz, CDCl3): d=200.2, 163.7, 144.9, 144.8, 144.0, 136.0, 134.7, 130.6,
129.0, 128.9, 128.5, 127.2, 127.1, 125.7, 73.0, 63.4, 48.9, 42.0, 31.6, 31.5,
25.7, 23.64, 23.61 ppm; IR: n˜max =2932, 2856, 1704, 1607, 1448, 1330, 1240,
130.6, 130.0 (d, JC,P =170.0 Hz), 129.8, 127.0, 126.8, 113.8, 62.0 (d, JC,P
5.4 Hz), 61.7 (d, JC,P =6.4 Hz), 61.1 (d, JC,P =12.7 Hz), 55.5, 49.7 (d, JC,P
10.5 Hz), 42.9 (d, JC,P =20.2 Hz), 16.3 (d, JC,P =6.8 Hz), 16.2 ppm (d, JC,P
=
=
=
6.8 Hz); 31P NMR (121 MHz, CDCl3): d=14.3 ppm; IR: n˜max =2978, 1671,
1599, 1259, 1170, 1023, 967, 841, 700 cmÀ1; HRMS (ESI): m/z: calcd for
C23H27NaO5P [M+Na]+: 437.1494; found: 437.1480; HPLC analysis:
Daicel CHIRACEL IC column, iPrOH/n-heptane (20%), 1 mLminÀ1
,
1090, 978, 752, 697 cmÀ1
; HRMS (ESI): m/z: calcd for C27H28NaO3
210 nm, retention times: 43.7 min (minor) and 59.1 min (major).
[M+Na]+: 423.1936; found: 423.1936; HPLC analysis: Daicel CHIRA-
CEL IC, iPrOH/n-heptane (20%), 1 mLminÀ1, 290 nm, retention times:
14.9 min (major) and 38.9 min (minor).
Diethyl 5-(4-nitrobenzoyl)-4-phenylcyclopent-1-enylphosphonate (3j):
Compound 3j was obtained in 60% yield and 84% ee. Rf =0.15 in
EtOAc/heptanes (80%); [a]2D5 =+48 (c=0.6, CHCl3); 1H NMR
(500 MHz, CDCl3): d=8.24 (d, J=8.5 Hz, 2H), 8.00 (d, J=8.5 Hz, 2H),
7.35–7.10 (m, 5H), 7.00 (d, J=11.0 Hz, 1H), 4.85 (brs, 1H), 4.05–3.90
(m, 4H), 3.75 (dt, J=9.3, 5.1 Hz, 1H), 3.30–3.20 (m, 1H), 2.77 (dm, J=
18.5 Hz, 1H), 1.21 ppm (d, J=7.0 Hz, 6H); 13C NMR (125 MHz, CDCl3):
d=207.5, 149.5, 143.6, 140.4, 128.7, 128.3, 127.0 (d, JC,P =192.0 Hz), 126.1,
125.8, 122.8, 66.6, 61.2 (d, JC,P =20.5 Hz), 48.9, 47.6, 41.8, 29.7, 15.5,
15.4 ppm; 31P NMR (121 MHz, CDCl3): d=13.7 ppm; IR: n˜max =2926,
Benzyl (4S,5R,E)-5-cinnamoyl-4-phenylcyclopent-1-enecarboxylate (7c):
Compound 7c was obtained in 70% yield and 91% ee, >25:1 regioselec-
tivity, after purification by column chromatography with EtOAc/heptanes
(10%, Rf =0.30); [a]2D4 =+168 (c=1.1, CHCl3); 1H NMR (300 MHz,
CDCl3): d=7.30–7.15 (m, 16H), 7.03 (m, 1H), 6.63 (d, J=15.9 Hz, 1H),
5.11 (d, J=12.6 Hz, 1H), 5.05 (d, J=12.6 Hz, 1H), 4.33 (m, 1H), 3.53
(dt, J=9.0, 6.0 Hz, 1H), 3.10 (ddt, J=19.2, 9.0, 2.4 Hz, 1H), 2.65 ppm
Chem. Eur. J. 2010, 16, 1033 – 1045
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1041

A. Marinetti et al.
(ddt, J=18.9, 5.7, 2.4 Hz, 1H); 13C NMR (75 MHz, CDCl3): d=200.0,
164.0, 145.9, 144.8, 144.2, 135.9, 135.1, 134.6, 130.6, 129.0, 128.9, 128.6,
128.5, 128.2, 127.1, 125.6, 66.5, 63.3, 48.8, 42.0 ppm; IR: n˜max =3061, 3028,
1710, 1658, 1605, 1574, 1494, 1449, 1329, 1090, 977 cmÀ1; HRMS (ESI):
m/z: calcd for C28H24NaO3 [M+Na]+: 431.1623; found: 431.1631; HPLC
Ethyl
(4S,5R,E)-5-cinnamoyl-4-(4-methoxyphenyl)cyclopent-1-enecar-
boxylate (7h’): Compound 7h’ was obtained in 32% yield and 95% ee,
>25:1 regioselectivity; Rf =0.20 (Et2O/heptanes 30%); [a]2D4 =+212 (c=
1, CHCl3); 1H NMR (300 MHz, CDCl3): d=7.43–7.33 (m, 6H), 7.16 (d,
J=8.7 Hz, 2H), 7.04 (m, 1H), 6.86 (d, J=8.7 Hz, 2H), 6.74 (d, J=
15.9 Hz, 1H), 4.34 (m, 1H), 4.17 (dq, J=7.2, 2.0 Hz, 2H), 3.80 (s, 3H),
3.56 (dt, J=9.0, 5.0 Hz, 1H), 3.14 (ddt, J=19.0, 9.0, 2.5 Hz, 1H), 2.68
(ddt, J=19.0, 6.0, 2.0 Hz, 1H), 1.24 ppm (t, J=7.2 Hz, 3H); 13C NMR
(75 MHz, CDCl3): d=200.2, 164.2, 158.6, 145.0, 143.9, 136.9, 135.4, 134.6,
130.5, 128.9, 128.4, 128.1, 125.6, 114.3, 63.4, 60.6, 55.4, 48.1, 42.0,
14.2 ppm; IR: n˜max =2924, 1705, 1650, 1512, 1243, 1170, 1101, 1033, 976,
829, 766, 698 cmÀ1; HRMS (ESI): m/z: calcd for C24H24NaO4 [M+Na]+:
399.1572; found: 399.1577; HPLC analysis: Daicel CHIRACEL AD-H,
iPrOH/n-heptane (10%), 1 mLminÀ1, 290 nm, retention times: 22.4 min
(minor) and 29.5 min (major).
analysis:
1 mLminÀ1
(major).
Daicel
CHIRACEL AD-H,
iPrOH/n-heptane
(5%),
,
206 nm, retention times: 18.0 min (minor) and 27.0 min
Ethyl (4S,5R,E)-4-(4-chlorophenyl)-5-[3-(4-chlorophenyl)acryloyl]cyclo-
pent-1-enecarboxylate (7d): Compound 7d was obtained in 67% yield
and 92% ee, >20:1 regioselectivity; Rf 0.13 in 30% Et2O/heptanes;
[a]2D4 =+247 (c=1, CHCl3); 1H NMR (300 MHz, CDCl3): d=7.30–7.17
(m, 7H), 7.12–7.05 (m, 2H), 6.94 (m, 1H), 6.63 (d, J=16.2 Hz, 1H),
4.25–4.18 (m, 1H), 4.09 (dq, J=7.2, 2.1 Hz, 2H), 3.50 (dt, J=9.0, 6.0 Hz,
1H), 3.07 (ddt, J=16.2, 6.3, 2.4 Hz, 1H), 2.59 (ddt, J=18.9, 5.7, 2.4 Hz,
1H), 1.15 ppm (t, J=7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=199.6
(C), 164.1 (C), 145.0 (CH), 143.3 (C), 142.6 (CH), 136.7 (C), 135.4 (C),
133.0 (C), 132.9 (C), 129.7 (2ꢃCH), 129.3 (2ꢃCH), 129.2 (2ꢃCH), 128.5
(2ꢃCH), 125.8 (CH), 63.4 (CH), 60.8 (CH2), 48.1 (CH), 41.9 (CH2),
14.3 ppm (CH3); HRMS (ESI): m/z: calcd for C23H20Cl2NaO3 [M+Na]+:
437.0687; found: 437.0697; HPLC analysis: Daicel CHIRACEL AD-H,
iPrOH/n-heptane (5%), 1 mLminÀ1, 300 nm, retention times: 16.5 min
(minor) and 21.4 min (major).
Ethyl
(4S,5R,E)-5-[3-(4-methoxyphenyl)acryloyl]-4-phenylcyclopent-1-
enecarboxylate (7h): Compound 7h was obtained in 55% yield and
92% ee, >25:1 regioselectivity; Rf =0.13 (Et2O/heptanes 30%); [a]D24
=
1
+222 (c=1, CHCl3); H NMR (300 MHz, CDCl3): d=7.38–7.20 (m, 8H),
7.04 (m, 1H), 6.86 (dt, J=9.0, 2.1 Hz, 2H), 6.62 (d, J=16.2 Hz, 1H), 4.36
(m, 1H), 4.17 (dq, J=7.2, 1.8 Hz, 2H), 3.82 (s, 3H), 3.59 (dt, J=9.0,
5.7 Hz, 1H), 3.16 (ddt, J=19.0, 9.0, 2.7 Hz, 1H), 2.70 (ddt, J=19.0, 5.7,
2.4 Hz, 1H), 1.24 ppm (t, J=7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3):
d=200.0, 164.3, 161.6, 145.1, 144.9, 143.8, 135.4, 130.2, 128.9, 127.3, 127.1,
127.0, 123.4, 114.4, 63.2, 60.5, 55.4, 48.8, 41.9, 14.2 ppm; IR: n˜max =2933,
1708, 1593, 1510, 1245, 1169, 1089, 1027, 827, 750, 700 cmÀ1; HRMS
(ESI): m/z: calcd for C24H24NaO4 [M+Na]+: 399.1572; found: 399.1580;
HPLC analysis: Daicel CHIRACEL AD-H, iPrOH/n-heptane (5%),
Ethyl (4S,5R,E)-4-p-tolyl-5-(3-p-tolylacryloyl)cyclopent-1-enecarboxylate
(7e): Compound 7e was obtained in 80% yield and 93% ee; >20:1 re-
gioselectivity; Rf =0.30 (10% EtOAc/heptanes); [a]2D4 =+229 (c=1.0,
CHCl3); 1H NMR (300 MHz, CDCl3): d=7.50–7.35 (m, 3H), 7.30–7.25
(m, 6H), 7.16 (m, 1H), 6.82 (d, J=16.2 Hz, 1H), 4.46 (m, 1H), 4.28 (q,
J=6.9 Hz, 2H), 3.68 (dt, J=8.9, 5.7 Hz, 1H), 3.30–3.20 (m, 1H), 2.85–
2.75 (m, 1H), 2.47 (s, 3H), 2.46 (s, 3H), 1.35 ppm (t, J=7.2 Hz, 3H);
13C NMR (75 MHz, CDCl3): d=200.3, 164.3, 145.1, 144.1, 142.0, 141.1,
136.6, 135.5, 131.9, 129.7, 129.6, 128.5, 127.0, 124.8, 63.3, 60.7, 48.5, 42.0,
21.6, 21.2, 14.3 ppm; IR: n˜max =2979, 1710, 1656, 1600, 1512, 1325, 1241,
1169, 1087, 978, 811, 750 cmÀ1; HRMS (ESI): m/z: calcd for C25H26NaO3
[M+Na]+: 397.1780; found: 397.1781; HPLC analysis: Daicel CHIRA-
CEL IC, iPrOH/n-heptane (20%), 1 mLminÀ1, 300 nm, retention times:
31.4 min (major) and 63.0 min (minor).
1 mLminÀ1
(major).
, 320 nm, retention times: 29.9 min (minor) and 42.5 min
b) Synthesis of the spirocyclic enones 10
Ethyl (E)-7-benzylidene-6-oxo-4-phenylspiroACTHNUTRGNE[NUG 4.4]non-1-ene-1-carboxylate
(10a, Table 4, entry 6): Ethyl buta-2,3-dienoate (35 mL, 34 mg, 0.3 mmol)
was added to a mixture of enone 8a (39 mg, 0.15 mmol) and Ferro-
PHANE I (7.1 mg, 0.015 mmol) in degassed toluene (0.5 mL). The mix-
ture was stirred at 408C for 18 h. After evaporation of the solvent, the
final product was purified by chromatography on silica gel with AcOEt/
heptane (10%) as the eluent (Rf 0.3). Compound 10a was obtained in
84% yield (47 mg) and 85% ee. NMR data for this compound have been
reported in ref. [6b]. HRMS (ESI): m/z: calcd for C25H24NaO3 [M+Na]+:
395.1623; found: 395.1634; HPLC analysis: Daicel CHIRACEL OD,
iPrOH/n-heptane (10%), 1 mLminÀ1, 295 nm, retention times: 7.0 min
(major) and 15.3 min (minor).
Ethyl (4R,5S,E)-4-(thiophen-2-yl)-5-[(E)-3-(thiophen-2-yl)acryloyl]cyclo-
pent-1-enecarboxylate (7 f): Compound 7 f was obtained in 60% yield
and 93% ee, >20:1 regioselectivity; Rf =0.3 (EtOAc/heptanes 10%);
[a]2D4 =+221 (c=1, CHCl3); 1H NMR (300 MHz, CDCl3): d=7.62 (d, J=
15.6 Hz, 1H), 7.38 (d, J=5.1 Hz, 1H), 7.23 (d, J=3.6 Hz, 1H), 7.16 (dd,
J=5.4, 1.2 Hz, 1H), 7.08–6.98 (m, 2H), 6.91 (m, 1H), 6.85 (m, 1H), 6.64
(d, J=15.9 Hz, 1H), 4.33 (m, 1H), 4.16 (m, 2H), 3.96 (dt, J=8.7, 6.3 Hz,
1H), 3.18 (ddt, J=18.6, 8.7, 2.4 Hz, 1H), 2.76 (ddt, J=18.6, 6.3, 2.4 Hz,
1H), 1.23 ppm (t, J=9.0 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=199.3,
164.0, 147.8, 144.6, 140.1, 136.4, 135.5, 132.0, 129.2, 128.4, 127.0, 124.6,
124.3, 123.8, 63.6, 60.8, 44.3, 42.4, 14.3 ppm; IR: n˜max =2922, 1708, 1589,
Ethyl
[4.4]non-1-ene-1-carboxylate (10b): This compound was obtained in
90% yield and 87% ee, >20:1; Rf 0.30 (AcOEt/heptanes 10%); [a]D24
(E)-7-(4-chlorobenzylidene)-4-(4-chlorophenyl)-6-oxospiro-
AHCTUNGTRENNUNG
=
+127 (c=3.9, CHCl3); 1H NMR (300 MHz, CDCl3): d=7.35 (t, J=
2.7 Hz, 1H), 7.32–7.24 (m, 4H), 7.16 (d, J=8.7 Hz, 2H), 7.04 (d, J=
8.7 Hz, 2H), 6.99 (t, J=2.7 Hz, 1H), 4.06 (q, J=7.2 Hz, 2H), 3.82 (t, J=
9.0 Hz, 1H), 2.80 (dd, J=8.7, 2.4 Hz, 2H), 2.75–2.60 (m, 1H), 2.05–1.85
(m, 2H), 1.78–1.65 (m, 1H), 1.15 ppm (t, J=7.2 Hz, 3H); 13C NMR
(75 MHz, CDCl3): d=210.3 (C), 163.5 (C), 144.9 (CH), 140.6 (C), 137.4
(C), 136.8 (C), 135.4 (C), 134.2 (C), 133.3 (C), 132.0 (3ꢃCH), 129.7 (2ꢃ
CH), 129.0 (2ꢃCH), 128.7 (2ꢃCH), 64.4 (C), 60.8 (CH2), 53.6 (CH), 36.7
(CH2), 27.1 (CH2), 26.8 (CH2), 14.2 ppm (CH3); IR: n˜max =2930, 1702,
1621, 1490, 1369, 1244, 1231, 1177, 1087, 1012, 920, 822, 759 cmÀ1; HRMS
(ESI): m/z: calcd for C25H22Cl2NaO3 [M+Na]+: 463.0844; found:
463.0845; HPLC analysis: Daicel CHIRACEL OD, iPrOH/n-heptane
1367, 1243, 1091, 968, 699 cmÀ1
; HRMS (ESI): m/z: calcd for
C19H18NaO3S2 [M+Na]+: 381.0595; found: 381.0594; HPLC analysis:
Daicel CHIRACEL IC, iPrOH/n-heptane (20%), 1 mLminÀ1, 320 nm, re-
tention times: 23.7 min (major) and 45.1 min (minor).
Ethyl (4S,5R,E)-5-[3-(2,6-dichlorophenyl)acryloyl]-4-phenylcyclopent-1-
enecarboxylate (7g): Compound 7g was obtained in 55% yield and
92% ee, 9:1 regioselectivity; Rf 0.3 (EtOAc/heptanes 10%); [a]2D4 =+155
(c=1, CHCl3); 1H NMR (500 MHz, CDCl3): d=7.53 (d, J=16.5 Hz, 1H),
7.30–7.00 (m, 9H), 6.85 (d, J=16.5 Hz, 1H), 4.35–4.30 (m, 1H), 4.20–4.10
(m, 2H), 3.64 (dt, J=9.0, 6.0 Hz, 1H), 3.13 (ddt, J=18.9, 9.0, 2.4 Hz,
1H), 2.69 (ddt, J=18.9, 5.7, 2.4 Hz, 1H), 1.22 ppm (t, J=7.2 Hz, 3H);
(10%), 1 mLminÀ1
30.7 min (minor).
, 305 nm, retention times: 7.7 min (major) and
IR: n˜max =2980, 1710, 1614, 1427, 1242, 1091, 975, 772, 755, 698 cmÀ1
;
Ethyl
AHCTUNGTRENNUNG
(E)-7-(4-bromobenzylidene)-4-(4-bromophenyl)-6-oxospiro-
HRMS (ESI): m/z: calcd for C23H20Cl2NaO3 [M+Na]+: 437.0687; found:
437.0696; HPLC analysis: Daicel CHIRACEL IC, iPrOH/n-heptane
yield and 92% ee, 20:1 regioselectivity; Rf =0.30 (AcOEt/heptanes
10%); [a]2D4 =+116 (c=2.8, CHCl3); 1H NMR (500 MHz, CDCl3): d=
7.50 (d, J=8.5 Hz, 2H), 7.45–7.38 (m, 3H), 7.29 (d, J=8.5 Hz, 2H), 7.10–
7.05 (m, 3H), 4.14 (q, J=7.0 Hz, 2H), 3.89 (t, J=9.0 Hz, 1H), 2.92–2.85
(m, 2H), 2.75 (m, 1H), 2.10–1.95 (m, 2H), 1.85–1.75 (m, 1H), 1.23 ppm
(t, J=7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=210.2, 163.5, 145.0,
(5%), 1 mLminÀ1
47.5 min (minor).
, 270 nm, retention times: 29.7 min (major) and
Entry 5 in Table 4: The two isomeric compounds 7h and 7h’ were ob-
tained and characterised as pure samples after separation by column
chromatography.
1042
www.chemeurj.org
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 1033 – 1045

ACHTUNGTRENNUNG[3+2] Annulations with a,b-Unsaturated Ketones
FULL PAPER
140.6, 138.0, 137.0, 134.6, 132.2, 132.0, 131.7, 130.1, 123.8, 121.3, 64.3,
60.8, 53.7, 36.6, 27.1, 26.8, 14.2 ppm; IR: n˜max =2938, 1698, 1621, 1486,
1243, 1231, 1177, 1072, 1006, 825, 813, 758 cmÀ1; HRMS (ESI): m/z: calcd
for C25H22Br2NaO3 [M+Na]+: 550.9833; found: 550.9830; HPLC analysis:
Daicel CHIRACEL OD, iPrOH/n-heptane (10%), 1 mLminÀ1, 305 nm,
retention times: 8.3 min (major) and 29.0 min (minor).
Daicel CHIRACEL IC, EtOH/n-heptane (10%), 1 mLminÀ1, 230 nm, re-
tention times: 7.5 min (major) and 30.8 min (minor).
Compound 12d: This compound was obtained in 48% yield and 93% ee;
Rf =0.4 (20% EtOAc/heptanes); [a]2D4 =+226 (c=1.3, CHCl3); 1H NMR
(500 MHz, CDCl3): d=7.15 (d, J=8.5 Hz, 4H), 6.96 (d, J=8.5 Hz, 4H),
6.86 (m, 2H), 4.19 (q, J=7.0 Hz, 4H), 3.79 (m, 2H), 3.57 (dt, J=9.0,
6.5 Hz, 2H), 3.04 (ddt, J=19.0, 9.0, 2.5 Hz, 2H), 2.51 (ddt, J=19.0, 6.0,
2.5 Hz, 2H), 1.30 ppm (t, J=7.0 Hz, 6H); 13C NMR (75 MHz, CDCl3):
d=207.3, 164.3, 144.2, 143.4, 134.3, 132.7, 129.0, 128.4, 64.8, 60.7, 46.0,
42.3, 14.5 ppm; IR: n˜max =2933, 1705, 1634, 1492, 1366, 1299, 1245, 1082,
Ethyl
(E)-4-(furan-2-yl)-7-(furan-2-ylmethylene)-6-oxospiroACTHNGUTERNNU[G 4.4]non-1-
ene-1-carboxylate (10d): This compound was obtained in 53% yield and
84% ee, >20:1 regioselectivity; Rf 0.3 (5% AcOEt/toluene); [a]2D4 =+65
(c=0.5, CHCl3); 1H NMR (300 MHz, CDCl3): d=7.53 (d, J=1.5 Hz,
1H), 7.33–7.23 (m, 2H), 6.99 (t, J=2.4 Hz, 1H), 6.61 (d, J=3.6 Hz, 1H),
6.49 (dd, J=3.3, 1.8 Hz, 1H), 6.29 (dd, J=3.0, 1.8 Hz, 1H), 6.10 (d, J=
3.3 Hz, 1H), 4.12 (q, J=7.2 Hz, 2H), 3.90 (t, J=9.0 Hz, 1H), 2.95–2.75
(m, 3H), 2.10–1.95 (m, 3H), 1.20 ppm (t, J=7.2 Hz, 3H); 13C NMR
(75 MHz, CDCl3): d=209.6, 163.5, 153.7, 152.8, 144.9, 144.3, 142.0, 140.9,
134.2, 119.6, 116.0, 112.6, 110.5, 107.5, 64.4, 60.7, 47.7, 35.5, 27.2, 26.5,
14.2 ppm; IR: n˜max =2360, 1707, 1620, 1476, 1236, 1181, 1092, 1019,
748 cmÀ1; HRMS (ESI): m/z: calcd for C21H20NaO5 [M+Na]+: 375.1208;
found: 375.1204; HPLC analysis: Daicel CHIRACEL OD, iPrOH/n-hep-
tane (5%), 1 mLminÀ1, 300 nm, retention times: 9.9 min (major) and
25.5 min (minor).
1009, 818, 748 cmÀ1
; HRMS (ESI): m/z: calcd for C29H28Cl2NaO5
[M+Na]+: 549.1211; found: 549.1219; HPLC analysis: Daicel CHIRA-
CEL AD-H, iPrOH/n-heptane (2%), 1 mLminÀ1
, 230 nm, retention
times: 14.7 min (major) and 33.7 min (minor).
Compound 12e: This compound was obtained in 53% yield and 92% ee;
Rf 0.4 (EtOAc/heptanes 20%); [a]2D4 =+227 (c=0.93, CHCl3); 1H NMR
(300 MHz, CDCl3): d=7.00–6.85 (m, 10H), 4.19 (q, J=7.2 Hz, 4H), 3.89
(m, 2H), 3.57 (m, 2H), 2.98 (m, 2H), 2.52 (m, 2H), 2.31 (s, 6H),
1.29 ppm (t, J=7.2 Hz, 6H); 13C NMR (75 MHz, CDCl3): d=208.1,
164.5, 144.5, 141.9, 136.1, 134.4, 129.4, 126.9, 64.3, 60.5, 46.3, 42.3, 21.2,
14.5 ppm; IR: n˜max =2980, 2924, 1706, 1635, 1514, 1371, 1241, 1181, 1085,
1031, 811, 749 cmÀ1; HRMS (ESI): m/z: calcd for C31H34NaO5 [M+Na]+:
509.2304; found: 509.2296; HPLC analysis: Daicel CHIRACEL IC,
iPrOH/n-heptane (5%), 1 mLminÀ1, 205 nm, retention times: 8.9 min
(major) and 36.9 min (minor).
Ethyl (E)-7-benzylidene-6-oxo-4-phenylspiroACTHNUTRGNE[NUG 4.5]dec-1-ene-1-carboxylate
(11): This compound was obtained in 35% yield and 85% ee, 20:1 regio-
selectivity; Rf =0.3 (AcOEt/heptanes 10%). [a]2D4 =+306 (c=1.3, CHCl3).
NMR data for this compound have been reported in ref. [6b]. HRMS
(ESI): m/z: calcd for C26H26NaO3 [M+Na]+: 409.1780; found: 409.1766;
HPLC analysis: Daicel CHIRACEL OD, iPrOH/n-heptane (5%),
Compound 12 f: This compound was obtained in 50% yield and 93% ee;
Rf =0.4 (EtOAc/heptanes 20%); [a]2D4 =+236 (c=0.6, CHCl3); 1H NMR
(500 MHz, CDCl3): d=7.10 (d, J=4.5 Hz, 2H), 6.91 (s, 2H), 6.85 (t, J=
3.5 Hz, 2H), 6.81 (s, 2H), 4.18 (q, J=7.0 Hz, 4H), 4.12 (m, 2H), 4.03 (m,
2H), 3.11 (dd, J=18.5, 9.0 Hz, 2H), 2.67 (dt, J=18.5, 2.5 Hz, 2H),
1.28 ppm (t, J=7.5 Hz, 6H); 13C NMR (125 MHz, CDCl3): d=207.6,
164.2, 148.4, 144.2, 134.3, 126.8, 124.5, 123.9, 65.1, 60.7, 42.9, 42.3, 29.8,
1 mLminÀ1
(minor).
, 305 nm, retention times: 7.9 min (major) and 12.2 min
c) Synthesis of d-menthyl (4S,5R)-5-cinnamoyl-4-phenylcyclopent-1-enyl-
carboxylate (7j, Scheme 6): d-Menthyl but-2-ynoate (0.10 mg, 0.45 mmol)
was added to a mixture of dba (35 mg, 0.15 mmol) and FerroPHANE I
(7.1 mg, 0.015 mmol) in degassed toluene (0.5 mL). The mixture was
stirred at 1208C for 18 h. After evaporation of the solvent, the final prod-
uct was purified by chromatography on silica gel with AcOEt/heptane
(5%) as the eluent (Rf 0.3). Compound 7j was obtained as a pale yellow
solid in 75% yield (51 mg) and as a single regioisomer, in 90% de. Rf =
0.30 (EtOAc/heptanes 5%); [a]2D4 =+150 (c=1, CHCl3); 1H NMR
(300 MHz, CDCl3): d=7.40–7.15 (m, 11H), 6.96 (m, 1H), 6.66 (d, J=
15.9 Hz, 1H), 4.63 (td, J=10.8, 4.5 Hz, 1H), 4.30 (m, 1H), 3.52 (dt, J=
9.0, 6.3 Hz, 1H), 3.08 (ddt, J=18.9, 9.0, 2.7 Hz, 1H), 2.66 (ddt, J=18.9,
6.0, 2.1 Hz, 1H), 1.95 (dm, J=12.0 Hz, 1H), 1.80–1.70 (m, 1H), 1.63–1.48
(m, 2H), 1.45–1.30 (m, 1H), 1.30–1.15 (m, 1H), 1.00–0.70 (m, 3H), 0.79
(d, J=6.9 Hz, 3H), 0.73 (d, J=6.9 Hz, 3H), 0.65 ppm (d, J=6.9 Hz, 3H);
13C NMR (75 MHz, CDCl3): d=200.1, 163.9, 144.8, 144.0, 135.9, 134.7,
130.6, 129.01, 128.96, 128.5, 127.2, 127.1, 125.6, 74.7, 63.4, 49.0, 47.2, 41.9,
41.0, 34.3, 31.5, 26.1, 23.3, 22.1, 21.0, 16.2 ppm; IR: n˜max =2952, 2358,
1704, 1607, 1448, 1242, 1091, 980, 752, 698 cmÀ1; HPLC analysis: Daicel
CHIRACEL IA, EtOH/n-heptane (1%), 1 mLminÀ1, 290 nm, retention
times: 10.3 min (minor) and 43.6 min (major).
14.4 ppm; IR: n˜max =2978, 1705, 1634, 1368, 1250, 1078, 1029, 707 cmÀ1
;
HRMS (ESI): m/z: calcd for C25H26NaO5S2 [M+Na]+: 493.1119; found:
493.1106; HPLC analysis: Daicel CHIRACEL IA, iPrOH/n-heptane
(1%), 1 mLminÀ1
36.9 min (minor).
, 230 nm, retention times: 28.9 min (major) and
Compound 12g: This compound was obtained in 43% yield and 90% ee;
Rf =0.13 (30% Et2O/heptanes); [a]2D4 =+191 (c=1.6, CHCl3); 1H NMR
(300 MHz, CDCl3): d=7.20–7.13 (m, 3H), 7.08 (d, J=8.4 Hz, 2H), 7.05–
6.99 (m, 2H), 6.93 (d, J=8.4 Hz, 2H), 6.90–6.85 (m, 2H), 4.18 (q, J=
7.2 Hz, 4H), 3.84 (m, 2H), 3.58 (m, 2H), 3.03 (m, 2H), 2.55 (m, 2H),
1.29 ppm (t, J=7.1 Hz, 6H); 13C NMR (75 MHz, CDCl3): d=207.6,
164.4, 164.3, 144.9, 144.5, 144.2, 143.3, 134.4, 134.2, 132.4, 129.0, 128.9,
128.4, 127.0, 126.8, 64.6, 64.5, 60.62, 60.59, 46.6, 46.0, 42.4, 42.2, 14.4 ppm;
IR: n˜max =2980, 1704, 1635, 1492, 1241, 1089, 1013, 972, 825, 750,
700 cmÀ1
;
HRMS (ESI): m/z: calcd for C29H29ClNaO5 [M+Na]+:
515.1601; found: 515.1594; HPLC analysis: Daicel CHIRACEL AD-H,
iPrOH/n-heptane (5%), 1 mLminÀ1, 250 nm, retention times: 8.2 min
(major) and 15.6 min (minor).
Representative procedure for the [3+2] annulations on cyclopentenylcar-
boxylates 7 (Scheme 3 and Table 5)
Compound 13: This compound was obtained in 58% yield and 90% dr;
1
Rf = 0.4 (EtOAc/heptanes 20%); [a]2D4 =+194 (c=1.0, CHCl3); H NMR
(300 MHz, CDCl3): d=7.18–7.10 (m, 6H), 7.06–6.98 (m, 4H), 6.95–6.87
(m, 2H), 4.76 (dt, J=10.8, 4.5 Hz, 1H), 4.20 (q, J=7.0 Hz, 2H), 3.98–
3.82 (m, 2H), 3.68–3.58 (m, 2H), 3.03 (ddt, J=18.9, 9.3, 2.4 Hz, 2H),
2.60–2.48 (m, 2H), 2.14–2.02 (m, 1H), 2.00–1.88 (m, 1H), 1.75–1.60 (m,
3H), 1.60–0.75 ppm (m, 16H); 13C NMR (75 MHz, CDCl3): d=207.6,
207.3, 164.3, 164.0, 145.1, 144.9, 144.8, 144.4, 134.8, 134.3, 128.8, 127.0,
126.9, 126.7, 74.4, 64.4, 64.2, 60.6, 47.4, 46.8, 46.3, 42.3, 42.1, 41.1, 34.6,
31.6, 26.5, 23.7, 22.2, 20.9, 16.6, 14.5 ppm; IR: n˜max =2953, 2926, 1704,
1241, 1086, 962, 754, 697 cmÀ1; HRMS (ESI): m/z: calcd for C37H44NaO5
[M+Na]+: 591.3086; found: 591.3087; HPLC analysis: Daicel CHIRA-
Synthesis of 12a: A mixture of cyclopentenylcarboxylate 7a (52 mg,
0.15 mmol), ethyl buta-2,3-dienoate (52 mL, 50 mg, 0.45 mmol) and PPh3
(4.0 mg, 10 mol%) in toluene was stirred under argon at RT for 24 h.
The final product 12a was purified by chromatography on silica gel with
EtOAc/heptane (20%) as the eluent (Rf 0.4). Yield: 45 mg (66%). The
final product displays the same enantiomeric excess as that of the starting
cyclopentene 7a (92% ee). [a]2D4 =+233 (c=1.3, CHCl3); 1H NMR
(300 MHz, CDCl3): d=7.20–7.10 (m, 6H), 7.05–6.95 (m, 4H), 6.90 (m,
2H), 4.19 (q, J=7.2 Hz, 4H), 3.95–3.88 (m, 2H), 3.63 (dt, J=9.3, 6.0 Hz,
2H), 3.03 (ddt, J=18.6, 9.0, 2.7 Hz, 2H), 2.54 (ddt, J=18.6, 5.7, 2.4 Hz,
2H), 1.29 ppm (t, J=7.2 Hz, 6H); 13C NMR (75 MHz, CDCl3): d=208.0
(C), 164.4 (2C), 144.8 (2C), 144.6 (2ꢃCH), 134.4 (2C), 128.8 (4ꢃCH),
127.0 (4ꢃCH), 126.7 (2ꢃCH), 64.3 (2ꢃCH), 60.6 (2ꢃCH2), 46.7 (2ꢃ
CH), 42.2 (2ꢃCH2), 14.5 ppm (2ꢃCH3); IR: n˜max =2980, 1699, 1326,
1241, 1196, 1088, 1029, 747, 698 cmÀ1; HRMS (ESI): m/z: calcd for
C29H30NaO5 [M+Na]+: 481.1991; found: 481.1988; HPLC analysis:
CEL AD-H, iPrOH/n-heptane (1%), 1 mLminÀ1
, 230 nm, retention
times: 17.8 min (major) and 23.0 min (minor).
Synthesis of 16: (2,4-Dinitrophenyl)hydrazine (26 mg, 0.13 mmol,
1.5 equiv) and H2SO4 (0.5n, 87 mL, 0.5 equiv) were added to a solution of
7j (40 mg, 0.087 mmol, 1.0 equiv) in ethanol (0.4 mL). The red heteroge-
neous mixture was heated at reflux for 2 h, and further (2,4-dinitrophe-
Chem. Eur. J. 2010, 16, 1033 – 1045
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A. Marinetti et al.
nyl)hydrazine (17 mg, 0.08 mmol, 0.5 equiv) was added. The mixture was
heated at reflux until completion of the reaction. The orange mixture
was concentrated and purified by column chromatography (heptane/Et2O
8:2) to afford 16 (50 mg, 71%) as an orange solid (Rf =0.3); [a]2D4 =+9
(c=1, CHCl3); 1H NMR (300 MHz, CDCl3): d=11.56 (s, 1H), 9.14 (d,
J=2.7 Hz, 1H), 8.31 (dd, J=9.6, 2.4 Hz, 1H), 7.87 (d, J=9.6 Hz, 1H),
7.03 (m, 1H), 7.00 (m, 10H), 6.96 (d, J=16.2 Hz, 1H), 6.67 (d, J=
15.9 Hz, 1H), 4.68 (dt, J=10.8, 4.2 Hz, 1H), 4.46 (m, 1H), 3.48 (dt, J=
9.0, 5.7 Hz, 1H), 3.19 (ddt, J=18.9, 9.0, 2.4 Hz, 1H), 2.76 (dm, J=
18.9 Hz, 1H), 2.05–1.95 (m, 1H), 1.80–0.90 (m, 8H), 0.83 (d, J=6.6 Hz,
3H), 0.71 (d, J=6.9 Hz, 3H), 0.53 ppm (d, J=6.9 Hz, 3H); 13C NMR
(75 MHz, CDCl3): d=164.5, 156.7, 145.7, 145.0, 142.6, 141.2, 138.2, 136.8,
135.0, 130.3, 130.2, 129.5, 129.1, 127.7, 127.4, 127.2, 123.6, 116.8, 114.5,
74.4, 58.2, 51.5, 47.2, 42.1, 41.4, 34.2, 31.4, 26.1, 23.2, 22.1, 20.9, 16.2 ppm;
IR: n˜max =2920, 2850, 1703, 1613, 1589, 1515, 1500, 1425, 1329, 1306, 1262,
1092, 959, 741, 691 cmÀ1; HRMS (ESI): m/z: calcd for C37H40N4NaO6
[M+Na]+: 659.2846; found: 659.2836. X-ray quality crystals of 16 were
obtained from a dichloromethane/heptane solution.
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X-ray data: Both structures were solved from single colourless crystals
suitable for X-ray diffraction. Data collection was in each case carried
out at 293(2) K on an Enraf–Nonius CCD diffractometer using MoKa ra-
diation (l=0.71070 ꢂ) and equipped with a graphite monochromator.
Complete data were measured according to a f-and-w-scan-strategy de-
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Crystal parameters were later post-refined in SCALEPACK[31] and inten-
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polarisation and absorption correction based on a multi-scan empirical
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full-matrix, least-squares methods (SHELXL-97). All non-hydrogen
atoms were refined anisotropically, whereas hydrogen atoms were located
from difference Fourier maps but refined as a riding model.
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CCDC-738660 (12a) and 738661 (16) contain the supplementary crystal-
lographic data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.ccdc.cam.a-
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Part of this work was carried out within the CP2D program (2007) of the
Agence Nationale de la Recherche (ANR). We thank I.C.S.N. (N.P.,
M.N. and A.P. grants) and COST action CM0802 “PhoSciNet” for sup-
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ACHTUNGTRENNUNG[3+2] Annulations with a,b-Unsaturated Ketones
FULL PAPER
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be ruled out either.
Received: July 8, 2009
Published online: November 24, 2009
Chem. Eur. J. 2010, 16, 1033 – 1045
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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