Diastereoselective access to polyoxygenated polycyclic spirolactones through a rhodium-catalyzed [3+2] cycloaddition reaction: Experimental and theoretical studies

Article abstract of DOI:10.1002/chem.201203155

The synthetic utility of γ-alkylidenebutenolides is demonstrated as highly competent dipolarophile partners in both intra- and intermolecular rhodium(II)-catalyzed 1,3-dipolar cycloaddition reactions. The strength of this approach lies in the formation of spiro[6,4]lactone moieties with the concomitant construction of quaternary spiro stereocenters. Typically, the construction of spirolactones involves an esterification step, which has often been reported as a "biosynthetic pathway", and often occurs either as or near to the final step of a total synthesis. Furthermore, a convergent and versatile route is reported for the formation of the (5,7) skeleton of molecules that were isolated from the Schisandra genus. Computational studies were performed to provide an overall picture of the mechanism of the intermolecular [3+2] cycloaddition between 2-diazo-1,3-ketoester and protoanemonin and to rationalize the empirical observations. In particular, we have demonstrated for the first time that the rhodium center plays an important role during the cyclization step itself and reacts with the dipolarophile as a complex with the ylide. A rapid regio- and diastereoselective access to functionalized rigid polycyclic systems that contain a spiro[6.4] moiety through a Rh-catalyzed [3+2] cycloaddition is described (see scheme). A theoretical treatment rationalized the empirical observations. Copyright

Full text of DOI:10.1002/chem.201203155

FULL PAPER
DOI: 10.1002/chem.201203155
Diastereoselective Access to Poly ACHUTNRGNENUGo xygenated Polycyclic Spirolactones
through a Rhodium-Catalyzed [3+2] Cycloaddition Reaction: Experimental
and Theoretical Studies
Fabien Rodier, Michel Rajzmann, Jean-Luc Parrain, Gaꢀlle Chouraqui,* and
[
a]
Laurent Commeiras*
Abstract: The synthetic utility of
g-alkylidenebutenolides is demonstrat-
ed as highly competent dipolarophile
partners in both intra- and intermolec-
ular rhodium(II)-catalyzed 1,3-dipolar
cycloaddition reactions. The strength of
this approach lies in the formation of
been reported as a “biosynthetic path-
way”, and often occurs either as or
near to the final step of a total synthe-
sis. Furthermore, a convergent and ver-
satile route is reported for the forma-
tion of the (5,7) skeleton of molecules
that were isolated from the Schisandra
genus. Computational studies were per-
formed to provide an overall picture of
the mechanism of the intermolecular
[3+2] cycloaddition between 2-diazo-
1,3-ketoester and protoanemonin and
to rationalize the empirical observa-
tions. In particular, we have demon-
strated for the first time that the rhodi-
um center plays an important role
during the cyclization step itself and
reacts with the dipolarophile as a com-
plex with the ylide.
spiro ACHTUNGTRENNUNG[ 6,4]lactone moieties with the con-
comitant construction of quaternary
spiro stereocenters. Typically, the con-
struction of spirolactones involves an
esterification step, which has often
Keywords: azo compound · cyclo-
addition · density functional calcu-
lations · spiro compounds · ylides
Introduction
Spirolactone-containing structures are of interest because
this moiety not only provides the parent compounds with
conformational constraint but also because they are often
[1]
responsible for their particular biological activities. Perti-
nent examples of such structures include drospirenone (1),
the active ingredient of a birth-control formulation that was
Figure 1. Examples of biologically active compounds that contain a spiro-
lactone moiety and the general structure of g-alkylidenebutenolide.
[2]
commercialized by Bayer Schering Pharma, and abyssomi-
cin C (2), the potent antibacterial agent that was isolated
[3]
from the actinomycete Verrucosispora strain (Figure 1).
[
5]
g-Alkylidenebutenolide 3 is a very attractive and valuable
precursor to such spirolactones and this building block has
been used successfully on a number of occasions to access
complex structures.
Recognizing this useful synthetic approach, we recently
reported a palladium-free Sonogashira reaction to access
manner and we have demonstrated their utility for the
[6]
construction of spirolactones through Diels–Alder
or
[7]
domino reactions. However, despite such potential, the
versatility of cycloaddition reactions onto conjugated g,d
double bonds, thereby leading to the formation of fused
[4]
[8]
quaternary stereocenters, remains relatively unexplored.
Notably, the spiro[6.4] ring system is a recurrent structural
such g-alkylidenebutenolides in
a
diastereoselective
ACHTUNGTRENNUNG
motif in numerous natural products (e.g., micrandilactone B
and lancifodilactone F). Accordingly, we wanted to develop
a general approach to this type of substructure through both
intra- and intermolecular rhodium-catalyzed [3+2] cycload-
dition reactions of g-alkylidenebutenolides and carbonyl
ylides (Scheme 1). The benefits of such an approach would
lie in its potential efficiency, broad substrate scope, stereose-
lectivity, and amenability for the synthesis of diverse oxapo-
lycyclic scaffolds. To the best of our knowledge, g-alkylide-
nebutenolides have never been used as dipolarophile part-
ners in such a transformation. Only one example of an inter-
molecular [3+2] cycloaddition, by using a-methylene butyr-
[
a] F. Rodier, M. Rajzmann, Dr. J.-L. Parrain, Dr. G. Chouraqui,
Dr. L. Commeiras
Aix-Marseille Universitꢀ
Institut des Sciences Molꢀculaires de Marseille iSm2
UMR AMU-CNRS 7313, service 532
Campus scientifique de Saint Jꢀrꢁme
1
3397 MARSEILLE cedex 20 (France)
Fax : (+33) 491-289-187
E-mail: gaelle.chouraqui@univ-amu.fr
laurent.commeiras@univ-amu.fr
[9]
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201203155.
Chem. Eur. J. 2013, 19, 2467 – 2477
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2467

through treatment with DCC and Meldrum’s acid. Heating
the ensuing adduct with tert-butanol furnished b-ketoester
[12]
7
a in 31% yield over three steps. The g-alkylidenebuteno-
lide functionality was then installed by using the palladium-
free Sonogashira procedure that we have developed within
[5]
our laboratory. Accordingly, the reaction of compound 7a
with (Z)-iodoacrylic acid in the presence of CuI smoothly
provided compound 8aa (55% yield). Finally, the target cyc-
lization substrate, diazo ketoester 4aa, was formed in 75%
yield upon treatment of compound 8aa with p-ABSA under
mildly basic conditions. With 2-diazo-3,6-diketoester 4aa at
our disposal, we were ready to explore the intramolecular
rhodium(II)-catalyzed [1,3]-dipolar cycloaddition reaction.
Indeed, we were delighted to observe the complete con-
sumption of compound 4aa in the presence of a catalytic
Scheme 1. Rhodium-catalyzed [3+2] cycloaddition reactions between g-
alkylidenebutenolides and carbonyl ylides.
[10]
olactone, has been reported to date by Snider et al.,
which proceeded in moderate (34%) yield but with good
regio- and diastereoselectivity.
Herein, we report a rapid regio-, chemo-, and diastereose-
lective route to highly functionalized rigid polycyclic systems
amount (5 mol%) of [Rh ACHTUNGRTNNEG(U OAc) ] in CH Cl at room tem-
2 4 2 2
perature, with the smooth formation of a single spirolactone
product 9aa in good yield (70%). This reaction presumably
proceeds through initial carbonyl-ylide formation, followed
by a chemo-, regio-, and diastereoselective intramolecular
cycloaddition reaction on the exocyclic double bond of the
dipolarophile.
that contain a spiro ACHUTNGRNENUG[ 6.4] moiety through a rhodium-cata-
lyzed [3+2] cycloaddition reaction, en route to the (5,7)
core of molecules that were isolated from the Schisandra
genus. A computational study, which incorporated the rhodi-
um complex for the first time, served not only to corrobo-
rate the experimental results but also to elucidate the reac-
tion mechanism.
This first result demonstrated the validity of this ap-
proach, in which four contiguous stereogenic centers were
generated, three of which were quaternary. Gratifyingly, the
corresponding alcohol (10aa) was crystalline and the rela-
tive stereochemistry of this polycyclic adduct was unambigu-
ously confirmed by X-ray crystallographic analysis
[13]
Results and Discussion
(Scheme 2). To the best of our knowledge, this result rep-
resents only the second example of an intramolecular [3+2]
cycloaddition reaction of a carbonyl ylide with a trisubstitut-
ed 2p partner and, certainly, the most complex example re-
Experimental results: Our initial plan was to use diazo com-
pound 4aa as a model substrate to investigate the intramo-
lecular version of the rhodium(II)-catalyzed [3+2] cycload-
dition reaction (Scheme 2). This molecule features the re-
quired diazo keto ester (precursor of the carbonyl ylide) on
one end and a g-alkylidenebutenolide moiety on the other
end. The synthesis commenced with the preparation of 4-
oxo-8-nonynoic acid (5a) in two steps from lithiated 2,3-di-
hydrofuran and trimethylsilyl)-protected 5-iodopent-1-yne
[14]
ported to date. Having established the feasibility of this
intramolecular cycloaddition reaction, we sought to further
examine its substrate scope and limitations (Table 1 and
Scheme 3). Changes were made by varying either the length
of the tether between the ketone and the exocyclic alkene
(n=1–4) and/or the nature of the substituents onto the lac-
tone (R=H, Me, CH OMe; Table 1). 2-Diazo-3,6-diketoest-
2
[11]
(
6a), according to a literature procedure. Homologation
ers (4) were synthesized according to the same procedure as
[15]
of crude keto acid 5a into diketo ester 7a was achieved
for the synthesis of compound 9aa. We were delighted to
Scheme 2. Reagents and conditions for the intramolecular rhodium(II)-catalyzed [1,3]-dipolar cycloaddition reaction: a) i) Meldrum’s acid, DCC, DMAP,
CH Cl ; ii) tBuOH, reflux (31% from compound 6a); b) K CO , CuI, DMF, 508C (55%); c) p-ABSA, Et N, MeCN (75%); d) [Rh (OAc) ], CH Cl
70%); e) NaBH , CeCl ·7H O, MeOH (76%). DCC=N,N’-dicyclohexylcarbodiimide, DMAP=4-dimethylaminopyridine, p-ABSA=p-acetamidobenze-
nesulfonyl azide.
2
2
2
3
3
2
A
H
U
T
E
N
N
4
2
2
,
(
4
3
2
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Polyoxygenated Polycyclic Spirolactones
FULL PAPER
Table 1. Scope of the intramolecular rhodium(II)-catalyzed [1,3]-dipolar
cycloaddition reaction.
which opposite p faces of the alkene are presented to the
carbonyl species in the energy-minimized substrate conform-
[16]
ers.
Nevertheless, when one/two more methylene groups were
added to extend the length of the tether (compounds 4c and
4
d, respectively), the limits of the reaction were reached
(
Scheme 4) and the sole product that formed was the 4H-
4
9
Yield
%]
[
1
2
3
4aa
4ab
4ba
9aa 70
9ab 58
9ba 82
Scheme 4. Limits of the intramolecular rhodium(II)-catalyzed [1,3]-dipo-
lar cycloaddition reaction.
pyran (11). Presumably, the intermediate carbonyl ylide un-
derwent a 1,4-H shift in preference to the cycloaddition,
[17]
which is in full agreement with the work of Padwa et al.
Modifying the reaction conditions (elevated temperatures,
mode of addition, including the slow addition of the diazo
compound to a refluxing solution of the catalyst in toluene)
failed to induce further reaction.
The intramolecular cycloaddition cascade rapidly gener-
ates molecular complexity (rigid tetracyclic polyoxygenated
folded structures were obtained) with well-defined stereo-
chemical information (the creation of four stereocenters
with complete control of their relative configuration). How-
ever, the intermolecular variant might also offer the benefits
of greater simplicity and efficiency and, therefore, was our
next target for development. This approach would allow a
rapid and convergent access to oxa-polycyclic systems that
4
5
4bb
4bc
9bb 82
9bc 42
contain a spiro AHCUTNGRNENUG[ 6.4]lactone moiety. The first task was to de-
termine the suitability of d-substituted-g-alkylidenebuteno-
lides as dipolarophiles in the dipolar cycloaddition reaction
[18]
of activated derivatives of compound 12a. However, de-
spite a significant degree of investigation (temperature, sol-
vent, concentration, order of addition), we were unable to
coax these species into undergoing a productive cycloaddi-
tion reaction. Further investigation focused on d-unsubsti-
Scheme 3. Transition state in the intramolecular rhodium(II)-catalyzed
1,3]-dipolar cycloaddition reaction.
[
tuted-g-alkylidenebutenolide
2-methylprotoanemonin
[19]
[18,20]
(
13a).
Pleasingly, under optimized conditions
(OAc) ] at 258C in
find that the cyclization reactions occurred in good-to-excel-
lent yield (up to 82%) and with total control of the chemo-,
regio-, and diastereoselectivity, irrespective of the type of
lactones that were utilized and with tethers that afforded
five- and six-membered rings (n=1, 2).
Interestingly, the diastereoselectivity appears to depend
on the length of the tether between the dipole and the dipo-
larophile. In the case of compounds 9aa/9ab, which involve
the formation of a five-membered ring (n=1), the hydrogen
atom at the junction of five and seven-membered rings is
trans to the oxa bridge. However, in the case of the six-
membered-ring substrates (9ba–9bc), the hydrogen atom is
cis to this same system. This result might be explained by
the two hypothetical transition states shown in Scheme 3, in
(1.2 equiv of lactone 13a, 5 mol% [Rh ACTHUNGTRENNNUG
2
4
CF C H ), the intermolecular Rh-catalyzed [3+2] cycloaddi-
3
6
5
tion reaction proceeded chemo- and regioselectively to give
the desired cycloadduct (14a) as a single diastereoisomer
(of the eight that could potentially be formed) in 60% yield.
Next, the scope of the reaction was explored by using a
[19a,21]
range of g-methylenebutenolides (13a–13d)
and 2-
diazo-3,6-diketoesters (12a/12b, Table 2). Whatever the sub-
stitutions onto the endocyclic double bond of the lactones
and the nature of the diazo compound, the intermolecular
cycloaddition reaction consistently proceeded with complete
chemo- and diastereoselectivity, along with good yields
(about 60%). Notably, in spite of its instability, the simplest
alkylidene-5H-furan-2-one, compound 13b (protoanemo-
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2469

G. Chouraqui, L. Commeiras et al.
Table 2. Scope of the intermolecular rhodium(II)-catalyzed [1,3]-dipolar
cycloaddition reaction.
understanding of 1) the experimentally observed regio-,
chemo-, and diastereoselectivities and 2) the influence of
the Rh catalyst during the cycloaddition step, a theoretical
treatment was carried out. We applied DFT calculations by
using the B3LYP functional to investigate the mechanism of
the intermolecular [3+2] cyclization reaction. Previous stud-
ies of this cycloaddition reaction revealed that it certainly
occurred through ylide–rhodium complex III (Scheme 5).
However, none of these previously reported theoretical
studies took into account the influence of the metal during
the cycloaddition step itself. In fact, the authors typically re-
1
2
13
14
Yield
%]
[
[23]
ferred to the rhodium-free ylide (IV), thus offering an in-
complete insight into the overall mechanism. In view of the
impressive selectivities that were observed experimentally
and because we thought that the role of the rhodium cata-
lyst should not be underestimated, we decided to investigate
and compare both pathways, that is, the metal-free cycload-
dition step versus the metal-catalyzed one. Previous results
suggest that the nature of the ligands on the rhodium cata-
lyst has a dramatic influence on the outcome of the reac-
1
2
3
4
14aa 60
14ab 59
14ac 43
14ad 50
[24]
tion and also that enantiodiscrimination is feasible when
[9aa–au]
the metal is adorned with chiral ligands.
The mechanistic scenario presented in Scheme 5 could
plausibly describe this catalytic process. The formation of
the rhodium carbene (II) from the diazo derivative (I), fol-
lowed by its attack by the oxygen atom on the carbonyl
5
6
7
8
14ba 62
14bb 47
14bc 57
14bd 59
group, should generate the Rh –ylide (III). Thereafter, the
pathway would call for a dissociation of complex III to re-
lease the active catalyst, [Rh ACHTNUGTRNEUNG( OAc) ], and to liberate a
2 4
2
stable ylide (IV, pathway 1). The cycloaddition step would
proceed next and eight possible approaches of the protoane-
monin have been envisioned (A–H; Scheme 6). At that
stage, the electrophilic or nucleophilic character of the latter
species had yet to be determined. A second pathway could
also be envisioned (pathway 2, Scheme 5) if rhodium–ylide
III is directly involved in the cycloaddition step. Similarly,
the same eight possible approaches of the protoanemonin
could be envisaged. Because the metal is mainly associated
with the negatively charged part of the ylide, if the chemose-
lectivity of the reaction favors the exocyclic double bond of
the protoanemonin, it could be concluded that the lactone
takes part in an inverse-electron-demand-type cycloaddition
reaction. The reverse (normal-electron-demand-type) would
nin), reacted smoothly to give the desired tricyclic spirolac-
tone (14ab and bb) in 59% and 47% yield, respectively
(
[25,9r]
Table 2, entries 2 and 6). The diastereoselectivity of the re-
be the case for the endocyclic double bond.
action was unambiguously established by X-ray structural
determination of compound 14aa.
Structures without a metal (pathway 1) were performed at
the B3LYP level (as implemented in the Gaussian 09 pro-
[22]
[26]
This approach provides rapid (four steps in the longest
linear sequence) and facile access to the (5,7) core of mole-
cules that were isolated from the Schisandra genus, includ-
ing lancifodilactone F and micrandilactone B in a highly
regio-, chemo-, and stereoselective manner. Notably, three
quaternary stereogenic centers were created with complete
control of their relative configuration.
gram package) and the 6-311G+ +(d,p) basis set. Report-
ed energies are computed as single-point energy calculations
and include the zero-point energy (ZPE), which was ob-
tained at the geometry-optimization level. Each stationary
point was adequately characterized by normal coordinate
analysis (no imaginary frequencies for an equilibrium struc-
ture and one imaginary frequency for a transition-state
structure). For structures that included a metal (pathway 2),
DFT calculations were initiated starting from diazo deriva-
tive I. In this study, we used dirhodium tetraformate (as a
model catalyst for dirhodium tetraacetate). This latter com-
Theoretical results: At this point, we were very pleased with
the outcome of the cycloaddition reactions in terms of selec-
tivity, especially in the intermolecular version. For a better
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Polyoxygenated Polycyclic Spirolactones
FULL PAPER
proaches. In each case, the cy-
cloaddition step was found to
be exothermic (more than
ꢀ
1
3
8 kcalmol ), with a transition
ꢀ
1
state of at least 6.6 kcalmol .
A closer look at the values of
the different TSs showed
a
preference for the formation of
spirolactone A and, therefore,
it could be concluded that the
cycloaddition reaction tends to
exhibit
inverse-electron-
demand character. All of the
other TSs that lead to spirolac-
tones B–H are higher in energy,
which could explain the experi-
mentally observed trend. How-
ever, we found that transition
state TSIV–G was indeed higher
Scheme 5. Proposed catalytic pathways for the intermolecular [3+2] cycloaddition reaction.
ꢀ
1
in energy (2.70 kcalmol , 41%
pound is commonly used in computational studies, especially
increase) but not sufficiently high to justify the total chemo-
selectivity that was observed (the formation of cycloadduct
G would correspond to the normal-electron-demand path-
way, which would occur through an exo approach).
To explain the observed diastereoselectivity in the in-
verse-electron-demand cycloaddition (spirolactone A versus
spirolactone B), we analyzed the corresponding TSs (TSIV–A
and TSIV–B respectively). TSIV–A has the following bond-
[27]
in locating transition states (TSs).
There are only slight
differences between these two rhodium salts; the less-donat-
ing formate ligands lead to an elongation of the RhꢀRh
bond, which gives more electrophilic character to the rhodi-
um atoms. All of the calculations were performed with the
Gaussian 09 software. Structures of the rhodium complexes
were optimized at the B3LYP level (as implemented in
[28]
[29]
Gaussian 09)
and the def2-SV(P) basis set.
Reported
length
2.28 ꢃ
characteristics:
and
1) C (protoanemonin)ꢀC
ACHTUNGTRENNUNG
(ylide)
3.08 ꢃ
5
6
energies are computed as single-point energy calculations
and include the ZPE, which was obtained at the geometry-
optimization level.
2) C (protoanemonin)ꢀC
2 ACHTUNGTRNENUNG( ylide)
4
(Figure 3). On the other hand, TS
exhibits similar bond-
IV–B
Pathway 1—non-catalyzed [3+2] cycloaddition: Firstly, in
[30]
accordance with the results reported by Padwa et al., we
assumed that ylide IV (Figure 2) was dissociated from rhodi-
um tetraacetate during the cycloaddition reaction. To gain
insight into the regio-, chemo-, and stereoselectivity of the
1,3-dipolar reaction, we considered the eight possible ap-
Figure 3. Structures of the transition states that lead to spirolactones A
and B.
length characteristics, that is, 1) C (protoanemonin)ꢀC -
5
6
A
H
U
G
R
N
N
2 ACHTUNGTRENNGNU( ylide) 2.91 ꢃ,
4
but an important difference between the two dihedral
angles was noted (53.78 versus 16.18 for TSIV–A and TSIV–B
,
respectively). This difference could be a consequence of
steric repulsion between hydrogen atoms H2p and H4y in
TSIV–B
.
To summarize, omitting the metal in the calculations led
to results that were in agreement with the general experi-
mental trend; however, they could not fully explain the ex-
clusive formation of spirolactone A over the other seven.
Figure 2. Energy profile of the metal-free [3+2] cycloaddition reaction
between ylide IV and protoanemonin.
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G. Chouraqui, L. Commeiras et al.
Scheme 6. Mechanistic hypotheses for the [Rh
2
A
H
U
G
R
N
N
(O
2
CH)
4
]-catalyzed [3+2] cycloaddition reaction between 2-diazo-1,3-ketoester and protoanemonin; for
calculation of the TSs, innocent protoanemonin and/or dinitrogen (omitted for clarity) were included (equally for final structures A’–H’), so that the en-
ergies could be compared one to another.
This result suggested that the rhodium metal might be in-
volved in forming a complex with the ylide (III) and, thus,
exert a subtle influence over the [3+2] cycloaddition step.
weak endothermicity, by a nitrogen-extrusion reaction
ꢀ
1
through transition state TSI’–II (16.2 kcalmol ). Interestingly,
the activation energy of the nitrogen extrusion is in good
agreement with a previously reported experimental value
ꢀ1
Pathway 2—rhodium(II)-catalyzed [3+2] cycloaddition: To
gain a better understanding of the entire catalytic cycle,
each step was detailed and studied. In addition, to reduce
the computational cost, calculations were performed on a
model system, in which the tert-butyl ester was simplified to
a methyl ester.
(16.4
A
H
U
G
R
N
U
G
ACHTUNGENTRNUNG( OAc) ] and ethyl diazoace-
4
[31]
ꢀ
1
approximately 16–17 kcalmol during their theoretical in-
vestigation of rhodium-catalyzed CꢀH insertion between a-
[27]
diazoacetates and alkanes.
Thereafter, both the S-trans
To begin with, the 2-diazo-1,3-ketoester (1) forms a com-
plex (I’) with 8.8 kcalmol of stabilization energy. Then,
Fisher carbene species II is formed from complex I’, with
and S-cis conformers of complex I’ (between the two car-
ꢀ
1
bonyl functions) were examined. The energy difference was
ꢀ
1
around 5.3 kcalmol in favor of the S-trans one; therefore,
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Polyoxygenated Polycyclic Spirolactones
FULL PAPER
only the latter compound was taken into consideration for
the next transformation. In the nitrogen-extrusion transition
state, TSI’–II, the RhꢀC bond shortens (2.49!2.08 ꢃ, 20%
decrease) and the CꢀN bond lengthens (1.35!1.98 ꢃ, 47%
of this result, the partial charge that is located on the oxa-
carbenium carbon atom is greater in ylide III (Mulliken
charge: +0.103) than in its analogue (IV, Mulliken charge:
+0.022). Regarding the formation of the free ylide (IV), the
ꢀ1
increase). In addition, a substantial change in hybridization
reaction was found to be endothermic (17.5 kcalmol from
complex III). Unfortunately, it was not possible to locate
the transition state (TSIII–IV); however, it goes without
saying that this activation free energy would be higher that
3
2
(
sp !sp ) at the malonic carbon atom takes place from
complex I’ to transition state TS
.
I’–II
Next, the carbon atom of rhodium carbene II is attacked
by the lone pair on the oxygen atom of the distal ketone
[32]
the energetic level of compound IV. Next, we compared
this hypothetical activation energy (TSIII–IV) to those that
lead to the final cycloadducts that result from the inverse-
electron-demand process, that is, spirolactones A’ and B’
(Figure 5). Both of these compounds were of lower energy
(TSIII–A’ and TSIII–B’ respectively) and, therefore, the afore-
mentioned pathway 1 was ruled out for energetic reasons
(Figure 4). The next step was to justify the exclusive forma-
tion of spirolactone A’ among the eight possible cycload-
ducts that could be obtained. First of all, it should be noted
that TSIII–D’, which led to spirolactone D’ through a normal-
electron-demand cycloaddition reaction, was not found, de-
spite many attempts. On the other hand, the energy barriers
to form transition states TSIII–C’ (normal-electron demand
cycloaddition), TSIII–E’, TSIII–F’, TSIII–G’, and TSIII–H’, which
correspond to the cycloaddition reaction with the endocyclic
olefin of the protoanemonin, dramatically increase by at
(
for the formation of rhodium–ylide III). Owing to the elec-
trophilic character of the carbon atom of the carbene, this
step was found to be facile (weak activation energy,
ꢀ
1
ꢀ1
4
.45 kcalmol ) and exothermic (16.9 kcalmol ). In the
transition state for ylide formation (TSII–III), the RhꢀC bond
lengthens very slightly (1.962!1.995 ꢃ, 1.6% increase) and
the newly created CꢀO bond is quite long compared to that
found in ylide III (2.76!1.45 ꢃ, 90% decrease), thus re-
vealing that this transition state is very close to the carbene
structure (II). In addition, a weak change of the hybridiza-
2
3
tion (sp !sp ) at the malonic carbon atom takes place be-
tween complex II and TS (sum of the bond angles
II–III
around the malonic carbon atom: 358.58).
At this stage, two options were open from a mechanistic
point of view: Either decomplexation of the rhodium to
afford the free ylide (IV) or the direct cyclization of rhodi-
um–ylide III with the proteanemonin. Firstly, the energy
cost of rhodium decomplexation to afford the free ylide
ꢀ
1
least 6.8 kcalmol when compared to transition state TSIII–
A’. This significant energy difference between the different
TSs could explain the experimentally observed chemoselec-
tivity in favor of the exocyclic double bond of the proteane-
monin (which predominantly exhibits enol ester-type reac-
tivity). Consequently, an analysis of the energetic and struc-
tural features of the two competing transition states, TSIII–A’
and TSIII–B’ (Figure 4), might finally reveal the origins of the
complete diastereoselectivity of the [3+2] cycloaddition re-
action. Accordingly, in this case, we found that transition
(
IV) was investigated (rhodium centered on the carbon
atom of the enolate!free ylide, in which the negative
charge was located on the oxygen atom of the ketone). In-
terestingly, a comparison between the two ylide structures
revealed significant differences: Free ylide IV exhibits a
planar conjugated p system for the C=OꢀC=CꢀO fragment,
whereas ylide III shows a non-conjugated system through its
3
rhodium-ligated sp carbon atom. As a direct consequence
ꢀ
1
Figure 4. Energy profile for the [3+2] cycloaddition reaction at the B3LYP/def2-SV(P) level; energies are given in kcalmol
.
Chem. Eur. J. 2013, 19, 2467 – 2477
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
2473

G. Chouraqui, L. Commeiras et al.
dium(II)-catalyzed 1,3-dipolar cycloadditions. The strength
of this approach lies in the formation of spiro ACHUTNGRENNUG[ 6,4]lactone
moieties with the concomitant construction of quaternary
spiro stereocenters. Typically, the construction of spirolac-
tones involves an esterification step, which has often been
reported as a “biosynthetic pathway”, and often occurs
either as or near to the final step of a total synthesis. Fur-
thermore, a convergent and versatile route is reported for
the formation of the (5,7) skeleton of molecules that were
isolated from the Schisandra genus in only four steps. Com-
putational studies were performed to provide an overall pic-
ture of the mechanism of the intermolecular [3+2] cycload-
dition between 2-diazo-1,3-ketoester and protoanemonin
and to rationalize the empirical observations (Scheme 7). In
particular, we have demonstrated for the first time that the
rhodium center plays an important role during the cycliza-
tion step itself and reacts with the dipolarophile as a com-
plex with the ylide.
Figure 5. Structures of the two less-energetic representative transition
states that lead to spirolactones A’ and B’ (C gray, H white, O red,
Rh blue).
state TS
was higher in energy (than TSIII–A’) by 5.5 kcal
III–Bꢁ
ꢀ
1
mol ; this value was significant enough to justify the com-
plete diastereoselectivity that was experimentally observed
in favor of spirolactone A. The main structural features of
transition states TSIII–A’ and TSIII–B’ reveal a more-compact
structure for the latter state: 1) The RhꢀC bond lengthens
Experimental Section
by 5% in transition state TS
(TS
from III: 2.30!
III–B’
III–B’
2.43 ꢃ), whereas it increases by 8% in transition state TS
III–
General procedure for the synthesis of compounds 9: To a stirring solu-
tion of diazo compound 4 (1 equiv) in anhydrous CH Cl (c=0.16m) was
(
TSIII–A’ from complex III: 2.30!2.49 ꢃ), and 2) the
A’
2
2
values for the newly created CꢀC bond are 2.49 and 2.43 ꢃ
2 4
added [Rh ACHTUNRTEGNNUNG( OAc) ] (0.05 equiv) in one portion. The mixture was stirred
at RT for 2 h, after which time the mixture was concentrated under re-
duced pressure. Then, the residue was purified by column chromatogra-
in transition states TS and TS , respectively.
III–A’
III–B’
To conclude, both pathways are in good agreement with
the experimental data and follow the general trend.
However, pathway 2, which takes into account the metal
during the cyclization step, ap-
pears to be more accurate than
the metal-free pathway (path-
way 1). Accordingly, the differ-
ences between the energies of
the different transition states
are more significant and can ex-
plain the experimentally ob-
served chemo-, regio-, and dia-
stereoselectivities. In addition,
the fact that the dirhodium
moiety of the Rh–ylide (IV)
stabilizes the C enolate and en-
hances the positive charge on
the oxonium appears to be a
determining factor in control-
ling the regioselectivity of this
reaction.
phy on silica gel to yield the desired product (9).
1
Compound 9aa:
400 MHz, [D
R
f
=0.22 (petroleum ether/EtOAc, 6:4); H NMR
(
6
]benzene, 258C, TMS): d=0.98–1.09 (m, 2H; 2ꢄCH
2
),
Conclusion
In summary, we have further
demonstrated the synthetic util-
ity of g-alkylidenebutenolides,
in this case as highly competent
dipolarophile partners in both
intra- and intermolecular rho- protoanemonin.
Scheme 7. Mechanism of the intermolecular [3+2] cycloaddition reaction between 2-diazo-1,3-ketoester and
2474
www.chemeurj.org
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 2467 – 2477

Polyoxygenated Polycyclic Spirolactones
FULL PAPER
1
(
1
.13–1.21 (m, 1H; CH
m, 4H; CH and CH), 1.90–2.10 (m, 4H; 4ꢄCH
H; CH), 2.27–2.37 (m, 1H; CH ), 5.54 ppm (br q, J=1.5 Hz, 1H; CH);
]benzene, 258C, TMS): d=13.5 (CH ), 26.1
), 27.3 (3ꢄCH ), 32.6 (CH ), 36.0 (CH ), 37.6 (CH ),
2
), 1.31–1.39 (m, 10H; 3ꢄCH
3
and CH
), 2.21 (d, J=9.3 Hz,
2
), 1.42–1.47
Compound 10aa: R
f
=0.28 (petroleum ether/EtOAc, 50:50); m.p. 1438C;
6
]benzene, 258C, TMS): d=0.93–1.05 (m, 3H; 3ꢄ
1
3
2
H NMR (400 MHz, [D
CH ), 1.34–1.40 (m, 11H; 3ꢄCH
1.71 (dd, J=13.0 Hz, J=5.5 Hz, 1H; CH
1.94–1.99 (m, 1H; CH ), 2.02 (br d, J=1.5 Hz, 3H; CH
1H; CH ), 2.22 (d, J=9.3 Hz, 1H; CH), 3.69 (s, 1H; OH), 3.91 (dd, J=
10.3 Hz, J=6.5 Hz, 1H; CH), 5.55 ppm (br q, J=1.5 Hz, 1H; CH);
2
2
3
and CH
2
), 1.47–1.58 (m, 2H; 2ꢄCH
), 1.85–1.92 (m, 1H; CH
2
),
),
1
3
C NMR (100 MHz, [D
CH ), 26.7 (CH
6
3
2
2
(
2
2
3
2
2
2
2
3
), 2.08–2.19 (m,
5
1
1
8
C
5.8 (CH), 83.1 (C), 92.1 (C), 95.9 (C), 97.7 (C), 120.6 (CH), 162.2 (C),
64.4 (C), 170.6 (C), 200.9 ppm (C); IR (film) n˜ =2978, 2963, 2941, 2875,
2
1
3
748, 1722, 1639, 1445, 1370, 1304, 1224, 1181, 1156, 1107, 1081, 981, 941,
C NMR (100 MHz, [D
6
]benzene, 258C, TMS): d=16.0 (CH
3
), 26.1
),
ꢀ
1
+
41 cm ; MS (eV): m/z 371 (100) [M+Na] ; HRMS (ESI): m/z calcd for
(CH ), 26.2 (CH ), 27.9 (3ꢄCH
2
2
3
), 28.3 (CH ), 32.4 (CH ), 37.2 (CH
2
2
2
+
+
19
H
24
O
6
+NH
4
: 366.1911 [M+NH
=0.39 (petroleum ether/EtOAc, 6:4); H NMR
]benzene, 258C, TMS): d=0.85–0.97 (m, 3H; 3ꢄCH ),
.21–1.45 (m, 11H; 3ꢄCH and 2ꢄCH ), 1.69 (d, J=9.5 Hz, 1H; CH),
.80–2.00 (m, 4H; 4ꢄCH ), 2.35–2.44 (m, 1H; CH ), 5.71 (d, J=5.8 Hz,
H; CH), 6.56 ppm (d, J=5.8 Hz, 1H; CH); C NMR (100 MHz,
]benzene, 258C, TMS): d=26.0 (CH ), 26.3 (CH ), 27.7 (3ꢄCH ), 32.1
CH ), 35.6 (CH ), 37.6 (CH ), 55.2 (CH), 83.4 (C), 91.4 (C), 95.4 (C),
6.2 (C), 122.5 (CH), 153.1 (CH), 161.4 (C), 171.4 (C), 202.8 ppm (C); IR
film) n˜ =2978, 2941, 2873, 1770, 1741, 1455, 1369, 1303, 1166, 1140, 1103,
4
] ; found: 366.1910
52.1 (CH), 70.1 (CH), 83.7 (C), 92.3 (C), 93.2 (C), 99.6 (C), 121.5 (CH),
165.8 (C), 169.4 (C), 170.3 ppm (C); IR (film ) n˜ =3478, 2959, 2878, 1732,
1
Compound 9ab:
400 MHz, [D
R
f
ꢀ
1
1
634, 1368, 1305, 1090, 1073, 971, 935 cm ; MS (eV): m/z 373 (100)
(
6
2
+
+
[
[
M+Na] ; HRMS (ESI): m/z calcd for C H O +NH : 368.2068
M+NH ] ; found: 368.2068.
4
19 26 6 4
1
1
1
3
2
+
2
2
1
3
General procedure for the synthesis of compounds 14: To a stirring solu-
tion of [Rh (OAc) (0.05 equiv) and g-alkylidenebutenolide 13
(1.2 equiv) in anhydrous C CF (c=0.9m) at 258C was slowly added a
solution of diazoketone 13 (1 equiv) in anhydrous C CF (c=0.7m) by
[
D
6
2
2
3
2
A
H
U
G
R
N
U
G
4
]
(
9
(
2
2
2
6
H
5
3
6
H
5
3
ꢀ
1
using a syringe pump (rate: 1 mLmin ). After the addition was com-
plete, the reaction mixture was filtered through a short pad of Celite and
the filtrate was concentrated in vacuo. The resulting crude product was
purified by column chromatography on silica gel to yield the desired
product (14).
ꢀ1
1
086, 1072, 985, 923, 880, 848, 820 cm ; HRMS (ESI): m/z calcd for
+
+
C
18
H
22
O
6
+NH
4
: 352.1755 [M+NH
=0.42 (petroleum ether/EtOAc, 6:4); m.p. 1688C;
H NMR (400 MHz, [D ]benzene, 258C, TMS): d=0.67–0.84 (m, 2H; 2ꢄ
CH ), 0.92–1.00 (m, 2H; CH ), 1.09–1.17 (m, 1H; CH ), 1.26–1.34 (11H;
ꢄCH and 2ꢄCH ), 1.37–1.48 (m, 5H; CH, CH , and CH ), 1.67 (br d,
J=11.8 Hz, 1H; CH ), 1.75 (dt, J=16.3 Hz, J=8.0 Hz, 1H; CH ), 2.30–
.44 (m, 2H; CH ), 5.45 ppm (br q, J=1.5 Hz, 1H; CH); C NMR
100 MHz, [D ]benzene, 258C, TMS): d=13.7 (CH ), 20.6 (CH ), 22.2
CH ), 24.8 (CH ), 25.3 (CH ), 27.7 (3ꢄCH ), 33.2 (CH ), 39.5 (CH ),
4.0 (CH), 81.4 (C), 83.0 (C), 92.3 (C), 95.4 (C), 117.2 (CH), 163.4 (C),
4
] ; found: 352.1756
Compound 9ba: R
f
1
6
2
2
2
Compound 14ad: R
f
=0.17 (petroleum ether/EtOAc, 70:30); m.p. 158–
1608C; H NMR (400 MHz, [D ]benzene, 258C, TMS): d=0.99 (s, 3H;
CH ), 1.18 (m, 1H; CH ), 1.30 (s, 9H; 3ꢄCH ), 1.51–1.58 (m, 7H; CH
2ꢄCH ), 1.65 (d, J=14.3 Hz, 1H; CH ), 1.82 (d, J=14.3 Hz, 1H; CH ),
2.18–2.24 (m, 1H; CH ); C NMR
(100 MHz, [D ), 25.7
(CH ), 27.8 (3ꢄCH ), 79.9 (C), 82.2
1
3
3
2
2
3
6
2
2
3
3
2
3
2
,
1
2
(
(
5
1
2
8
2
3
2
2
1
3
6
3
2
2
), 2.62–2.71 ppm (m, 1H; CH
2
2
2
2
3
2
2
6
]benzene, 258C, TMS): d=8.5 (CH
3 3
), 10.7 (CH
3
3
), 35.0 (CH ), 38.4 (CH ), 44.0 (CH
2
2
2
66.9 (C), 169.8 (C), 198.1 ppm (C); IR (film) n˜ =3118, 2985, 2948, 2933,
(C), 90.1 (C), 92.6 (C), 123.6 (C), 158.5 (C), 164.1 (C), 171.8 (C),
197.0 ppm (C); IR (film) n˜ =2979, 2935, 2874, 1766, 1745, 1731, 1683,
1453, 1394, 1367, 1318, 1288, 1253, 1154, 1129, 1097, 1086, 1029, 1013,
863, 1796, 1739, 1725, 1293, 1178, 1161, 1135, 1097, 1081, 1067, 921, 880,
ꢀ
1
+
35 cm
; HRMS (ESI): m/z calcd for C H O +NH : 380.2068
20 26 6 4
+
ꢀ1
+
4
[
M+NH
4
] ; found: 380.2068
=0.25 (petroleum ether/EtOAc, 7:3); m.p. 1558C;
H NMR (400 MHz, [D ]benzene, 258C, TMS): d=0.60–0.80 (m, 2H; 2ꢄ
CH ), 0.86–0.95 (m, 2H; CH ), 1.04–1.13 (m, 1H; CH ), 1.26–1.43 (m,
3H; 3ꢄCH , 3ꢄCH , and CH), 1.63–1.78 (m, 2H; 2ꢄCH ), 2.24–2.46
m, 2H; CH ), 5.58 (d, J=5.7 Hz, 1H; CH), 6.64 ppm (d, J=5.7 Hz, 1H;
CH); C NMR (100 MHz, [D ]benzene, 258C, TMS): d=20.2 (CH ),
2.1 (CH ), 24.4 (CH ), 25.0 (CH ), 27.9 (3ꢄCH ), 33.2 (CH ), 39.3
CH ), 55.1 (CH), 81.6 (C), 83.1 (C), 93.1 (C), 94.0 (C), 118.8 (CH), 156.6
CH), 163.6 (C), 170.0 (C), 198.9 ppm (C); IR (film) n˜ =2977, 2940, 2870,
997, 840 cm ; HRMS (ESI): m/z calcd for C18
H
24
O
6
+NH
: 354.1911
+
[
M+NH
4
] ; found: 354.1911.
Compound 9bb: R
f
1
6
Compound 14ab: R
f
=0.12 (petroleum ether/EtOAc, 70:30); m.p. 204–
2058C; H NMR (400 MHz, [D ]benzene, 258C, TMS): d=0.95 (s, 3H;
CH ), 1.10 (m, 1H; CH ), 1.33 (s, 9H; 3ꢄCH ), 1.51 (m, 2H; 2ꢄCH ),
1.67 (d, J=14.3 Hz, 1H; CH ), 2.14–2.20 (m, 1H; CH ), 2.50–2.59 (m,
1H; CH ), 5.47 (d, J=5.4 Hz, 1H; CH), 6.44 ppm (d, J=5.4 Hz, 1H;
1
2
2
2
6
1
(
3
2
2
3
2
3
2
2
2
2
1
3
6
2
2
1
3
2
(
(
2
2
2
3
2
CH); C NMR (100 MHz, [D
6
]benzene, 258C, TMS): d=26.0 (CH
3
),
2
27.8 (3ꢄCH ), 35.0 (CH ), 38.0 (CH
3
2
2
), 44.3 (CH ), 80.1 (C), 82.6 (C), 89.6
2
(C), 92.9 (C), 120.3 (CH), 155.8 (CH), 163.4 (C), 170.3 (C), 196.9 ppm
1
8
770, 1736, 1369, 1296, 1255, 1163, 1138, 1100, 1085, 1070, 985, 920, 876,
(C); IR (film) n˜ =2979, 2933, 2866, 1774, 1750, 1740, 1456, 1369, 1318,
ꢀ
1
+
ꢀ1
40, 821 cm ; HRMS (ESI): m/z calcd for C19
H
24
O
6
+NH
4
: 366.1911
1248, 1162, 1137, 1094, 1070 cm
;
HRMS (ESI): m/z calcd for
+
+
+
[
M+NH
Compound 9bc: R
400 MHz, [D ]benzene): d=0.72–0.87 (m, 2H; 2ꢄCH
), 1.26–1.50 (m, 12H; 3ꢄCH and 3ꢄCH
H; CH and 2ꢄCH ), 2.36–2.40 (m, 2H; CH ), 2.88 (s, 3H; CH
), 3.75 (br dd, J=15.3 Hz, J=
4
] ; found: 366.1908
C
16
H
20
O
6
+NH
4
: 326.1598 [M+NH
=0.18 (petroleum ether/EtOAc, 70:30); m.p. 157–
1588C; H NMR (400 MHz, [D ]benzene, 258C, TMS): d=1.02 (s, 3H;
CH ), 1.15 (m, 1H; CH ), 1.32 (s, 9H; 3ꢄCH ), 1.58–1.62 (m, 5H; CH
2ꢄCH ), 1.78 (d, J=14.3 Hz, 1H; CH ), 2.17–2.23 (m, 1H; CH ), 2.25–
2.62 (m, 1H; CH ), 6.13 ppm (s, 1H; CH); C NMR (100 MHz,
[D ]benzene, 258C, TMS): d=10.4 (CH ), 26.0 (CH ), 27.9 (3ꢄCH ), 35.0
(CH ), 38.2 (CH ), 44.4 (CH ), 80.2 (C), 82.3 (C), 89.8 (C), 90.9 (C),
4
] ; found: 326.1598.
1
f
=0.23 (petroleum ether/EtOAc, 65:45); H NMR
Compound 14aa: R
f
1
(
3
3
6
2
), 0.98–1.16 (m,
), 1.59–1.81 (m,
), 3.70
6
H; 2ꢄCH
2
3
2
3
2
3
3
,
2
2
3
2
2
2
1
3
(
1
br dd, J=15.3 Hz, J=1.8 Hz, 1H; CH
.8 Hz, 1H; CH ), 5.93 ppm (br t, J=1.8 Hz, 1H; CH); C NMR
100 MHz, [D ]benzene): d=20.6 (CH ), 22.1 (CH ), 24.6 (CH ), 25.3
), 27.7 (3ꢄCH ), 33.2 (CH ), 39.6 (CH ), 54.9 (CH), 58.6 (CH ), 67.8
), 81.4 (C), 83.3 (C), 92.8 (C), 94.3 (C), 116.9 (CH), 163.6 (C), 167.3
2
2
1
3
2
6
3
3
3
(
(
(
(
6
2
2
2
2
2
2
CH
CH
2
2
3
2
2
3
129.1 (CH), 148.8 (CH), 163.6 (C), 177.7 (C), 197.2 ppm (C); IR (film)
n˜ =2979, 2930, 2868, 1772, 1750, 1734, 1663, 1453, 1369, 1315, 1289, 1254,
ꢀ
1
C), 169.3 (C), 198.4 ppm (C); IR (film) n˜ =2978, 2941, 2869, 1770, 1736,
1156, 1129, 1102, 1040, 999, 840 cm ; HRMS (ESI): m/z calcd for
+
+
1
8
4
647, 1449, 1366, 1303, 1254, 1163, 1137, 1100, 1083, 1066, 1031, 985, 925,
71, 840, 736 cm
C
17
H
22
O
6
+Na : 345.1309 [M+Na] ; found: 345.1304.
Compound 14bd: R =0.20 (petroleum ether/EtOAc, 85:15); m.p. 91–
28C; H NMR (400 MHz, [D ]benzene, 258C, TMS): d=0.04 (s, 6H; 2ꢄ
), 1.30 (m, 10H; CH , 3ꢄCH ), 1.54 (m, 1H;
), 1.69 (m, 3H; CH ), 1.78 (d, J=14.2 Hz, 1H;
), 2.36 (d, J=14.2 Hz, 1H; CH ), 2.68–2.81
), 3.50 ppm (d, J=11.0 Hz,
ꢀ
1
+
;
HRMS (ESI): m/z calcd for
21 28 7 4
C H O +NH :
f
+
10.2173 [M+NH
4
] ; found: 410.2173.
1
9
6
Procedure for the preparation of compound 10aa: To a cooled (08C) stir-
ring solution of cycloadduct 9aa (1 equiv) in anhydrous MeOH (c=
0
temperature, the mixture was allowed to warm to RT. After the comple-
tion of the reaction (by TLC), the reaction was quenched with water and
the aqueous phase was extracted with CH
CH
CH
CH
(m, 1H; CH
1H; CH
3
2
2
), 0.92 (s, 9H; 3ꢄCH
), 1.60 (m, 3H; CH
), 2.23–2.34 (m, 1H; CH
3
2
3
3
3
.13m) was added NaBH
4
(1 equiv) in one portion. After 5 min at this
2
2
2
3
), 3.28 (d, J=11.0 Hz, 1H; CH
2
1
2
); C NMR (100 MHz, [D
), 8.5 (CH ; 1C), 11.0 (CH , C), 18.7 (C), 26.1 (3ꢄCH
), 34.1 (CH ), 34.5 (CH ), 39.2 (CH ), 67.3 (CH ), 82.5 (2C), 90.1
6
]benzene, 258C, TMS): d=ꢀ5.3 (2ꢄ
2
Cl
2
. The organic layers were
SO , filtered, and concen-
CH
CH
3
3
3
3
), 27.8 (3ꢄ
washed with brine, dried over anhydrous Na
2
4
3
2
2
2
2
trated in vacuo. The resulting oil was purified by column chromatography
(C), 92.3 (C), 123.6 (C), 158.8 (C), 164.0 (C), 171.7 (C), 196.8 ppm (C);
on silica gel to afford alcohol 10aa.
IR (film) n˜ =2985, 2965, 2933, 2860, 1766, 1745, 1726, 1682, 1461, 1369,
Chem. Eur. J. 2013, 19, 2467 – 2477
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
2475

G. Chouraqui, L. Commeiras et al.
ꢀ
1
1
318, 1253, 1156, 1115, 1067, 1026, 837, 780 cm ; MS (eV): m/z 489 (100)
+ +
[
[
M+Na] ; HRMS (ESI): m/z calcd for
M+NH
C
24
H
38
O
7
Si+NH
4
:
484.2725
[1] a) R. Pradhan, M. Patra, A. K. Behera, B. K. Mishra, R. K. Behera,
Tetrahedron 2006, 62, 779–828; b) I. Denissova, L. Barriault, Tetra-
hedron 2003, 59, 10105–10146.
+
4
] ; found: 484.2723.
=0.28 (petroleum ether/EtOAc, 80:20); m.p. 124–
258C; H NMR (400 MHz, [D ]benzene, 258C, TMS): d=0.073 (d, J=
.8 Hz, 6H; 2ꢄCH ), 0.94 (s, 9H; 3ꢄCH3), 1.22–1.32 (m, 11H; CH and
ꢄCH ), 1.46–1.54 (m, 1H; CH ), 1.69 (d, J=14.1 Hz, 1H; CH ), 2.22–
.29 (m, 2H; CH ), 2.56–2.65 (m, 1H; CH ), 3.19 (d, J=11.1 Hz, 1H;
), 3.39 (d, J=11.1 Hz, 1H; CH ), 5.56 (d, J=5.4 Hz, 1H; CH ),
]benzene,
), 26.0 (C), 26.0 (3ꢄCH ), 27.8
), 67.0 (CH ), 82.7 (C), 82.8 (C),
Compound 14bb: R
f
ꢅ
1
[2] Yaz is ranked in the “top 200 brand-name drugs by total US pre-
1
7
3
2
CH
6
6
scription, 2010”. http://cbc.arizona.edu/njardarson/group/top-phar-
maceuticals-poster.
3
2
3
2
2
[
3] Methicillin-resistant minimum inhibitory concentration (MIC)=
2
2
ꢀ
1
ꢀ1
4
mgmL ; vancomycin-resistant MIC=13 mgmL ; a) B. Bister, D.
2
2
2
1
3
Bischoff, M. Strobele, J. Riedlinger, A. Reicke, F. Wolter, A. T. Bull,
H. Zahner, H. P. Fiedler, R. D. Sꢆssmuth, Angew. Chem. 2004, 116,
.81 ppm (d, J=5.4 Hz, 1H; CH
58C, TMS): d=ꢀ5.4 and ꢀ5.0 (2ꢄCH
), 34.5 (CH ), 39.3 (CH
2 6
); C NMR (100 MHz, [D
2
3
3
2
628–2630; Angew. Chem. Int. Ed. 2004, 43, 2574–2576; b) J. Ried-
(
C), 33.5 (CH
2
2
2
2
linger, A. Reicke, H. Zahner, B. Krismer, A. T. Bull, L. A. Maldona-
do, A. C. Ward, M. Goodfellow, B. Bister, D. Bischoff, R. D. Sꢆs-
smuth, H. P. Fiedler, J. Antibiot. 2004, 57, 271–279.
8
1
1
9.5 (C), 92.0 (C), 120.6 (CH), 155.3 (CH), 163.3 (C), 170.3 (C),
96.7 ppm (C); IR (film) n˜ =2957, 2933, 2857, 1777, 1747, 1736, 1604,
ꢀ1
477, 1461, 1372, 1312, 1250, 1159, 1134, 1110, 1083, 837, 778, 753 cm
;
+
[4] a) B. Vaz, M. Domꢇnguez, R. ꢈlvarez, A. R. de Lera, J. Org. Chem.
2006, 71, 5914–5920; b) G.-Z. Liu, H.-W. Xu, G.-W. Chen, P. Wang,
Y.-N. Wang, Bioorg. Med. Chem. 2010, 18, 1626–1632.
[5] a) S. Inack-Ngi, R. Rahmani, L. Commeiras, G. Chouraqui, J. Thi-
bonnet, A. DuchÞne, M. Abarbri, J.-L. Parrain, Adv. Synth. Catal.
MS (eV): m/z 456 (100) [M+NH ] ; HRMS (ESI): m/z calcd for
4
+
+
C
22
H
34
O
7
Si+NH
4
: 456.2412 [M+NH
=0.17 (petroleum ether/EtOAc, 60:40); m.p. 161–
638C; H NMR (400 MHz, [D ]benzene, 258C, TMS): d=0.94 (s, 3H;
), 1.33 (s, 9H; 3ꢄCH ), 1.51–1.5 (m, 4H;
), 1.60 (d, J=14.3 Hz, 1H; CH ), 1.77 (d, J=14.3 Hz, 1H;
), 2.16–2.22 (m, 1H; CH ), 2.57–2.67 (m, 1H; CH ), 5.33 ppm (m,
]benzene, 258C, TMS): d=12.5
), 34.9 (CH ), 38.2 (CH ), 44.1 (CH ),
4
] ; found: 456.2409.
Compound 14ac: R
1
CH
CH
CH
f
1
6
3
2
2
), 1.13–1.18 (m, 1H; CH
and CH
2
3
2
009, 351, 779–788; b) S. Inack Ngi, K. Cherry, V. Hꢀran, L. Com-
3
2
meiras, J.-L. Parrain, A. DuchÞne, M. Abarbri, J. Thibonnet, Chem.
Eur. J. 2011, 17, 13692–13696.
6] a) R. Blanc, V. Hꢀran, R. Rahmani, L. Commeiras, J.-L. Parrain,
Org. Biomol. Chem. 2010, 8, 5490–5494; b) S. Dubois, F. Rodier, R.
Blanc, R. Rahmani, J. Thibonnet, V. Hꢀran, L. Commeiras, J.-L. Par-
rain, Org. Biomol. Chem. 2012, 10, 4712–4719.
[7] A. Bartoli, G. Chouraqui, J.-L. Parrain, Org.Lett. 2012, 14, 122–125.
[8] A. Bartoli, F. Rodier, L. Commeiras, J.-L. Parrain, G. Chouraqui,
Nat. Prod. Rep. 2011, 28, 763–782.
9] For articles, books, and reviews on the 1,3-dipolar cycloaddition re-
actions of carbonyl ylides, see: a) A. Padwa, M. D. Weingarten,
Chem. Rev. 1996, 96, 223–270; b) M. P. Doyle, M. A. McKervey, T.
Ye, Modern Catalytic Methods for Organic Synthesis with Diazo
Compounds; Wiley-Interscience: New York, 1998; Chapter 7;
c) D. M. Hodgson, F. Y. T. M. Pierard, P. A. Stupple, Chem. Soc.
Rev. 2001, 30, 50–61; d) G. Mehta, S. Muthusamy, Tetrahedron 2002,
2
2
1
3
1
H; CH); C NMR (100 MHz, [D
6
[
(
CH ), 25.6 (CH ), 27.7 (3ꢄCH
3
3
3
2
2
2
7
1
1
9.9 (C), 82.6 (C), 90.0 (C), 93.7 (C), 117.1 (CH), 164.0 (C), 167.7 (C),
70.1 (C), 196.8 ppm (C); IR (film) n˜ =3003, 2984, 2933, 1769, 1739,
728, 1650, 1453, 1364, 1315, 1248, 1161, 1131, 1110, 1086, 1037, 994, 940,
ꢀ
1
+
8
42 cm ; MS (eV): m/z 340 (100) [M+NH
4
] ; HRMS (ESI): m/z calcd
] ; found: 340.1752.
=0.33 (petroleum ether/EtOAc, 80:20); m.p. 98–
98C; H NMR (400 MHz, [D ]benzene, 258C, TMS): d=0.08 (d, J=
0.8 Hz, 6H; 2ꢄCH ), 0.94 (s, 9H; 3ꢄCH ), 1.31–1.37. (m, 10H; CH
), 1.53–1.60 (1H; CH ), 1.63 (d, J=1.5 Hz, 3H; CH ), 1.80 (d,
), 2.61–2.70 (m, 1H;
),
]benzene, 258C, TMS):
), 18.5 (C), 26.0 (3ꢄCH ), 27.9
), 39.6 (CH ), 67.3 (CH ), 82.4 (C), 82.8
C), 89.8 (C), 90.6 (C), 129.5 (C), 148.3 (CH), 163.4 (C), 171.7 (C),
+
+
for C17
22 6 4 4
H O +NH : 340.11754 [M+NH
Compound 14ba: R
9
1
f
[
1
6
3
3
2
and 3ꢄCH
J=14.0 Hz, 1H; CH
CH
.51 ppm (m, 1H; CH); C NMR (100 MHz, [D
) and ꢀ5.0 (CH ), 10.4 (CH
), 33.8 (CH ), 34.6 (CH
3
2
3
2
), 2.25–2.31 (m, 2H; 2ꢄCH
2
2
2 2
), 3.27 (d, J=10.8 Hz, 1H; CH ), 3.46 (d, J=10.8 Hz, 1H; CH
1
3
6
6
d=ꢀ5.4 (CH
3
3
3
3
5
8, 9477–9504; e) R. M. Savizky, D. J. Austin in Modern Rhodium-
(
3ꢄCH
3
2
2
2
2
Catalyzed Organic Reactions (Ed. P. A. Evans), Wiley-VCH, Wein-
heim, 2005, Chapter 19; f) C. Y. Zhou, P. W. H. Chan, W.-Y. Yu, C.-
M. Che, Synthesis 2003, 1403–1412; g) H. Suga, Y. Ebiura, K. Fu-
kushima, A. Kakehi, T. Baba, J. Org. Chem. 2005, 70, 10782–10791;
h) S. Muthusamy, J. Krishnamurthi, M. Nethaji, Chem. Commun.
(
1
1
97.0 ppm (C); IR (film) n˜ =2981, 2957, 2933, 2863, 1774, 1755, 1734,
ꢀ1
469, 1369, 1321, 1256, 1156, 1115, 1086, 1040, 999, 835, 778 cm ; HRMS
+
+
(
36 7 4 4
ESI): m/z calcd for C23H O Si+NH : 470.2568 [M+NH ] ; found:
4
70.2567.
2
005, 3862–3864; i) D. M. Hodgson, D. Angrish, A. H. Labande,
Compound 14bc: R
f
=0.20 (petroleum ether/EtOAc, 90:10); m.p. 74–
68C; H NMR (400 MHz, [D ]benzene, 258C, TMS): d=0.02 (d, J=
.8 Hz, 6H; 2ꢄCH ), 0.91 (s, 9H; 3ꢄCH ), 1.24–1.29 (m, 1H; CH ), 1.33
), 1.47–1.1.58 (m, 1H; CH ), 1.69 (d, J=1.5 Hz, 3H; CH
.73 (d, J=14.4 Hz, 1H; CH ), 2.21–2.34 (m, 2H; 2ꢄCH
H; CH ), 3.23 (d, J=10.9 Hz, 1H; CH
Chem. Commun. 2006, 627–628; for applications in the synthesis of
natural products, see: j) M. C. McMills, D. Wright in Synthetic Appli-
cations of 1,3-Dipolar Cycloaddition Chemistry Toward Heterocycles
and Natural Products (Eds. A. Padwa, W. H. Pearson), Wiley, Hobo-
ken, 2003, Chapter 4; k) S. Nakamura, Y. Hirata, T. Kurosaki, M.
Anada, O. Kataoka, S. Kitagaki, S. Hashimoto, Angew. Chem. 2003,
1
7
2
6
3
3
2
(
9H; 3ꢄCH
3
2
3
),
),
1
1
5
2
2
), 2.64–2.76 (m,
2
2
), 3.46 (d, J=10.9 Hz, 1H; CH
2
1
3
.35 ppm (br s, 1H; CH); C NMR (100 MHz, [D
), ꢀ5.2 (CH ), 12.9 (CH ), 18.7 (C), 26.1 (3ꢄCH
), 33.9 (CH ), 34.4 (CH ), 39.3 (CH ), 67.2 (CH ), 82.6 (C), 89.9 (C),
3.4 (C), 117.0 (CH), 163.9 (C), 168.0 (C), 170.1 (C), 196.6 ppm (C); IR
film) n˜ =2960, 2933, 2860, 1777, 1747, 1734, 1650, 1458, 1369, 1307, 1253,
6
]benzene, 258C, TMS):
1
15, 5509–5513; Angew. Chem. Int. Ed. 2003, 42, 5351–5355; l) A.
d=ꢀ5.4 (CH
3
3
3
3
), 27.7 (3ꢄ
Padwa, Helv. Chim. Acta 2005, 88, 1357–1374; m) A. Padwa, J. Or-
ganomet. Chem. 2005, 690, 5533–5540; n) Z. Geng, B. Chen, P.
Chiu, Angew. Chem. 2006, 118, 6343–6347; Angew. Chem. Int. Ed.
CH
3
2
2
2
2
9
(
2
006, 45, 6197–6201; o) Y. Hirata, S. Nakamura, N. Watanabe, O.
ꢀ
1
1
C
158, 1113, 1077, 838, 780, 754 cm
;
HRMS (ESI): m/z calcd for
+
+
Kataoka, T. Kurosaki, M. Anada, S. Kitagaki, M. Shiro, S. Hashimo-
to, Chem. Eur. J. 2006, 12, 8898–8925; p) D. B. England, A. Padwa,
Org. Lett. 2007, 9, 3249–3252; q) V. Nair, T. D. Suja, Tetrahedron
23
H O Si+NH :470.2568 [M+NH ] ; found: 470.2567.
36 7 4 4
2007, 63, 12247–12275; r) D. B. England, A. Padwa, J. Org. Chem.
2008, 73, 2792–2802; s) S. K. Lam, P. Chiu, Chem. Eur. J. 2007, 13,
9589–9599; t) C. H. Kim, K. P. Jang, S. Y. Choi, Y. K. Chung, E.
Acknowledgements
Lee, Angew. Chem. 2008, 120, 4073–4075; Angew. Chem. Int. Ed.
008, 47, 4009–4011; u) V. Singh, U. M. Krishna, G. Vikrant, K. Triv-
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009, 38, 3072–3081; w) H. Li, B. Cheng, N. Boonnak, A. Padwa,
Tetrahedron 2011, 67, 9829–9836; x) N. Shimada, T. Hanari, Y. Kur-
osaki, M. Anada, H. Nambu, S. Hashimoto, Tetrahedron Lett. 2010,
The Agence Nationale pour la Recherche (A.N.R.-09-JCJC-0036), the
CNRS, and Aix-Marseille Universitꢀ (UMR 7313) are gratefully ac-
knowledged for financial support. The authors wish to thank Michel
Giorgi for performing the X-ray analysis.
2
2
5
1, 6572–6575; y) N. Shimada, T. Hanari, Y. Kurosaki, K. Takeda,
M. Anada, H. Nambu, M. Shiro, S. Hashimoto, J. Org. Chem. 2010,
2476
www.chemeurj.org
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 2467 – 2477

Polyoxygenated Polycyclic Spirolactones
FULL PAPER
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[
8
11] The preparation of compound 6a has been reported previously in
two steps from commercially available pent-4-yn-1-ol; see referen-
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[
12] a) U. Ur sˇ i cˇ , D. Bevk, S. Pirs, L. Pezdirc, B. Stanovnik, J. Svete, Syn-
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[32] As judiciously suggested by one of the referee: “It is often likely
that there is no transition state in the ligand dissociation on a poten-
tial-energy surface (i.e., the reaction path is uphill)”.
[
[
[
14] D. M. Hodgson, D. Angrish, Adv. Synth. Catal. 2006, 348, 2509–
2
514.
15] Details of the formation of these molecules are given in the Sup-
porting Information.
16] The relative stereochemistry of cycloadducts 9ba and 9bb were un-
ambiguously determined through X-ray structural determination
(see the Supporting Information). CCDC-864494 (9ba) and CCDC-
8
64495 (9bb) contain the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
Received: September 5, 2012
Revised: October 23, 2012
Published online: January 7, 2013
Chem. Eur. J. 2013, 19, 2467 – 2477
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
2477