A formal total synthesis of eleutherobin using the ring-closing metathesis (RCM) reaction of a densely functionalized diene as the key step: Investigation of the unusual kinetically controlled RCM stereochemistry

Article abstract of DOI:10.1002/chem.200500749

Asymmetric oxyallylation reactions and ring-closing metathesis have been used to synthesize compound 3, a key advanced intermediate used in the total synthesis of eleutherobin reported by Danishefsky and co-workers. The aldehyde 6, which is readily prepar

Full text of DOI:10.1002/chem.200500749

FULL PAPER
Chem. Eur. J. 2006, 12, 51 – 62
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
51

DOI: 10.1002/chem.200500749
A Formal Total Synthesis ofEleutherobin Using the Ring-Closing Metathesis
(RCM) Reaction ofa Densely Functionalized Diene as the Key Step:
Investigation ofthe Unusual Kinetically Controlled RCM Stereochemistry
Damiano Castoldi,[a] Lorenzo Caggiano,[a, c] Laura Panigada,[a] Ofer Sharon,[a]
Anna M. Costa,[b] and Cesare Gennari*[a]
Abstract: Asymmetricoxyallylation re-
actions and ring-closing metathesis
have been used to synthesize com-
pound 3, a key advanced intermediate
used in the total synthesis of eleuthero-
bin reported by Danishefsky and co-
workers. The aldehyde 6, which is read-
ily prepared from commercially avail-
able R-(ꢀ)-carvone in six steps in 30%
overall yield on multigram quantities,
was converted into the diene 5 utilizing
two stereoselective titanium-mediated
Hafner–Duthaler oxyallylation reac-
tions. The reactions gave the desired
products (8 and 12) in high yields (73
and 83%, respectively) as single dia-
stereoisomers, with the allylicalochol
already protected as the p-methoxy-
phenyl (PMP) ether, which previous
work has demonstrated actually aids
ring-closing metathesis compared to
other protective groups and the corre-
sponding free alcohol. Cyclization
under forcing conditions, using Grubbsꢁ
second-generation catalyst 13, gave the
ten-membered carbocycle (E)-14 in
64% yield. This result is in sharp con-
trast to similar, but less functionalized,
dienes, which have all undergone cycli-
zation to give the Z stereoisomers ex-
clusively. A detailed investigation of
this unusual cyclization stereochemistry
by computational methods has shown
that the E isomer of the ten-membered
carbocycle is indeed less thermody-
namically stable than the correspond-
ing Z isomer. In fact, the selectivity is
believed to be due to the dense func-
tionality around the ruthenacyclobu-
tane intermediate that favors the trans-
ruthenacycle, which ultimately leads to
the less stable E isomer of the ten-
membered carbocycle under kinetic
control. During the final synthetic ma-
nipulations the double bond of ene-
dione (E)-16 isomerized to the more
thermodynamically stable enedione
(Z)-4, giving access to the advanced
key-intermediate 3, which was spectro-
scopically and analytically identical to
the data reported by Danishefsky and
co-workers, and thereby completing
the formal synthesis of eleutherobin.
Keywords: antitumor agents · natu-
ral products · ring-closing metathe-
sis · stereocontrol · total synthesis
Introduction
[a] Dr. D. Castoldi, Dr. L. Caggiano, L. Panigada, Dr. O. Sharon,
Prof. Dr. C. Gennari
Sarcodictyins A (1a) and B (1b) were isolated in 1987 by
Pietra and co-workers from the Mediterranean stoloniferan
coral Sarcodictyon roseum.[1] Their antitumor activity and
Dipartimento di Chimica Organica e Industriale
Centro di Eccellenza C.I.S.I.
Università degli Studi di Milano
Istituto di Scienze e Tecnologie Molecolari (ISTM) del CNR
Via G. Venezian, 21, 20133 Milano (Italy)
Fax : (+39)02-5031-4072
E-mail: cesare.gennari@unimi.it
[b] Dr. A. M. Costa
Departament de Química Orgànica
Universitat de Barcelona, Av. Diagonal 647
08028 Barcelona (Spain)
[c] Dr. L. Caggiano
Current address: Department of Chemistry
University of Sheffield, Dainton Building, Brook Hill
Sheffield, S3 7HF (UK)
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Chem. Eur. J. 2006, 12, 51 – 62

Total Synthesis
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paclitaxel-like mechanism of action were recognized about a
decade later (1996).[2] In the meantime, the diterpene glyco-
side eleutherobin (2) was reported by Fenical et al. from an
Eleutherobia species of Australian soft coral, accompanied
by disclosure of its potent cytotoxicity (1995).[3] Two years
later, eleutherobin was shown to act similarly to sarcodic-
tyins, effecting mitotic arrest through tubulin polymeri-
zation.[4] Both sarcodictyins and eleutherobin (the “eleuthe-
side” family of microtubule-stabilizing drugs) are character-
ized by an activity profile different from that of paclitaxel;
in particular, they are active against paclitaxel-resistant
tumor cell lines and therefore have potential as second-gen-
eration microtubule-stabilizing anticancer agents.[4,5] The
scarce availability of 1 and 2 from natural sources makes
their total syntheses vital for further biological investiga-
tions.[5] To date, sarcodictyins A and B have been synthe-
sized successfully by Nicolaou et al.,[6] who have also ex-
ploited a similar route to eleutherobin.[7] A subsequent
report by Danishefsky and co-workers details an elegant al-
ternative access to eleutherobin.[8] A number of synthetic
approaches to the eleutheside natural products and synthe-
ses of simplified analogues have also been described.[9]
Herein we report the preparation of 3, a key intermediate
in the synthesis reported by Danishefsky and co-workers,[8]
and thus a formal total synthesis of eleutherobin (2)
(Scheme 1).[10]
Results and Discussion
Synthesis ofthe key-intermediate 3 : Diene 5 was synthe-
sized from aldehyde 6 (prepared in six steps on a multigram
scale from R-(ꢀ)-carvone in 30% overall yield)[9a,g] incorpo-
rating two stereoselective Hafner–Duthaler oxyallylation re-
actions[12] (Scheme 2). The first oxyallylation, in the pres-
Scheme 2. Reagents and conditions: a) sec-BuLi (1.3m in cyclohexane),
PMPOAllyl, [TiCl(Cp){(S,S)-Taddol}] (7), THF/Et2O (57:43), ꢀ788C!
08C, 73%; b) DIPEA, TBAI, MOMCl, CH2Cl2, 258C, 95%; c) LiBF4,
CH3CN/H2O (98:2), 258C; d) NaBH4, EtOH, 258C, 75% over two steps;
e) MsCl, TEA, CH2Cl2, 08C!258C, 95%; f) KCN, [18]crown-6, CH3CN,
808C, quant.; g) DIBAL-H, toluene/hexane (1:2), ꢀ788C, quant.; h) sec-
BuLi (1.4m in cyclohexane), PMPOAllyl, [TiCl(Cp){(R,R)-Taddol}] (7),
Et2O/THF (81:19), ꢀ788C!258C, 83%; i) PivCl, DMAP, DIPEA,
CH2Cl2, 258C, 96%. PMP=p-methoxyphenyl; DIPEA=diisopropyl-
ethylamine; TBAI=tetrabutylammonium iodide; MOMCl=chlorometh-
yl methyl ether; MsCl=methanesulfonyl chloride; TEA=triethylamine;
DIBAL-H=diisobutylaluminum hydride; Piv=tert-BuCO; DMAP=4-
(dimethylamino)pyridine.
Scheme 1. Retrosynthetic analysis of eleutherobin (2).
ence of the [TiCl(Cp){(S,S)-Taddol}] complex 7, proceeded
with complete stereocontrol to give the desired stereoisomer
8 in 73% isolated yield. After standard protection of the al-
cohol as methoxymethyl ether 9 in 95% yield, cleavage of
the dimethylacetal group and reduction with NaBH4 to give
10 in 75% yield, an efficient and well-established sequence
of steps[8c,9n] led to the homologated aldehyde 11 (95%).[9q]
The same oxyallylation procedure described above was
again applied, this time using the [TiCl(Cp){(R,R)-Taddol}]
complex 7, to give the desired alcohol 12 in 83% yield with
The key step of our strategy, used for obtaining the
[8.4.0]-fused bicyclic ring system 4, is a ring-closing metathe-
sis (RCM)[11] reaction of the densely functionalized diene 5.
The unusual kinetically controlled RCM stereochemical out-
come has been investigated using computational methods.
Chem. Eur. J. 2006, 12, 51 – 62
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53

C. Gennari et al.
complete stereocontrol. Homoallylic alcohol 12 was then
transformed into the pivalate 5 (96%), and this diene was
subjected to ring-closing metathesis (RCM).
tion Grubbs catalyst, these dienes lead to the more stable Z-
cyclized products under thermodynamic control.[16]
Confident that the greater stability of the Z isomer of the
ten-membered carbocycle would eventually prevail, we con-
tinued our planned synthesis by removal of the PMP groups
The RCM reaction of a number of densely functionalized
diene cyclization precursors of type 5 (bearing protected
and/or free alcohol functionalities at both the allylic and the
homoallylicpositions) had previously been investigated with
a variety of catalysts, but no desired cyclized frameworks
were ever obtained.[9o] However, none of the previously ex-
amined diene precursors had the allylic alcohols protected
as p-methoxyphenyl (PMP) ethers, which were discovered
to facilitate the RCM reaction with respect to other protec-
tive groups and the corresponding free alcohols.[9o]
(CAN, 80%) and oxidation of the allylicdiol (DMP, 90%).
3
Enedione 16 (H-5, H-6: d=7.07, 6.64 ppm; JH-5/H-6
=
17.3 Hz) showed remarkable properties: while recording its
1H NMR spectrum in CDCl3 it cleanly isomerized to the
more thermodynamically stable stereoisomer (Z)-4 (H-5, H-
3
6: d=7.20, 6.13 ppm; JH-5/H-6 =14.0 Hz; t1/2 =63 h). By addi-
tion of a catalytic amount of I2 (10 mol%) a complete iso-
merization was observed in a shorter time (24 h). Bis-hemi-
acetal 17 (H-5, H-6: d=6.29, 6.18 ppm; 3JH-5/H-6 =5.8 Hz)
was obtained as the only product after flash chromatography
of the enedione (Z)-4, showing the propensity of 4 to add a
molecule of water and equilibrate with its hydrated form.[17]
Finally, the MOM protective group of the 16/4/17 mixture
was removed (BF3·Et2O, Me2S)[18] to give compound 3
(78%), which produced analytical data identical to those
previously reported by Danishefsky and co-workers
(1H NMR, 13C NMR, and IR spectroscopy, HRMS, Rf, and
[a]D).[8c]
Based on these premises, diene 5 was treated with the
second-generation Grubbs RCM catalyst[13] 13 (Scheme 3).
Under forcing conditions[14] [slow addition by syringe-pump
The RCM reaction of 20, a diastereoisomer of diene 5,
was also investigated (Scheme 4). Aldehyde 11 was oxyal-
lylated using the (Z)-oxyallylborane derived from (ꢀ)-a-
Scheme 3. Reagents and conditions: a) cat. 13 (30% mol), toluene,
1108C, 6.5 h, 64%; b) CAN, CH3CN/H2O (4:1), 08C, 80%; c) DMP,
CH2Cl2, 258C, 90%; d) CDCl3, 258C; e) BF3·Et2O, Me2S, CH2Cl2,
ꢀ788C!ꢀ208C, 78%. CAN=ceric ammonium nitrate; DMP=Dess–
Martin periodinane.
Scheme 4. Reagents and conditions: a) PMPOAllyl, sec-BuLi (1.4m in cy-
clohexane), dIpc2BOMe, BF3·Et2O, THF, ꢀ788C!258C, 40% 18, 14%
19; b) PivCl, DMAP, DIPEA, CH2Cl2, 258C, 83%; c) cat. 13 (30% mol),
toluene, 1108C, 6.5 h, 27% 21, 15% 22. PMP=p-methoxyphenyl; Piv=
tert-BuCO; DMAP=4-(dimethylamino)pyridine; DIPEA=diisopropyl-
ethylamine; Ipc=isopinocamphenyl.
(over 2.5 h) of a solution of RCM catalyst 13 (30% mol) in
toluene to a boiling solution of 5 in toluene, and additional
stirring for 4 h at 1108C], the (E)-14[15] stereoisomer was
formed and isolated in 64% yield. This result contrasts
sharply with many other Z-selective RCM reactions of
diene cyclization precursors less densely functionalized than
diene 5, which possessed protected and/or free alcohol func-
pinene[19] to give the syn products 18 (40%) and 19 (14%)
in an approximate 3:1 ratio. The major alcohol 18 was then
transformed into the pivalate 20 (83%), and this diene was
subjected to ring-closing metathesis under the same forcing
conditions described above. Two compounds were obtained,
both with the exact molecular ion (HRMS analysis) for the
desired product: the structures were determined to be the
tionalities at both the homoallylicpositions and at only one
[9h,m–o,q]
allylicposition.
In the presence of a second-genera-
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Total Synthesis
FULL PAPER
stereoisomer (E)-21 (3JH-5/H-6 =17.0 Hz) (27%)[20] together
with the rearranged product 22 (15%),[21] originating from a
ring-opening metathesis/ring-closing metathesis (ROM/
RCM) process involving the trisubstituted double bond of
the cyclohexene ring and the two terminal alkenes. Com-
pound 21 was then transformed into the target molecule 3
by using the same sequence of reactions described in
Scheme 3.
Table 1. Global minimum energy differences between the (E) and the
(Z)-stereoisomers of structures A–E.
EEꢀEZ
EEꢀEZ
EEꢀEZ
EEꢀEZ
(MM2*)[a]
(PM3)[a]
(MM2*)[a]
(PM3)[a]
A
C
E
6.6
7.9
15.0
6.2
5.7
B
D
ꢀ4.6[b]
17.1
8.0
ꢀ5.6[b]
21.7[b]
[a] Energy differences in kJmolꢀ1. [b] See text for the presence of low-
quality torsional parameters.
Molecular mechanics and semiempirical calculations: Mo-
lecular mechanics and semiempirical PM3[22] calculations
were undertaken in order to investigate the stereochemical
outcome of the RCM reactions and of the subsequent ene-
dione isomerization (16!4).
sions around the enedione, and therefore the quality of the
calculations was also considered unacceptable. The struc-
tures generated with MacroModel were then optimized at
the PM3 level[22] with the Gaussian 03 package.[27] These cal-
culations showed that the Z stereoisomers of structures A–E
are consistently more stable than the E stereoisomers, with
energy differences ranging from 5.7 to 17.1 kJmolꢀ1
(Table 1). This result is in agreement with our previous ex-
Compounds 14, 21, 16, and 4 were simplified into struc-
tures A–E (E and Z stereoisomers). The following changes
were made to the protective groups to reduce the number of
perimental observations and calculations, for which
a
number of similar but less densely functionalized structures
(i.e. bearing protected and/or free alcohol functionalities at
both the homoallylicpositions and at only one allylicposi-
tion) were shown to be consistently more stable as Z rather
than as E stereoisomers.[9q] In all those cases, the exclusive
formation of the Z isomer of the ten-membered carbocycles
in the RCM reactions was interpreted as the result of ther-
[9q]
modynamiccontrol.
The reasons why the less stable E stereoisomers 14 and 21
were formed on this occasion and no trace of the more
stable Z stereoisomer could be identified in the reaction
mixture have been investigated in detail. Our working hy-
pothesis is the following: the trans-ruthenacyclobutane inter-
mediate is more stable than the cis isomer, leading to the
[28]
less stable E stereoisomer under kineticocntrol.
Once
formed, the E double bond of 14 (and 21), flanked by two
bulky -OPMP groups, is too sterically hindered to react
again with the ruthenium–methylidene complex by means of
[2+2] cycloaddition and cycloreversion (according to the
generally accepted HØrisson–Chauvin mechanism),[29] thus
arresting the equilibrium between the ring-closed and ring-
opened products and inhibiting thermodynamic control
(Scheme 5).
rotatable bonds and low-quality torsional parameters: OPiv
into OAc, OPMP into either OMe (A and C) or OPh (B
and D), and OMOM into OMe. Initially, conformational
searches were carried out with MacroModel[23] (MM2*,
CHCl3 GB/SA) on each of the structures A–E. In the case
of structures A and C, only four low-quality torsional pa-
rameters were in use,[24] and therefore the quality of the cal-
culations was considered acceptable (Table 1).
In the case of structures B and D, ten low-quality torsion-
al parameters were in use,[25] in particular those relevant for
the torsions around the allylicphenyl ethers, and therefore
the quality of the calculations was considered unacceptable.
In the case of structure E, six low-quality torsional parame-
ters were in use,[26] in particular those relevant for the tor-
Density functional theory (DFT) calculations of the ruthe-
nacyclobutane intermediates: Density functional theory
(DFT) calculations were undertaken to determine the rela-
tive stabilities of the trans- and cis-ruthenacyclobutane inter-
mediates (trans/cis-F–I). The core structure of the ruthena-
cyclobutane intermediate was taken from the structure cal-
culated for the reaction of [(H2IMes)(PCy3)(Cl2)Ru=CH2]
with ethyl vinyl ether, for which full DFT calculations had
been carried out using the BP86 gradient-corrected density
functional.[30] Preliminary conformational searches were car-
ried out with MacroModel[23] (MM2*, CHCl3 GB/SA) on
each of the structures F–I, freezing the core ruthenacyclobu-
tane fragment (including the mesityl-substituted N-heterocy-
clic carbene) in the original DFT-calculated geometry.[30,31]
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C. Gennari et al.
cycle. The resulting minima were then fully optimized by
using DFT methods[32] at the B3LYP[33]/3–21G* level of
theory (Table 2), and finally submitted to single-point
energy calculations at the B3LYP/LANL2DZ[34]//B3LYP/3–
21G* level (Table 3).
Table 2. Relative energies (B3LYP/3–21G*)[33] of the ruthenacyclobutane
intermediates trans/cis-F–I.
trans[a]
cis[a]
trans[a]
cis[a]
F
H
34.1
18.0
47.3
56.2
G
I
0.0
11.6
56.9
71.9
[a] Relative energies in kJmolꢀ1
.
Table 3. Relative energies (B3LYP/LANL2DZ)[34] of the ruthenacyclo-
butane intermediates trans/cis-F–I.
trans[a]
cis[a]
trans[a]
cis[a]
F
H
13.4
6.1
50.3
56.1
G
I
6.5
0.0
55.7
67.9
[a] Relative energies in kJmolꢀ1
.
The calculations show that the trans-ruthenacyclobutane
intermediates are consistently more stable than the corre-
sponding cis isomers, in particular the lowest energy trans
(trans-I) and cis (cis-F) structures have a 50.3 kJmolꢀ1
energy difference (Table 3). According to the generally ac-
cepted HØrisson–Chauvin mechanism,[29] the metathesis re-
action consists of a series of formal [2+2] cycloadditions and
cycloreversions. The overall process starts with olefin coor-
dination to the transition-metal–carbene complex to form a
p complex, followed by migratory insertion of the olefin
into the metal–carbene bond to give a metallacyclobutane,
breaking of two different bonds in the metallacyclobutane
to form another p complex, and finally dissociation to yield
the products. Experimental and theoretical studies on olefin
methatesis have shown that the reaction proceeds through a
phosphane dissociative mechanism,[35] that the olefin coordi-
nation to the tetracoordinate 14-electron ruthenium com-
plex occurs trans to the ancillary ligand,[36] and that the ruth-
enacyclobutane is a real intermediate.[36,37] Recently, DFT
calculations have been carried out to gain insight into the
factors that govern the stereochemistry of the cycloolefin
formed by a RCM reaction.[38] These studies have identified
either the formation or the cleavage of the ruthenacyclobu-
tane intermediate as the rate-determining step, which ulti-
mately determines the stereochemical (Z/E) outcome of the
cycloolefin under kinetic control, depending on the types of
catalysts used, olefins, and reaction pathway.[38] Calculations
performed on olefins lacking substitution at the allylic posi-
tion (i.e., different from our case) suggest that with N-het-
erocyclic carbene (NHC)-based catalysts (e.g., the second-
generation Grubbs catalyst), the rate-determining step is the
cleavage of the ruthenacyclobutane intermediate.[36–38] This
implies that the less stable cis-ruthenacyclobutane inter-
mediates (from Tables 2 and 3) would face a smaller cleav-
age barrier compared to the more stable trans-ruthenacyclo-
Scheme 5. Working hypothesis for the RCM reaction under kinetic con-
trol, leading to the thermodynamically less stable E stereoisomer 14.
These initial minimizations were important to relieve the
nonbonded interactions between the sterically bulky mesityl
groups and the densely functionalized ten-membered carbo-
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Total Synthesis
FULL PAPER
silica gel 60 Š, particle size 40–64 mm, following the procedure by Still
butanes, thus determining the preferential formation of the
(Z)-cycloolefin, which is not observed experimentally. How-
ever, DFT calculations for more hindered diene substrates
(either methyl-disubstituted olefins[38] or cyclic with allylic
substitution as in the case of norbornene[37]) have shown
that the relative importance of the ruthenacycle formation
and cleavage steps is inverted and the formation of the ruth-
enacyclobutane is the rate-determining step in those cases.
The increased ruthenacycle formation barrier and decreased
cleavage barrier are mainly due to the generation/release of
repulsive nonbonded interactions during the formation/
cleavage of the ruthenacyclobutane. This effect may also be
present in the densely functionalized system described here,
which has substitution at both the allylicand homoallylicpo-
sitions of both olefinicfragments. If the rate-determining
step is indeed the formation of the ruthenacyclobutane,
there would be a diminished energy barrier and therefore a
strong kineticpreferenec for the formation of the more
stable trans-ruthenacyclobutane intermediate (Tables 2 and
3), which would lead to the observed (E)-cycloolefin prod-
uct.
and co-workers.[39]
Proton NMR spectra were recorded on 400, 300, or 200 MHz spectrome-
ters. Proton chemical shifts are reported in ppm (d) with the solvent ref-
erence relative to tetramethylsilane (TMS) employed as the internal stan-
dard (CDCl3, d=7.26 ppm; [D6]DMSO, d=2.50 ppm). The following ab-
breviations are used to describe spin multiplicity: s=singlet, d=doublet,
t=triplet, q=quartet, m=multiplet, br=broad signal, dd=doublet of
doublets, dt=doublet of triplets, ddd=doublet of doublet of doublets.
Carbon NMR spectra were recorded on 400 (100 MHz), 300 (75 MHz) or
200 MHz (50 MHz) spectrometers with complete proton decoupling.
Carbon chemical shifts are reported in ppm (d) relative to TMS with the
respective solvent resonance as the internal standard (CDCl3, d=77.0).
Optical rotation values were measured on an automatic polarimeter at
the sodium D-line. Infrared spectra were recorded on a standard infrared
spectrophotometer; peaks are reported in cmꢀ1. High-resolution mass
spectra (HRMS) were performed on a hybrid quadrupole time-of-flight
mass spectrometer equipped with an ESI ion source. A Reserpine solu-
tion 100 pgmLꢀ1 (about 100 countsꢀ1), 0.1% HCOOH/CH3CN 1:1, was
used as reference compound (Lock Mass).
[(1R,5R,6R)-6-Dimethoxymethyl-5-isopropyl-2-methylcyclohex-2-enyl]-
acetaldehyde (6): Aldehyde 6 was prepared on a multigram scale in six
steps from R-(ꢀ)-carvone (30% overall yield) according to referen-
ce [9a,g].
{(1R,2R,6R)-6-Isopropyl-2-[(2S,3R)-2-methoxymethoxy-3-(4-methoxy-
phenoxy)pent-4-enyl]-3-methylcyclohex-3-enyl}acetaldehyde (11): Alde-
hyde 11 was prepared in seven steps from aldehyde 6 (49–50% overall
yield) according to reference [9q].
In summary, we have accomplished a formal total synthe-
sis of eleutherobin (2) making use of: 1) multiple stereose-
lective titanium-mediated oxyallylations, 2) an unprecedent-
ed kinetically controlled second-generation Grubbs cata-
lyzed RCM reaction of a densely functionalized diene bear-
ing two allylic alcohols protected as p-methoxyphenyl
(PMP) ethers, and 3) the isomerization of the E isomer of a
ten-membered enedione to the more stable Z isomer. The
unusual kinetically controlled RCM stereochemical outcome
has been investigated using computational methods. Semi-
empirical PM3 calculations have shown that the E isomers
of the ten-membered carbocycles resulting from the RCM
reaction are less thermodynamically stable than the Z iso-
(2R,3S)-1-{(1R,2R,6R)-6-Isopropyl-2-[(2S,3R)-2-methoxymethoxy-3-(4-
methoxyphenoxy)pent-4-enyl]-3-methylcyclohex-3-enyl}-3-(4-meth-
oxyphenoxy)pent-4-en-2-ol (12): sec-BuLi (1.4m in cyclohexane, 714 mL,
1.00 mmol) was added to a cold (ꢀ788C), stirred solution of 1-allyloxy-4-
methoxybenzene[40] (164 mg, 1.00 mmol) in THF (8.0 mL). After stirring
for 1 h, the resulting orange solution (color is important) was transferred,
through a cannula, to a cold (ꢀ788C) suspension of complex (R,R)-7[12]
(613 mg, 1.00 mmol) in Et2O (20.0 mL). The reaction mixture was stirred
for 3.5 h at ꢀ788C (color changed from yellow to orange and finally dark
brown), and then was treated with a solution of aldehyde 11 (269 mg,
0.6 mmol) in Et2O (15.0 mL) and warmed to room temperature over-
night. The reaction mixture was treated with a NH4F aqueous solution
(45%, 20 mL) and stirred for further 24 h. The organicphase was sepa-
rated and the aqueous layer was extracted with EtOAc (2”50 mL). Puri-
fication of the crude product by flash chromatography (petroleum ether/
EtOAc, 7:3) afforded alcohol 12 (300 mg, 83%) as a colorless oil. Rf =
0.42 (petroleum ether/EtOAc, 7:3); [a]2D0 =+29.7 (c=1.72 in EtOAc);
1H NMR (400 MHz, CDCl3): d=6.90–6.74 (m, 8H), 5.97–5.83 (m, 2H),
5.40–5.25 (m, 5H), 4.88 (d, J=6.8 Hz, 1H), 4.76 (d, J=6.8 Hz, 1H), 4.72–
4.64 (m, 1H), 4.43 (dd, J=7.1, 4.4 Hz, 1H), 4.11–4.01 (m, 1H), 3.89 (dt,
J=9.6, 3.1 Hz, 1H), 3.77 (s, 6H), 3.36 (s, 3H), 2.39 (br, 1H), 2.10–1.47
(m, 13H), 0.94 (d, J=6.7 Hz, 3H), 0.85 ppm (d, J=6.6 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=154.2, 153.9, 152.2, 151.7, 136.7, 134.6,
134.4, 121.0, 120.1, 118.8, 117.7, 117.1, 114.5, 114.4, 97.4, 83.9, 82.7, 79.3,
71.0, 55.8, 55.6, 38.6, 35.0, 34.5, 30.9, 29.9, 27.0, 24.2, 22.6, 21.0 ppm; FT-
IR (CCl4): n˜ =3598, 3468, 3080, 3045, 2943, 2834, 2289, 2070, 2003, 1858,
1741, 1641, 1500, 1466, 1441, 1387, 1369, 1289, 1237, 1181, 1152, 1105,
1029, 930 cmꢀ1; HRMS (ESI): calcd for C36H50NaO7: 617.34487 [M+
Na]+; found: 617.34252 (resolution 19000).
mers
(EEꢀEZ =6.2–17.1 kJmolꢀ1).
DFT
calculations
(B3LYP/LANL2DZ)[34] have shown that the trans-ruthena-
cyclobutane intermediates are more stable than the corre-
sponding cis isomers (lowest energy EcisꢀEtrans
=
50.3 kJmolꢀ1). The calculations lend support to a proposed
mechanism where the more stable trans-ruthenacyclobutane
intermediate leads to the less stable E stereoisomer under
kineticcontrol.
Experimental Section
General procedures: All reactions were carried out in flame-dried glass-
ware under argon atmosphere. All commercially available reagents were
used as received. The solvents were dried by distillation over the follow-
ing drying agents and were transferred under nitrogen: CH3CN (CaH2),
CH2Cl2 (CaH2), (CH2Cl)2 (CaH2), MeOH (CaH2), Et3N (CaH2), iPr2EtN
(CaH2), HN(TMS)2 (CaH2), THF (Na), Et2O (Na), benzene (Na), tolu-
ene (Na), n-hexane (Na), and xylenes (Na). Organicextracts were dried
over anhydrous Na2SO4. Reactions were monitored by analytical thin-
layer chromatography (TLC) by using silica gel 60 F254 precoated glass
plates (0.25 mm thickness) or basic alumina supported on aluminium
foils. TLC Rf values are reported; visualization was accomplished by irra-
diation with a UV lamp and/or staining with ceric ammonium molybdate
(CAM) solution. Flash column chromatography was performed by using
(1R,2S)-1-{(1R,2R,6R)-6-Isopropyl-2-[(2S,3R)-2-methoxymethoxy-3-(4-
methoxyphenoxy)pent-4-enyl]-3-methylcyclohex-3-enylmethyl}-2-(4-meth-
oxyphenoxy)but-3-enyl ester of2,2-dimethylpropionic acid (5) : PivCl
(51 mL, 0.41 mmol) was added to a stirred solution of alcohol 12 (82 mg,
0.14 mmol), DMAP (17 mg, 0.14 mmol), and DIPEA (122 mL,
0.70 mmol) in CH2Cl2 (5.0 mL). After stirring for 16 h, the reaction mix-
ture was treated with a saturated NaHCO3 aqueous solution (15 mL) and
CH2Cl2 (15 mL) and stirred for further 15 min. The organicphase was
separated, and the aqueous layer was extracted with CH2Cl2 (3”10 mL).
Purification of the crude product by flash chromatography (petroleum
ether/EtOAc, 9:1) afforded compound 5 (89 mg, 96%) as a colorless oil.
Chem. Eur. J. 2006, 12, 51 – 62
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
57

C. Gennari et al.
Rf =0.47 (petroleum ether/EtOAc, 7:3); [a]2D0 =+34.3 (c=1.55 in
EtOAc); 1H NMR (400 MHz, CDCl3): d=6.91–6.73 (m, 8H), 5.96–5.82
(m, 2H), 5.38–5.24 (m, 6H), 4.89 (d, J=6.7 Hz, 1H), 4.81 (d, J=6.7 Hz,
1H), 4.76 (dd, J=6.2, 3.4 Hz, 1H), 4.59–4.51 (m, 1H), 3.96–3.89 (m, 1H),
3.77 (s, 3H), 3.76 (s, 3H), 3.39 (s, 3H), 2.33 (br, 1H), 2.11–2.00 (m, 1H),
1.92–1.58 (m, 10H), 1.51–1.42 (m, 1H), 1.17 (s, 9H), 0.93 (d, J=6.8 Hz,
3H), 0.85 ppm (d, J=6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=
177.8, 154.2, 153.9, 152.3, 152.2, 137.0, 134.6, 120.9, 119.4, 118.9, 117.9,
117.2, 114.4, 97.4, 82.5, 82.4, 79.1, 72.6, 55.8, 55.6, 38.9, 38.3, 35.1, 34.9,
30.6, 27.6, 27.2, 27.1, 24.2, 22.7, 20.9 ppm; FT-IR (CCl4): n˜ =3046, 2960,
2834, 2305, 2004, 1857, 1729, 1559, 1505, 1479, 1442, 1423, 1387, 1369,
2,2-dimethylpropionic acid (16), (Z)-(4R,4aR,11S,12aR)-4-isopropyl-11-
methoxymethoxy-1-methyl-7,10-dioxo-3,4,4a,5,6,7,10,11,12,12a-decahy-
drobenzocyclodecen-6-yl ester of2,2-dimethylpropionic acid (4), and
(4R,5R,9R,11S)-1,12-dihydroxy-5-isopropyl-11-methoxymethoxy-8-
methyl-15-oxa-tricyclo[10.2.1.04,9]pentadeca-7,13-dien-2-yl ester of2,2-di-
methylpropionic acid (17): DMP (60 mg, 0.14 mmol) was added to a stir-
red solution of compound 15 (12.4 mg, 0.028 mmol) in CH2Cl2 (375 mL).
After stirring for 3 h, the reaction mixture was treated with a NaOH
aqueous solution (1.0m, 2 mL) and CH2Cl2 (2 mL) and stirred for further
15 min. The organicphase was separated and the aqueous layer was ex-
tracted with CH2Cl2 (4”3 mL). Purification of the crude product by flash
chromatography afforded the enedione (E)-16 (10.9 mg, 90%) as a white
amorphous solid.
1229, 1181, 1157, 1104, 1040, 930 cmꢀ1
; HRMS (ESI): calcd for
C41H58NaO8: 701.40239 [M+Na]+; found: 701.40002 (resolution 16700).
1
Compound (E)-16: Rf =0.34 (n-hexane/EtOAc, 8:2); H NMR (400 MHz,
(E)-(4R,4aR,6R,7S,10R,11S,12aR)-4-Isopropyl-11-methoxymethoxy-
CDCl3): d=7.07 (br, 1H), 6.64 (d, J=17.3 Hz, 1H), 5.51 (br, 1H), 5.38
(br, 1H), 4.76 (d, J=7.2 Hz, 1H), 4.73 (d, J=7.2 Hz, 1H), 4.56 (d, J=
9.2 Hz, 1H), 3.44 (s, 3H), 2.49 (br, 1H), 2.15–1.50 (m, 11H), 1.41 (br,
1H), 1.29 (s, 9H), 0.92 (d, J=6.4 Hz, 3H), 0.79 ppm (d, J=6.4 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=198.2, 195.9, 178.2, 137.2, 134.8, 122.2,
121.2, 95.6, 80.2, 76.8, 56.1, 39.2, 38.7, 37.1, 36.9, 34.2, 33.1, 29.7, 27.1,
26.5, 24.6, 23.3, 20.7 ppm; FT-IR (CCl4): n˜ =2962, 2932, 2284, 2007, 1741,
1725, 1548, 1397, 1388, 1370, 1259, 1145, 1099, 1062, 1008 cmꢀ1; HRMS
(ESI): calcd for C25H38NaO6: 457.25606 [M+Na]+; found: 457.25503 (res-
olution 25900).
7,10-bis(4-methoxyphenoxy)-1-methyl-3,4,4a,5,6,7,10,11,12,12a-decahy-
drobenzocyclodecen-6-yl ester of2,2-dimethylpropionic acid (14)
: A
freshly prepared solution of the second-generation Grubbs catalyst 13
(16 mg, 0.019 mmol) in toluene (3.4 mL) was added through a syringe
pump over a period of 2.5 h to a heated (1108C), stirred solution of com-
pound 5 (42 mg, 0.062 mmol) in toluene (6.8 mL). After 4 h at 1108C, the
reaction mixture was cooled to room temperature, treated with DMSO[41]
(67 mL, 0.94 mmol) and stirred for 15 h at room temperature. Purification
of the crude product by flash chromatography over two consecutive col-
umns (first: petroleum ether/EtOAc, 85:15; second: CH2Cl2/iPr2O, 97:3)
afforded compound 14 (26 mg, 64%) as a white amorphous solid. Rf =
0.46 (petroleum ether/EtOAc, 8:2); [a]2D0 =+38.4 (c=1.27 in EtOAc);
1H NMR (400 MHz, CDCl3): d=6.89–6.64 (m, 8H), 5.96 (br, 1H), 5.71
(br, 1H), 5.29 (br, 1H), 5.04 (br, 2H), 4.86–4.63 (m, 3H), 3.85 (br, 1H),
3.75 (s, 3H), 3.73 (s, 3H), 3.28 (br, 3H), 2.44 (br, 1H), 2.17–1.20 (m,
12H), 1.13 (s, 9H), 0.91 (d, J=6.8 Hz, 3H), 0.74 ppm (br, 3H); 13C NMR
(100 MHz, C6D6): d=179.8, 154.8, 154.5, 153.0, 140.8, 135.2, 127.0, 120.9,
117.5, 117.3, 115.1, 95.7, 81.0, 79.1, 78.5, 76.6, 55.6, 55.3, 41.0, 40.3, 39.1,
37.0, 32.5, 27.4, 26.9, 25.1, 24.3, 21.2, 14.1 ppm; FT-IR (CCl4): n˜ =2960,
2932, 2833, 2289, 2009, 1854, 1722, 1548, 1508, 1479, 1464, 1441, 1396,
1387, 1368, 1284, 1230, 1181, 1156, 1103, 1008, 917 cmꢀ1; HRMS (ESI):
calcd for C39H54NaO8: 673.37109 [M+Na]+; found: 673.36999 (resolution
18000).
1
While recording the H NMR spectrum of compound 16 in CDCl3, the E
enedione cleanly isomerized to the more stable enedione (Z)-4 (t1/2
=
63 h). A complete isomerization of the enedione (E)-16 to (Z)-4 was ac-
complished by addition of a catalytic amount (10 mol%) of I2 in CDCl3
at room temperature (24 h).
Compound (Z)-4: Rf =0.34 (n-hexane/EtOAc, 8:2); 1H NMR (400 MHz,
CDCl3): d=7.20 (d, J=14.0 Hz, 1H), 6.13 (d, J=14.0 Hz, 1H), 5.53 (d,
J=9.2 Hz, 1H), 5.34 (br, 1H), 4.75 (d, J=6.4 Hz, 1H), 4.69 (d, J=
6.4 Hz, 1H), 4.20 (dd, J=12.0, 5.8 Hz, 1H), 3.40 (s, 3H), 2.12 (br, 1H),
2.05–1.53 (m, 11H), 1.35 (br, 1H), 1.27 (s, 9H), 0.90 (d, J=6.9 Hz, 3H),
0.74 ppm (d, J=6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=204.4,
196.7, 177.6, 138.1, 137.2, 133.4, 120.6, 96.6, 84.3, 73.2, 56.1, 38.7, 37.1,
36.9, 34.2, 33.0, 30.2, 27.1, 26.4, 24.5, 22.7, 20.9, 14.1 ppm; FT-IR (CCl4):
n˜ =2962, 2932, 2290, 2204, 1744, 1701, 1547, 1479, 1463, 1397, 1388, 1379,
1369, 1254, 1217, 1146, 1100, 1061, 1006 cmꢀ1; HRMS (ESI): calcd for
C25H38NaO6: 457.25606 [M+Na]+; found: 457.25582 (resolution 25800).
Minor by-products (5–10%) were tentatively identified by HRMS analy-
sis as the corresponding mono- and dibenzylidene derivatives of the start-
ing diene 5, arising from the cross-metathesis reaction promoted by the
second-generation Grubbs catalyst 13. Monobenzylidene derivative:
HRMS (ESI): calcd for C47H62NaO8: 777.43369 [M+Na]+; found:
777.43360 (resolution 14700). Dibenzylidene derivative: HRMS (ESI):
calcd for C53H66NaO8: 853.46499 [M+Na]+; found: 853.46552 (resolution
14700).
Bis-hemiacetal 17 was obtained after flash chromatography of the Z ene-
dione 4.
Compound 17: Rf =0.27 (n-hexane/EtOAc, 6:4); 1H NMR (400 MHz,
CDCl3): d=6.29 (d, J=5.8 Hz, 1H), 6.18 (d, J=5.8 Hz, 1H), 5.25 (br,
1H), 5.02–4.96 (m, 1H), 4.83 (d, J=6.4 Hz, 1H), 4.73 (d, J=6.4 Hz, 1H),
4.08 (br, 2H), 3.96 (dd, J=11.6, 2.4 Hz, 1H), 3.44 (s, 3H), 2.60 (br, 1H),
1.88–1.48 (m, 10H), 1.40–1.14 (m, 11H), 0.88 (d, J=6.8 Hz, 3H),
0.71 ppm (d, J=6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=178.8,
138.8, 133.1, 132.2, 119.2, 111.7, 110.3, 96.6, 80.6, 76.6, 55.7, 39.5, 38.7,
37.7, 37.5, 33.5, 31.5, 26.9, 26.6, 24.3, 22.8, 21.2, 14.7 ppm; FT-IR (CCl4):
n˜ =3430, 3028, 2960, 2929, 2289, 2006, 1728, 1548, 1397, 1388, 1368, 1260,
1217, 1151, 1102, 1008, 809 cmꢀ1; HRMS (ESI): calcd for C25H40NaO7:
475.26662 [M+Na]+; found: 475.26681 (resolution 25800).
(E)-(4R,4aR,7S,10R,11S,12aR)-7,10-Dihydroxy-4-isopropyl-11-
methoxymethoxy-1-methyl-3,4,4a,5,6,7,10,11,12,12a-decahydrobenzocy-
clodecen-6-yl ester of2,2-dimethylpropionic acid (15) : Cericammonium
nitrate (92 mg, 0.168 mmol) was added in one portion to a cold (08C),
stirred solution of compound 14 (26 mg, 0.04 mmol) in CH3CN/H2O
(1.38 mL, v/v: 4:1). After 2 min, the reaction mixture was treated with
water (5 mL) and iPr2O (5 mL). The aqueous phase was separated and
the organic layer was extracted with water (2”5mL). Purification of the
crude product by flash chromatography (n-hexane/EtOAc, 6:4), followed
by further purification by flash chromatography (CH2Cl2/EtOAc, 7:3) af-
forded compound 15 (14 mg, 80%) as a white amorphous solid. Rf =0.20
(n-hexane/EtOAc, 6:4); [a]2D0 =+25.5 (c=0.80 in EtOAc); 1H NMR
(400 MHz, CDCl3): d=6.15–5.97 (m, 1H), 5.63–5.44 (m, 1H), 5.26 (br,
1H), 4.83–4.53 (m, 5H), 3.81 (br, 1H), 3.41 (s, 3H), 2.70 (br, 1H), 2.26–
1.36 (m, 14H), 1.23 (s, 9H), 0.86 (d, J=6.4 Hz, 3H), 0.67 ppm (br, 3H);
13C NMR (100 MHz, CDCl3): d=177.3, 140.4, 132.7, 126.9, 120.6, 94.1,
78.5, 77.1, 71.6, 70.4, 55.7, 39.7, 39.0, 36.1, 29.9, 29.7, 27.2, 26.8, 26.5, 24.5,
24.1, 20.9, 13.7 ppm; FT-IR (CCl4): n˜ =3620, 3589, 2960, 2290, 2207, 1856,
1727, 1549, 1396, 1369, 1258, 1217, 1152, 1098, 1070, 1010 cmꢀ1; HRMS
(ESI): calcd for C25H42NaO6: 461.28736 [M+Na]+; found: 461.28555 (res-
olution 21900).
(1S,3R,7R,8R,10R,11S)-11-Hydroxy-7-isopropyl-4-methyl-14-oxo-15-oxa-
tricyclo[9.3.1.03,8]pentadeca-4,12-dien-10-yl ester of2,2-dimethylpropionic
acid (3): Me2S (15.4 mg, 0.25 mmol) and BF3·OEt2 (42.7 mg, 0.30 mmol)
were added to a cold (ꢀ788C), stirred solution of a mixture of 16/4/17
(12.0 mg, 0.028 mmol based on 4) in CH2Cl2 (920 mL). The reaction was
slowly warmed to ꢀ208C (over 3 h), treated with a saturated NaHCO3
aqueous solution (5 mL), and warmed to room temperature under vigo-
rous stirring. The organicphase was separated and the aqueous layer was
extracted with CH2Cl2 (3”5mL). Purification of the crude product by
flash chromatography (n-hexane/EtOAc, 9:1) afforded the Danishefsky
key-intermediate 3[8c] (8.4 mg, 78%) as a white amorphous solid. Rf =
0.25 (n-hexane/EtOAc, 8:2); [a]2D0 =ꢀ60.0 (c=0.60 in CHCl3); 1H NMR
(300 MHz, CDCl3): d=7.08 (d, J=10.5 Hz, 1H), 6.19 (d, J=10.5 Hz,
1H), 5.35 (br, 1H), 4.88 (d, J=7.6 Hz, 1H), 4.67 (t, J=4.4 Hz, 1H), 3.27
(br, 1H), 2.47–2.28 (m, 1H), 2.10–1.65 (m, 7H), 1.65–1.32 (m, 2H), 1.58
(E)-(4R,4aR,11S,12aR)-4-Isopropyl-11-methoxymethoxy-1-methyl-7,10-
dioxo-3,4,4a,5,6,7,10,11,12,12a-decahydrobenzocyclodecen-6-yl ester of
58
www.chemeurj.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 51 – 62

Total Synthesis
FULL PAPER
(s, 3H), 1.26 (s, 9H), 0.92 (d, J=6.9 Hz, 3H), 0.76 ppm (d, J=6.9 Hz,
3H); 1H NMR (400 MHz, CDCl3): d=7.08 (d, J=10.5 Hz, 1H), 6.19 (d,
J=10.5 Hz, 1H), 5.35 (br, 1H), 4.88 (d, J=7.6 Hz, 1H), 4.67 (t, J=
4.4 Hz, 1H), 3.31 (br, 1H), 2.46–2.33 (m, 1H), 2.11–1.69 (m, 7H), 1.65–
1.38 (m, 2H), 1.58 (s, 3H), 1.26 (s, 9H), 0.92 (d, J=6.8 Hz, 3H),
0.76 ppm (d, J=6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=195.5,
177.4, 151.0, 126.7, 121.6, 92.5, 78.6, 77.7, 38.8, 38.1, 32.8, 27.0, 26.7, 24.0,
21.3, 21.2 ppm; FT-IR (CCl4): n˜ =3589, 3395, 3028, 2961, 2930, 2872,
2289, 2205, 1856, 1731, 1693, 1549, 1480, 1462, 1254, 1217, 1147, 1109,
1067, 1006, 980 cmꢀ1; HRMS (ESI): calcd for C23H34NaO5: 413.22984
[M+Na]+; found: 413.22821 (resolution 24300).
(m, 6H), 4.77 (br, 1H), 4.72 (d, J=6.7 Hz, 1H), 4.68–4.59 (m, 2H), 3.88–
3.73 (m, 7H), 3.31 (s, 3H), 2.35 (br, 1H), 2.14–2.03 (m, 1H), 1.92–1.55
(m, 10H), 1.46–1.36 (m, 1H), 1.21 (s, 9H), 0.94 (d, J=6.7 Hz, 3H),
0.84 ppm (d, J=6.6 Hz, 3H); 13C NMR (50 MHz, CDCl3): d=177.9,
154.0, 153.8, 152.3, 152.0, 136.6, 134.6, 133.7, 120.9, 118.8, 117.1, 116.9,
114.5, 114.3, 97.3, 82.1, 79.8, 79.1, 72.4, 55.7, 55.6, 38.9, 38.7, 34.6, 34.4,
30.1, 27.2, 27.1, 27.0, 24.1, 22.6, 20.8, 17.8 ppm; FT-IR (CCl4): n=2957,
2833, 2290, 2005, 1857, 1727, 1549, 1509, 1479, 1465, 1441, 1407, 1396,
1386, 1368, 1281, 1223, 1181, 1155, 1105, 1042, 929 cmꢀ1; HRMS (ESI):
calcd for C41H58NaO8: 701.40239 [M+Na]+; found: 701.40172 (resolution
16600).
(2R,3R)-1-{(1R,2R,6R)-6-Isopropyl-2-[(2S,3R)-2-methoxymethoxy-3-
(4-methoxyphenoxy)pent-4-enyl]-3-methylcyclohex-3-enyl}-3-(4-methoxy-
phenoxy)pent-4-en-2-ol (18) and (2S,3S)-1-{(1R,2R,6R)-6-isopropyl-2-
[(2S,3R)-2-methoxymethoxy-3-(4-methoxyphenoxy)pent-4-enyl]-3-meth-
ylcyclohex-3-enyl}-3-(4-methoxyphenoxy)pent-4-en-2-ol (19): sec-BuLi
(1.4m in cyclohexane, 280 mL, 0.39 mmol) was added to a cold (ꢀ788C),
stirred solution of 1-allyloxy-4-methoxybenzene[40] (77.2 mg, 0.47 mmol)
in THF (1.2 mL). After stirring for 1 h at ꢀ788C, the resulting orange so-
lution (color is important) was treated with a solution of dIpc2BOMe[19]
(1.0m in THF, 390 mL, 0.39 mmol), and stirred for further 1 h. BF3·Et2O
(63 mL, 0.50 mmol) and aldehyde 11 (68 mg, 0.16 mmol) were subse-
quently added and the resulting solution was warmed to room tempera-
ture overnight. The mixture was then treated with a NaOH aqueous solu-
tion (6.0m, 1.5 mL), H2O2 (36%, 1.5 mL) and stirred for further 8 h. The
organicphase was separated and the aqueous layer was extracted with
iPr2O (3”5mL). Purification of the crude product by flash chromatogra-
phy (petroleum ether/EtOAc, 85:15) afforded alcohols 18 (37.6 mg,
40%) and 19 (13.2 mg, 14%) as colorless oils.
Compound 18: Rf =0.31 (petroleum ether/EtOAc, 85:15); [a]2D0 =+39.7
(c=1.06 in EtOAc); 1H NMR (400 MHz, CDCl3): d=6.90–6.76 (m, 8H),
5.95–5.82 (m, 2H), 5.39–5.24 (m, 5H), 4.81 (d, J=6.8 Hz, 1H), 4.70–4.63
(m, 2H), 4.35 (dd, J=6.2, 6.2 Hz, 1H), 3.91 (br, 1H), 3.83–3.74 (m, 7H),
3.35 (s, 3H), 2.37 (br, 2H), 2.02 (br, 2H), 1.95–1.70 (m, 5H), 1.70–1.55
(m, 3H), 1.55–1.44 (m, 2H), 0.93 (d, J=6.8 Hz, 3H), 0.86 ppm (d, J=
6.4 Hz, 3H); 13C NMR (50 MHz, CDCl3): d=154.3, 153.9, 152.3, 151.9,
136.9, 134.9, 134.6, 121.1, 119.5, 118.8, 117.5, 117.2, 114.5, 114.4, 97.2,
84.0, 82.6, 79.2, 71.4, 55.8, 55.6, 38.6, 35.0, 34.6, 30.8, 30.3, 27.1, 24.2, 22.6,
21.0, 17.3 ppm; FT-IR (CCl4): n˜ =3585, 2960, 2834, 2291, 2004, 1856,
1548, 1507, 1465, 1442, 1226, 1181, 1151, 1103, 1010, 930 cmꢀ1; HRMS
(ESI): calcd for C36H50NaO7: 617.34487 [M+Na]+; found: 617.34252 (res-
olution 18900).
Compound 19: Rf =0.23 (petroleum ether/EtOAc, 85:15); [a]2D0 =+3.6
(c=0.97 in EtOAc); 1H NMR (400 MHz, CDCl3): d=6.95–6.74 (m, 8H),
5.98–5.78 (m, 2H), 5.40–5.26 (m, 5H), 4.92–4.84 (m, 2H), 4.82 (d, J=
6.8 Hz, 1H), 4.32–4.23 (m, 1H), 4.01–3.95 (m, 1H), 3.79–3.77 (m, 7H),
3.30 (s, 3H), 2.56–2.39 (m, 2H), 2.20 (br, 1H), 2.15–2.04 (m, 1H), 2.04–
1.87 (m, 2H), 1.80–1.50 (m, 5H), 1.50–1.30 (m, 3H), 0.94 (d, J=6.8 Hz,
3H), 0.90 ppm (d, J=6.4 Hz, 3H); 13C NMR (50 MHz, CDCl3): d=154.2,
153.8, 152.5, 151.9, 135.6, 135.2, 134.7, 120.7, 119.4, 118.1, 117.5, 116.9,
114.5, 98.0, 84.7, 82.2, 79.1, 71.3, 55.6, 39.7, 33.1, 31.0, 29.3, 28.5, 27.6,
24.0, 22.1, 21.2, 20.6 ppm; FT-IR (CCl4): n˜ =3592, 2959, 2833, 2288, 2003,
1855, 1741, 1544, 1503, 1465, 1441, 1421, 1386, 1372, 1232, 1181, 1151,
1105, 1041, 930 cmꢀ1; HRMS (ESI): calcd for C36H50NaO7: 617.34487
[M+Na]+; found: 617.34336 (resolution 18900).
(E)-(4R,4aR,6R,7R,10R,11S,12aR)-4-Isopropyl-11-methoxymethoxy-
7,10-bis(4-methoxyphenoxy)-1-methyl-3,4,4a,5,6,7,10,11,12,12a-decahy-
drobenzocyclodecen-6-yl ester of2,2-dimethylpropionic acid (21) and
(Z)-(1R,2R,6R,7R)-6-isopropyl-7-[(1R,4R,5S)-5-methoxymethoxy-4-(4-
methoxyphenoxy)-2-methylcyclohex-2-enyl]-2-(4-methoxyphenoxy)cy-
clooct-3-enyl ester of2,2-dimethylpropionic acid (22) : A freshly prepared
solution of the second-generation Grubbs catalyst 13 (13 mg,
0.015 mmol) in toluene (3.3 mL) was added, through a syringe pump
over a period of 2 h, to a heated (1108C), stirred solution of compound
20 (35 mg, 0.051 mmol) in toluene (3.2 mL). After 4.5 h at 1108C, the re-
action mixture was cooled to room temperature, treated with DMSO[41]
(54 mL, 0.75 mmol) and stirred for 15 h at room temperature. Purification
of the crude product by flash chromatography (CH2Cl2/iPr2O, 97:3) af-
forded compound 21 (9 mg, 27%) as a white amorphous solid and com-
pound 22 (5 mg, 15%) as a colorless oil.
Compound 21: Rf =0.47 (petroleum ether/EtOAc, 8:2); [a]2D0 =ꢀ17.6 (c=
1
1.12 in EtOAc); H NMR (400 MHz, CDCl3): d=6.95–6.72 (m, 8H), 5.87
(dd, J=17.0, 4.2 Hz, 1H), 5.60 (dd, J=17.0, 9.1 Hz, 1H), 5.33 (br, 1H),
5.13 (br, 1H), 4.86 (br, 1H), 4.78 (d, J=7.2 Hz, 1H), 4.70 (d, J=7.2 Hz,
1H), 4.51 (dd, J=8.2, 8.2 Hz, 1H), 3.80 (s, 3H), 3.78 (s, 3H), 3.61 (br,
1H), 3.33 (s, 3H), 2.29 (br, 1H), 2.24–1.94 (m, 4H), 1.91–1.60 (m, 7H),
1.53 (br, 1H), 1.14 (s, 9H), 0.98 (d, J=8.0 Hz, 3H), 0.93 ppm (d, J=
8.0 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=171.7, 154.1, 152.4, 151.9,
138.0, 133.5, 128.4, 122.5, 117.1, 116.5, 114.6, 114.4, 95.7, 85.0, 80.3, 76.9,
75.4, 55.7, 55.4, 40.4, 38.7, 35.6, 29.4, 29.0, 27.1, 25.4, 22.0, 20.2 ppm; FT-
IR (CCl4): n˜ =2959, 2931, 2289, 2003, 1856, 1728, 1550, 1507, 1464, 1441,
1368, 1227, 1153, 1105, 1006, 816 cmꢀ1
; HRMS (ESI): calcd for
C39H54NaO8: 673.37109 [M+Na]+; found: 673.36808 (resolution 17200).
Compound 22: Rf =0.40 (petroleum ether/EtOAc, 8:2); [a]2D0 =ꢀ24.6 (c=
0.63 in EtOAc); 1H NMR (400 MHz, CDCl3): d=6.95–6.78 (m, 8H),
6.04–5.94 (m, 1H), 5.66 (dd, J=11.0, 7.0 Hz, 1H), 5.57 (br, 1H), 5.32–
5.25 (m, 1H), 5.01 (br, 1H), 4.75–4.66 (m, 3H), 4.25 (br, 1H), 3.79 (s,
3H), 3.77 (s, 3H), 3.33 (s, 3H), 2.65 (br, 2H), 2.42 (br, 1H), 2.33–2.10 (m,
3H), 1.96 (br, 1H), 1.85–1.67 (m, 5H), 1.38–1.26 (m, 1H), 1.18 (s, 9H),
1.05 (d, J=6.8 Hz, 3H), 1.03 ppm (d, J=6.8 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=177.8, 154.0, 152.9, 140.4, 122.9, 117.1, 116.5,
114.7, 114.6, 95.6, 74.2, 71.3, 55.7, 55.4, 44.9, 39.0, 29.7, 29.1, 28.3, 27.3,
24.2, 23.1, 22.9 ppm; FT-IR (CCl4): n˜ =2956, 2833, 2289, 2004, 1855, 1729,
1553, 1504, 1479, 1465, 1441, 1396, 1368, 1226, 1180, 1152, 1104, 1043,
1007, 917 cmꢀ1; HRMS (ESI): calcd for C39H54NaO8: 673.37109 [M+
Na]+; found: 673.36828 (resolution 17300).
Molecular mechanics and semiempirical calculations: The potential-
energy surface of structures A–E (Z and E stereoisomers) was searched
using Monte Carlo[23b] conformational searches with MacroModel
(v8.5)[23a] running on a 3.0 GHz Intel Pentium 4 with LINUX Red Hat 9
operating system. The calculations were performed with the MM2* force
field using the GB/SA continuum solvent model for CHCl3.[23c] Intercon-
version of ring structures was enabled by using the ring-opening method
of Still.[42] Ring-closure bonds were defined for both the six- and ten-
membered rings present in structures A–E. Each search was run in
blocks of 15000 steps until convergence was reached, that is, no new
structures were found and the global minimum energy remained constant
throughout the search. Typically, 50000–60000 steps were enough to
ensure convergence. Each new cycle used as input the results of the pre-
vious cycle and different ring-closure bond choices were used. During the
search, structures with energy 20 kJmolꢀ1 higher than the current global
minimum were discarded. Structures were fully minimized for up to 5000
(1R,2R)-1-{(1R,2R,6R)-6-Isopropyl-2-[(2S,3R)-2-methoxymethoxy-3-
(4-methoxyphenoxy)pent-4-enyl]-3-methylcyclohex-3-enylmethyl}-2-(4-
methoxyphenoxy)but-3-enyl ester of2,2-dimethylpropionic acid (20)
:
PivCl (67 mL, 0.54 mmol) was added to a stirred solution of compound 18
(107 mg, 0.18 mmol), DMAP (22 mg, 0.18 mmol), and DIPEA (157 mL,
0.90 mmol) in CH2Cl2 (11.0 mL). After 7 h, the reaction mixture was
treated with a saturated NaHCO3 aqueous solution (10 mL) and stirred
for further 15 min. The organicphase was separated and the aqueous
layer was extracted with CH2Cl2 (3”10 mL). Purification of the crude
product by flash chromatography (petroleum ether/EtOAc, 9:1) afforded
compound 20 (101 mg, 83%) as a colorless oil. Rf =0.57 (petroleum
ether/EtOAc, 9:1); [a]D20 =+66.3 (c=1.32 in EtOAc); 1H NMR
(400 MHz, CDCl3): d=6.95–6.75 (m, 8H), 5.94–5.80 (m, 2H), 5.41–5.24
Chem. Eur. J. 2006, 12, 51 – 62
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
59

C. Gennari et al.
steps until the gradient was less than 0.05 kJŠꢀ1 molꢀ1 by using the
Polak–Ribiere conjugate gradient method.[43] Redundant conformations
were removed after heavy atom superimposition (RMSD cutoff=
0.25 Š). The lowest energy conformers obtained with MacroModel for
the Z and the corresponding E stereoisomers of structures A–E (using a
20.0 kJmolꢀ1 energy window from the global minima) were then opti-
mized at the PM3 level[22] by using the Gaussian 03 package.[27]
[6] a) K. C. Nicolaou, J. Y. Xu, S. Kim, T. Ohshima, S. Hosokawa, J.
Pfefferkorn, J. Am. Chem. Soc. 1997, 119, 11353–11354; b) K. C.
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Nicolaou, S. Kim, J. Pfefferkorn, J. Y. Xu, T. Ohshima, S. Hosokawa,
D. Vourloumis, T. Li, Angew. Chem. 1998, 110, 1484–1487; Angew.
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[7] a) K. C. Nicolaou, F. van Delft, T. Ohshima, D. Vourloumis, J. Y. Xu,
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2631–2634; Angew. Chem. Int. Ed. Engl. 1997, 36, 2520–2524;
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1998, 120, 8674–8680.
[8] a) X.-T. Chen, C. E. Gutteridge, S. K. Bhattacharya, B. Zhou,
T. R. R. Pettus, T. Hascall, S. J. Danishefsky, Angew. Chem. 1998,
110, 195–197; Angew. Chem. Int. Ed. 1998, 37, 185–187; b) X.-T.
Chen, B. Zhou, S. K. Bhattacharya, C. E. Gutteridge, T. R. R.
Pettus, S. J. Danishefsky, Angew. Chem. 1998, 110, 835–838; Angew.
Chem. Int. Ed. 1998, 37, 789–792; c) X.-T. Chen, S. K. Bhattacharya,
B. Zhou, C. E. Gutteridge, T. R. R. Pettus, S. J. Danishefsky, J. Am.
Chem. Soc. 1999, 121, 6563–6579.
[9] a) S. Ceccarelli, U. Piarulli, C. Gennari, Tetrahedron Lett. 1999, 40,
153–156; b) A. Baron, V. Caprio, J. Mann, Tetrahedron Lett. 1999,
40, 9321–9324; c) R. Carter, K. Hodgetts, J. McKenna, P. Magnus, S.
Wren, Tetrahedron 2000, 56, 4367–4382; d) S. Ceccarelli, U. Piarulli,
C. Gennari, J. Org. Chem. 2000, 65, 6254–6256; e) Q. Xu, M. Weer-
esakare, J. D. Rainier, Tetrahedron 2001, 57, 8029–8037; f) S. Ceccar-
elli, U. Piarulli, J. Telser, C. Gennari, Tetrahedron Lett. 2001, 42,
7421–7425; g) S. Ceccarelli, U. Piarulli, C. Gennari, Tetrahedron
2001, 57, 8531–8542; h) J. Telser, R. Beumer, A. A. Bell, S. M. Cec-
carelli, D. Monti, C. Gennari, Tetrahedron Lett. 2001, 42, 9187–
9190; i) C. Sandoval, E. Redero, M. A. Mateos-Timoneda, F. A. Ber-
mejo, Tetrahedron Lett. 2002, 43, 6521–6524; j) K. P. Kaliappan, N.
Kumar, Tetrahedron Lett. 2003, 44, 379–381; k) J. D. Winkler, K. J.
Quinn, C. H. MacKinnon, S. D. Hiscock, E. C. McLaughlin, Org.
Lett. 2003, 5, 1805–1808; l) G. Scalabrino, X.-W. Sun, J. Mann, A.
Baron, Org. Biomol. Chem. 2003, 1, 318–327; m) R. Beumer, P.
Bayꢂn, P. Bugada, S. Ducki, N. Mongelli, F. Riccardi Sirtori, J.
Telser, C. Gennari, Tetrahedron Lett. 2003, 44, 681–684; n) R.
Beumer, P. Bayꢂn, P. Bugada, S. Ducki, N. Mongelli, F. Riccardi Sir-
tori, J. Telser, C. Gennari, Tetrahedron 2003, 59, 8803–8820; o) L.
Caggiano, D. Castoldi, R. Beumer, P. Bayꢂn, J. Telser, C. Gennari,
Tetrahedron Lett. 2003, 44, 7913–7919; p) N. Ritter, P. Metz, Synlett
2003, 2422–2424; q) D. Castoldi, L. Caggiano, P. Bayꢂn, A. M.
Costa, P. Cappella, O. Sharon, C. Gennari, Tetrahedron 2005, 61,
2123–2139; r) G. C. H. Chiang, A. D. Bond, A. Ayscough, G. Pain,
S. Ducki, A. B. Holmes, Chem. Commun. 2005, 1860–1862; s) H.
Bruyꢃre, S. Samaritani, S. Ballereau, A. Tomas, J. Royer, Synlett
2005, 1421–1424.
DFT calculations ofthe ruthenacyclobutane intermediates : Structures
trans F–I and cis F–I used as input for the quantum mechanical calcula-
tions were generated through Monte Carlo[23b] conformational searches
carried out with MacroModel (v9.0)[23] running on a 3.2 GHz Intel Penti-
um IV computer under Linux Fedora Core 3. The core ruthenacycle
structure was taken from reference [30] and was frozen during the
searches,[31] which were performed with the MM2* force field using the
GB/SA continuum solvent model for CHCl3,[23c] as described in the previ-
ous section. Each search was run in blocks of 10000 steps until conver-
gence was reached. Typically, 20000–30000 steps were sufficient to
ensure convergence. The lowest energy conformers for trans F–I and cis
F–I generated during the search were optimized using the DFT
method[32] at the B3LYP[33]/3–21G* level of theory. Single-point energy
calculations were carried out at the B3LYP/LANL2DZ[34]//B3LYP/3–
21G* level. All quantum mechanical calculations were carried out with
the Gaussian 03 package.[27]
Acknowledgements
We thank the European Commission for financial support (IHP Network
grant “Design and synthesis of microtubule stabilizing anticancer agents”
HPRN-CT-2000–00018) and for postdoctoral fellowships to L.C. (HPRN-
CT-2000–00018) and O.S. (“Marie Curie” MEIF-CT-2003–500880). We
also gratefully acknowledge the Spanish “Ministerio de Ciencia y Tecno-
logia” for a “Ramon y Cajal” fellowship to A.M.C., “Merck Research
Laboratories” (Merckꢁs Academic Development Program Award to C.
G.) and Università degli Studi di Milano for financial support and for
graduate fellowships (to D.C. and L.P.). We thank Dr. Raphael Beumer,
Dr. Pau Bayꢂn, Dr. Joachim Telser, and Dr. Fabienne Pradaux for pre-
liminary experiments related to this work, and Dr. Nicola Mongelli
(Nerviano Medical Science) and Prof. Jaume Vilarrasa (University of
Barcelona) for inspiring discussions.
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[5] For a comprehensive review on the chemistry and biology of the
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60
www.chemeurj.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 51 – 62

Total Synthesis
FULL PAPER
[14] For a discussion of these optimized RCM conditions, see: a) K. Ya-
mamoto, K. Biswas, C. Gaul, S. J. Danishefsky, Tetrahedron Lett.
2003, 44, 3297–3299; b) C. Aꢅssa, R. Riveiros, J. Ragot, A. Fꢄrstner,
J. Am. Chem. Soc. 2003, 125, 15512–15520, and references therein.
[15] The H-5/H-6 coupling constant was determined from a decoupled
1H NMR spectrum acquired by irradiation at d=5.04 ppm, which
corresponds to the frequency of protons H-4 and H-7. The signals of
the olefinicprotons (at d=5.96 and 5.71 ppm, assigned to protons
H-5 and H-6) became two doublets whose coupling constant, typical
of an E double bond, was easily determined: 3JH-5/H-6 =16.5 Hz. The
NOESY spectrum showed two positive cross peaks due to scalar
coupling (E double bond), instead of two negative cross peaks due
to NOE (Z double bond).
signal at d=6.04–5.94 ppm was assigned to proton H-12 due to the
couplings with two different signals at d=2.7 and 2.2 ppm (the two
diastereotopicprotons H-13 and H-13b). The signal of the proton of
a
the trisubstituted double bond (H-6, d=5.57 ppm) showed a cou-
pling with the signal at d=4.72 ppm (H-7), which, in turn, coupled
with the signal at d=4.25 ppm (H-8).
[22] J. J. P. Steward, J. Comput. Chem. 1989, 10, 209–220.
[23] a) F. Mohamadi, N. G. J. Richards, W. C. Guida, R. Liskamp, M.
Lipton, C. Caufield, G. Chang, T. Hendrickson, W. C. Still, J.
Comput. Chem. 1990, 11, 440–467; b) G. Chang, W. C. Guida, W. C.
Still, J. Am. Chem. Soc. 1989, 111, 4379–4386; c) W. C. Still, A.
Tempczyk, R. C. Hawley, T. Hendrickson, J. Am. Chem. Soc. 1990,
112, 6127–6129.
[16] The use of “second-generation” metathesis catalysts usually results
in the selective formation of the thermodynamically favored stereo-
isomeric products in RCM reactions furnishing medium-sized rings,
see: a) C. W. Lee, R. H. Grubbs, Org. Lett. 2000, 2, 2145–2147;
b) A. Fꢄrstner, O. R. Thiel, N. Kindler, B. Bartkowska, J. Org.
Chem. 2000, 65, 7990–7995; c) A. Fꢄrstner, M. Schlede, Adv. Synth.
Catal. 2002, 344, 657–665; d) A. Fꢄrstner, K. Radkowski, C. Wirtz,
R. Goddard, C. W. Lehmann, R. Mynott, J. Am. Chem. Soc. 2002,
124, 7061–7069; e) J. Murga, E. Falomir, J. Garcꢆa-Fortanet, M.
Carda, J. A. Marco, Org. Lett. 2002, 4, 3447–3449; f) J. Prunet,
Angew. Chem. 2003, 115, 2932–2936; Angew. Chem. Int. Ed. 2003,
42, 2826–2830; g) E. Díez, D. J. Dixon, S. V. Ley, A. Polara, F. Ro-
dríguez, Helv. Chim. Acta 2003, 86, 3717–3729; h) S. Lebreton, X.-S.
Xie, D. Ferguson, J. K. De Brabander, Tetrahedron 2004, 60, 9635–
9647.
[24] The four low-quality torsional parameters are: two Lp-O3-C0*00
ꢀ
[for the Lp-O(sp3) C(sp2)=O(sp2) torsion, ester group] and two
ꢀ
ꢀ
ꢀ
H1-C2-C3-O3 [for the H C(sp2) C(sp3) O(sp3) torsion, allylic
ethers].
[25] The ten low-quality torsional parameters are: two Lp-O3-C0*00 [for
ꢀ
ꢀ
the Lp O(sp3) C(sp2)=O(sp2) torsion, ester group], two H1-C2-
ꢀ
ꢀ
ꢀ
C3-O3 [for the H C(sp2) C(sp3) O(sp3) torsion, allylicethers],
ꢀ
ꢀ
ꢀ
two 00-C3-O3-00 [for the C(sp2) C(sp3) O(sp3) C(sp2) torsion, al-
lylicphenyl ethers], four Lp-O3-C0*00 [for the Lp O(sp3) C(sp2)=
C(sp2) torsion, phenyl ethers].
ꢀ
ꢀ
[26] The six low-quality torsional parameters are: two Lp-O3-C0*00 [for
ꢀ
ꢀ
the Lp O(sp3) C(sp2)=O(sp2) torsion, ester group], one 00*C2=
ꢀ
ꢀ
C2*00 [for the (O=)C CH=CH C(=O) torsion, enedione], two 00-
ꢀ
ꢀ
ꢀ
C2-C3-00 [for the O(sp3) C(sp3) C(sp2) C(sp2) torsion], one C0-
ꢀ
ꢀ
ꢀ
C3-O3-C2 [for the (O=)C C(sp3) O(sp3) C(=O) torsion].
[27] Gaussian 03, Revision B.04, M. J. Frisch, G. W. Trucks, H. B. Schle-
gel, G. E. Scuseria, M. A. Robb, J. R. Cheeseman, J. A. Montgomer-
y, Jr., T. Vreven, K. N. Kudin, J. C. Burant, J. M. Millam, S. S. Iyen-
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[17] ESI-HRMS (resolution: 25800) of the enedione (Z)-4, from
a
MeOH/H2O (98:2) solvent mixture, gave the exact molecular ions
[M+Na]+ for 4 (calcd for C25H38NaO6: 457.25606; found: 457.25582;
error=ꢀ0.52 ppm), the hydrated form 17 (calcd for C25H40NaO7:
475.26662; found: 475.26681; error=+0.40 ppm), and the hemiace-
tal methylacetal corresponding to the addition of MeOH (calcd for
C26H42NaO7: 489.28227; found: 489.28031; error=ꢀ4.00 ppm). The
structure of the bis-hemiacetal 17 was confirmed by 1H NMR spec-
troscopy (H-5, H-6: 6.29, 6.18 ppm; 3JH-5/H-6 =5.8 Hz), by 13C NMR
spectroscopy (absence of carbonyl carbon atom signals at 204.4 and
196.7 ppm, presence of hemiacetal carbon atom signals at 111.7 and
110.3 ppm) and by IR spectroscopy (absence of the strong C=O
stretching band at 1701 cmꢀ1), see the Experimental Section.
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pared from (+)-a-pinene according to: H. C. Brown, P. K. Jadhav,
K. S. Bhat, J. Am. Chem. Soc. 1988, 110, 1535–1538, and references
therein.
[20] The signals of the olefinicprotons (at d=5.87 and 5.60 ppm, as-
signed to protons H-5 and H-6) were two doublets of doublets with
coupling constants of 17.0 Hz and 4.2 Hz and of 17.0 Hz and 9.1 Hz,
respectively. 3JH-5/H-6 =17.0 Hz is typical of an E double bond. The
NOESY spectrum showed two positive cross peaks due to scalar
coupling (E double bond), instead of two negative cross peaks due
to NOE (Z double bond).
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Grubbs catalyzed cross-metathesis reaction, see: F. C. Engelhardt,
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[31] The Ru atom was substituted with a carbon atom. The “frozen”
core structure (corresponding to the original ruthenacyclobutane
fragment including the substituents at ruthenium) maintained its ini-
tial geometry, while the rest of the structure was smoothly mini-
mized. After the conformational search and the minimization, the
Ru atom was reinstalled, and the structures were optimized with the
DFT calculations.
[21] In the case of compound 22, complete proton resonance assignments
were made with the aid of COSY, TOCSY, and HSQC experiments.
1
The H NMR spectrum (400 MHz) showed the following signals due
to the three olefinicprotons: a multiplet at d=6.04–5.94, a doublet
of doublets at d=5.66 (dd, 1H, J=11.0, 7.0 Hz) indicating the pres-
ence of a Z double bond, and a broad signal at d=5.57 ppm. With
the aid of the COSY spectrum, the signal at d=5.66 ppm was as-
signed to H-5, due to the correlation with the multiplet at d=
5.01 ppm (H-4), which, in turn, had a coupling with the multiplet at
d=5.32–5.25 ppm (H-3). Furthermore, the COSY spectrum showed
a coupling between the signal at d=5.66 ppm (H-5) and the multip-
let at d=6.04–5.94 ppm, thus assigning the other proton of the Z
double bond (H-12); consequently, the signal at d=5.57 ppm was as-
signed to the proton of the trisubstituted double bond (H-6). The
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basis set for first-row atoms (T. H. Dunning, Jr., P. J. Hay in Modern
Theoretical Chemistry (Ed.: H. F. Schaeffer III), Plenum, New
York, 1976, pp. 1–28) and the Los Alamos effective core potential
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C. Gennari et al.
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Ru.
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Received: June 29, 2005
Published online: September 20, 2005
62
www.chemeurj.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 51 – 62