Zirconocene-mediated selective c-c bond cleavage of strained carbocycles: Scope and mechanism

Article abstract of DOI:10.1021/acs.joc.7b03115

Several approaches using organozirconocene species for the remote cleavage of strained three-membered ring carbocycles are described. ω-Ene polysubstituted cyclopropanes, alkylidenecyclopropanes, ω-ene spiro[2.2]pentanes, and ω-ene cyclopropyl methyl ethe

Full text of DOI:10.1021/acs.joc.7b03115

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Zirconocene-Mediated Selective C-C Bond Cleavage
of Strained Carbocycles: Scope and Mechanism
Jeffrey Bruffaerts, Alexandre Vasseur, Sukhdev Singh, Ahmad Masarwa,
Dorian Didier, Liron Oskar, Lionel Perrin, Odile Eisenstein, and Ilan Marek
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b03115 • Publication Date (Web): 14 Mar 2018
Downloaded from http://pubs.acs.org on March 16, 2018
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Zirconocene-Mediated Selective C-C Bond Cleavage of Strained Carbo-
cycles: Scope and Mechanism
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‡
‡
Jeffrey Bruffaerts,a Alexandre Vasseur,a Sukhdev Singh,a Ahmad Masarwa,a Dorian Didier,a
Liron Oskar,a Lionel Perrin,*b Odile Eisenstein,*c Ilan Marek*a
a
The Mallat Family Laboratory of Organic Chemistry, Schulich Faculty of Chemistry and Lise Meitner-Minerva
Center for Computational Quantum Chemistry, Technion-Israel Institute of Technology, Haifa 3200009, Israel.
b
Université de Lyon, Université Claude Bernard Lyon 1, CPE Lyon, INSA Lyon, ICBMS, CNRS UMR 5246, Equipe
ITEMM, Bât. Curien, 43 Bd. du 11 Novembre 1918, 69622 Villeurbanne, France.
c
Institut Charles Gerhardt, UMR 5253, CNRS-UM-ENSCM, Université de Montpellier, cc 1501, Place E. Bataillon,
34095 Montpellier, France.
KEYWORDS. C-C bond cleavage – allylic C-H bond activation – remote functionalization – organozirconium – quaternary carbon
stereocenters – DFT calculations
ABSTRACT: Several approaches using organozirconocene species for the remote cleavage of strained three-membered
ring carbocycles are described. -Ene polysubstituted cyclopropanes, alkylidenecyclopropanes, -ene spiro[2.2]pentanes
and -ene cyclopropyl methyl ethers were successfully transformed into stereodefined organometallic intermediates
allowing an easy access to highly stereoenriched acyclic scaffolds in good yields and in most cases excellent selectivities.
DFT calculations and isotopic labeling experiments were performed to delineate the origin of the obtained chemo- and
stereoselectivities, demonstrating the importance of microreversibility.
1. INTRODUCTION
mote functionalization via transition-metal assisted olefin
isomerization represents a highly promising synthetic tool.9
Initiated by the pioneering work of Breslow1 and defined by
Schwarz,2 the concept of remote functionalization – consist- Among directionally selective alkene isomerization reac-
ing in an initial interaction of a functional group with a tions, Negishi initially showed that treating an olefin with a
reactant leading to a selective reaction at a distal position - low-valent zirconocene reagent (Cp2ZrC4H8)10 efficiently
has increasingly been regarded as a cornerstone to alterna- enabled its long-range migration across methylene chains,
tively solve challenging problems in organic synthesis.3 This to, in this case, provide a conjugated diene (Scheme 1, part
indirect activation of a site distant from the initial function- I).11 This migration reaction, promoted by the later called
al group allowing the relay of chemical information across a Negishi reagent, was shown to occur through rapid and
molecular backbone strongly modifies our perception of successively reversible allylic C-H bond activations. Later,
retrosynthetic analysis. Not surprisingly, this concept has
already sparked the development of numerous innovative
transformations and nowadays represents a vibrant field of
activity.4 Among those, transition-metal based methodolo-
gies, and more particularly metal-assisted alkene isomeriza-
tions across a hydrocarbon chain, have played a preponder-
ant role in popularizing this conceptual approach.5,6 This
property can be harnessed for the development of powerful
tandem, cascade or sequential reactions involving a site
distant from the initial double bond.7 An additional inher-
ent advantage of such “zipping” process8 is that the chemi-
cal outcome is usually independent from the position and
geometry of the initial double bond. Therefore, reactions
involving even geometrical or positional mixture of olefins
should converge towards the same product, as the unsatu-
ration is used as a versatile chemical handle to trigger a
chain of events leading to a predetermined termination site.
As alkenes are ubiquitous motifs in organic chemistry, re-
we reported the zirconocene-mediated transformation of -
unsaturated fatty alcohol derivatives into allylzirconocene
species (Scheme 1, part II).12 In this case, the isomerization
(process also called Zr-walk or Zr-promenade) was driven by
the β-alkoxide elimination step. It should be stressed that
neither the double-bond geometry (E or Z) nor its relative
position towards the alcohol affects the chemical outcome.
This tandem isomerization-elimination reaction was also
successfully applied to transform ω-ene enol ethers into
stereodefined polysubstituted conjugated (E,Z)-dienyl zir-
conocene derivatives.13 Following these works, we anticipat-
ed that the release of a ring strain, provided by the selective
ring opening of a three-membered carbocycle14 might also
provide a sufficient driving force for the desired bidirec-
tional zirconocene alkene-migration. In parallel, numerous
and various strategies have been developed to prepare di-
verse cyclopropane moieties with excellent levels of stere-
ocontrol.15 Reckoning on their straightforward preparations,
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we envisioned them as precursors to acyclic systems bearing steroid (Scheme, part IV).18a Notably, such synthetically
stereocenters through selective C–C bond cleavage. This challenging motifs (1,4–stereocenters adjacent to an (E)–
seemingly indirect strategy would constitute a valuable new olefin) may also be found in natural products, such as bot-
tool to access challenging acyclic organic synthons, featur- ryococcene derivatives.19 In this Article, we wish to report
ing for instance all–carbon quaternary stereocenters,16 with an extension of these initial findings to fully probe the
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high stereocontrol.17
scope and mechanism of these unique transformations in
In particular, seminal works18 already established the effi- the context of stereoselective synthesis (Scheme 1, part V).
cient zirconocene insertion into vinylcyclopropane (Scheme Furthermore, such unique reactivity raised several funda-
1, part III) and its synthetic utility was further demonstrated mental mechanistic questions, herein addressed through
through the stereoselective construction of the motif- both experimental and theoretical studies.
containing acyclic side chain of an active metabolite of a
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Scheme 1. Illustration of several zirconocene–assisted transposition of olefins and their synthetic applications
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2. RESULTS AND DISCUSSION
would give VI. If one still assumed that the C–C bond cleav-
However, to achieve such zirconocene–mediated selective age would be selective (i.e. unique formation of III), then
and remote cleavage, many issues need to be solved and the issue of configurational stability of the sp3 C1–[M] of the
pitfalls to be circumvented. Remarkably, the formation of, metalacyclobutane III would become of crucial importance
for example the acyclic product 2 from 1, relies on the per- for the diastereoselectivity of the reaction. One additional
fect control of a cascade of events (Scheme 2). More specifi- issue would be the site selectivity for the reaction with dif-
cally, the reaction of 1 with the Negishi reagent would pro- ferent electrophiles. Would III first react through the C1–
vide the metal–alkene complex I (with n = 1 and m = 0 for [M] or C3–[M] bond (formation of IV vs. VII)? Supposing
the sake of simplicity) that would be required to successive- that the site selectivity would be controlled (i.e. reaction of
ly undergo the following sequence: (i) an efficient migration III with the first electrophile via the allylic C1–[M] bond),
of the double bond to reach the vinyl position of the cyclo- then the mode of reactivity would also need to be con-
propane II; (ii) a selective ring–opening leading to III; (iii) trolled. Would it provide VIII or IV? Could the addition of
selective reactions with two different electrophiles leading the electrophile be stereoselectively? Which geometry
to 2. The first issue of the proposed sequence lies in the would the resulting olefin adopt? Could the remaining or-
directionality of the unsaturation migration, as the for- ganometallic species IV be further functionalized with a
mation of the thermodynamically more stable organometal- second electrophile? All these potential synthetic pathways
lic compound V should be prevented. If the metal migrates and pitfalls stress the overall difficulty to selectively achieve
towards the cyclopropane ring, two possibilities might arise such strategy.
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for the carbocycle metal insertion. A C1–C3 bond cleavage
would provide III whereas the cleavage of the C1–C2 bond
Scheme 2. Illustration of all plausible intermediates for the metal–mediated conversion of 1 into 2.
2.1. DFT Calculations. Initially, one of the first issues that
we wanted to clarify was the original formation of the zir-
conacyclopropane obtained by treating an olefin with the
Negishi reagent (Scheme 3). In the literature, a direct ligand
exchange reaction is generally postulated20 although a
stepwise mechanism of addition–elimination was also sug-
gested.21 Surprisingly, this event had never been previously
computationally examined. The mechanism by which the
zirconocene is transferred from the Negishi reagent to the
terminal –bond of the substrate was thus investigated
using but–1–ene as model substrate and DFT(M06) calcula-
tions with implicit SMD solvation (Et2O) (Scheme 3). This
reaction is driven by the strong negative charge that is lo-
cated at the  carbons of the butyl groups in c1. An intra-
molecular –H abstraction, (best viewed as a proton trans-
fer) from one of the two butyl groups by the  carbon of the
other ligand and subsequent elimination of butane (TS c2,
∆G‡ = 23.4 kcal mol-1) yields the Negishi reagent Cp2ZrC4H8
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c3. An NBO population analysis revealed that the charge on shift allows the rotation of Cp2ZrH relative to the allyl
group. Return to the 3–mode and reinsertion of the allyl
group into the rotated Zr–H bond formally yields a –C=C
bond shifted by a methylene group. Through this mecha-
nism, zirconocene walks in the two directions along the
carbon backbone. E/Z isomerization combines the above
sequence and a rotation about the single C–C bond of the
1–coordinated allyl complex. Return to the 3–mode and
reinsertion of the allyl group into the rotated Zr–H bond
yield the isomerized E/Z olefin complex. The same E/Z
isomerization operates the re to si face exchange. In the
latter case, the initial C–H bond activation has to be per-
formed on an allylic –cis conformation. These transfor-
mations therefore involve numerous elementary steps
whose transition states are low in energy (G≠ < 15 kcal mol–
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Zr remains almost unchanged during this step. This shows
that the formal oxidation state of Zr remains unchanged
from c1 to c3 and that the zirconocene complex Cp2Zr(2–
H2C=CHEt) should be viewed as a zirconacyclopropane
[Zr(IV)]. The formal alkene exchange is a two-step process
that starts with a carbozirconation reaction [insertion of the
C=C double bond of the incoming alkene into the
Cp2ZrC4H8 drawn as a zirconacyclopropane in Scheme 3,
following the transition state represented in c4 to yield the
zirconacyclopentane intermediate c5. The formation of the
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final zirconacyclopropane is achieved by
a
ring–
fragmentation with the release of but–1–ene from c5.22 The
free energy barrier for this exchange reaction is moderate,
and the irreversibility of the reaction is driven by the vola-
tility of but–1–ene. It should be emphasized that the zir-
conacyclopropane character of c3 prevents a direct alkene
exchange towards c3’.23
1
with respect to separate reactants Cp2ZrC4H8 and but–1–
ene) and all of similar energy (G≠ < 7 kcal mol-1). The
combination of these previous sequences, that have com-
mon intermediates and similar energy profiles, allows the
coordination of zirconocene to all carbons without confor-
mational restriction. The Gibbs energy profiles for these
isomerizations are shown in Figures S2 to S4 in the SI.
Scheme 3. Computed reaction pathway by which the
zirconacyclopropanes is transferred to an external
alkene
Figure 1. Free Gibbs energy profile (in kcal mol-1) for
the Zr–walk: (i) switch of prochiral faces (ii) and (iii)
isomerization of stereochemistry.
After studying the transfer of the Negishi reagent to an
external alkene, we then examined the migration of the
zirconacyclopropane along the carbon skeleton. During this
migration, three types of isomerization were identified for
pent–1–ene as model substrate: (i) zirconacyclopropane
walking along a –trans skeleton, (ii) facial interconversion
of the zirconacyclopropane via the –cis allylic intermedi-
ate, (iii) E to Z double bond isomerization i.e. syn/anti allyl
isomerization (Figure 1). The initial coordination of electron
deficient zirconocene to the  C=C double bond promotes
the activation of the allylic C—H bond. This yields a zir-
conocene hydride 3–allyl complex, which is the pivotal
intermediate to the dynamics of this complex. This equilib-
rium between the zirconacyclopropane and allyl–hydride
complexes enables the Zr–walk (Figure 1). Starting from the
most stable 3–allyl binding mode, a 3– to 1–haptotropic
2.2. Reactivity of ω–ene–cyclopropanes. In parallel, we
experimentally started by investigating the reactivity of ω–
ene–cyclopropane 1a (with two identical groups; R1 = R2)
into acyclic product 2a by addition of the Negishi reagent
Cp2ZrC4H8,10 freshly prepared from Cp2ZrCl2 and 2 equiva-
lents of n–BuLi at low temperature in Et2O as solvent
(Scheme 4). We were pleased to observe that the Negishi
reagent enabled us to convert 1a into 2a as a single E–
isomer after hydrolysis in a good isolated yield through the
expected allylic C–H bond activation sequence followed by
a selective C–C bond cleavage (Scheme 4). Our mechanistic
rationalization for the above transformation was that the π–
allyl zirconocene hydride species X, resulting from an allylic
C–H bond activation reaction of the zirconacyclopropane
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IX, would initiate the isomerization and would generate the
new zirconacyclopropane XI after readdition of the metal–
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2
hydride species onto the hydrocarbon chain.24 As –
metalated cyclopropyl species are known to undergo ring–
opening reactions,25 the zirconacyclopropane XI undergoes
a selective C1–C3 bond cleavage to form the π–alkyl–
allylzirconocene intermediate IIIa (probably in haptotropic
equilibrium with its –bonded form IIIb) as described in
Scheme 4. The origin of the selectivity for the ring cleavage
(C1–C3 versus C1–C2) is kinetically and thermodynamically
governed by the formation of the primary carbon zirconium
bond (C3–Zr, formation of III) rather than the formation of
the tertiary carbon zirconium bond (formation of a C2–Zr
bond as represented in VI), although the activation could
have potentially occurred at the benzylic position (if one
uses 1a,b as starting materials).26 The formation of a dis-
crete bismetalated σ,π–allylzirconocene species IIIa was
confirmed by deuterolysis after the isomerization/ring–
opening sequence and 2ad2 was obtained with both isotopic
incorporation at the primary alkyl (C3) and allylic (C2’) posi-
tions. From this experiment, we could already conclude that
the zirconocene complex allowed not only an isomerization
of the double bond (Zr–walk) but also a selective C1–C3
bond cleavage and site–selective electrophilic substitutions.
When the chain length between the cyclopropyl unit and
the unsaturation was increased (n = 6 for 1b), comparable
yields were obtained (2b) albeit with a slight decrease in
yield. Additionally, we could take advantage of the different
nucleophilic properties of the resulting bimetallic species
(allyl– vs. alkylzirconocene moieties) by discriminating
their reactivity towards different electrophiles. Indeed, the
allylzirconocene fragment of III, whose reactivity has been
well established,27 may selectively react with carbonyl com-
pounds, such as acetone, at the C2’ position in a SE2’ fashion.
Even in the presence of an excess of acetone, no trace of
compounds resulting from the reaction of alkylzirconocene
moiety with ketone at C3 was detected. However, the subse-
quent addition of I2 allowed the functionalization of the
remaining alkylzirconocene segment yielding 2C.
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The singularity of this dual reactivity was further exploited
(see Schemes 5 and 6). Importantly, exclusively E–alkenes
were produced (E/Z > 98:2) through this methodology,
independently of the nature of the substituents (R1), chain–
length (n) and electrophiles (E1–X and E2–X) used. Once the
sequence of allylic C–H activations and selective C–C bond
cleavage was established, the potential of this transfor-
mation to obtain two stereogenic centers in a controlled
1,4–relationship was further investigated (Scheme 5). When
diastereomerically pure compound 1d (R1 = Me, R2 = Bu)
was treated with Cp2ZrC4H8 under similar experimental
conditions, derivative 2d was formed as a mixture of two
diastereoisomers in a 3:1 ratio (Scheme 5). To rationalize the
obtained ratio, we hypothesized that a mixture of trans–
and cis–allylzirconocene species might be responsible for
this impediment (IIIb-trans and IIIb-cis respectively), both
reacting with acetone and consequently leading to the two
observed sp3–centered diastereoisomers. To improve this
ratio, one solution consisted in isomerizing the Z–
configured species IIIb-cis into its more thermodynamically
stable E–isomer IIIb-trans prior to the addition of the first
electrophile.17e We were pleased to observe that this inter-
conversion was effective by adding THF and heating the
reaction mixture at 56 °C for 3 hours, following our pre–set
experimental conditions. By introducing this additional
event, the transformation of 1d then provided the product
Scheme 4. Representative examples of the remote zir-
conocene–induced fragmentation of –ene cyclopro-
panes (for the extended scope, see reference 17e).
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2d in an excellent 95:5 diastereomeric ratio, highlighting chemical information could be altered. To get insights for
the excellent relay of stereochemical information from posi- this thermal isomerization step, DFT(MO6) calculations
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tion C1 to C2’ (Scheme 5).
with implicit SMD solvation (Et2O) were carried out
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(Scheme 5).17e, To further investigate this thermally in-
duced interconversion (Scheme 5), we are detailing the
computational studies previously initiated. Thanks to the
reversible isomerizations shown in Figure 1, four zircono-
cene isomers (A–D) are produced in equilibrium via a
common zirconocene–allyl–hydride intermediate I. The
ring opening events from these four isomers were consid-
ered, and this highlights the importance of the syn– vs anti–
periplanar relationship required between the cyclopropane
methylene unit and the zirconocene. In intermediates C
and D, zirconacyclopropane is trans–periplanar to the less
substituted cyclopropane C–C bond. Thus, the cyclopro-
pane ring opening requires a large distortion that is kinet-
ically prohibitive (G≠ > 35 kcal mol-1) (Figure 2). In con-
trast, in intermediates A and B, a syn relationship between
these bonds lowers the energy barrier by 30 kcal mol-1,
Scheme 5. 1,4–diastereoselectivity in acyclic products 2
from –ene cyclopropanes 1 (for the extended scope,
see reference 17e).
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yielding G≠ of 1.5 and 5.4 kcal mol-1 for TSB-IMaj and TSA-Imin
,
respectively. Complex IMaj, which accounts for the major
final diastereoisomer is kinetically favored over Imin. It is
also the most stable ring opening activation isomer by 4
kcal mol-1. Hence, TSA-Imin accounts for the formation of the
final minor diastereoisomer. To explain the epimerization
in favor of IMaj observed upon heating, all plausible routes
that connect Imin to IMaj were explored. The most favora-
ble pathway entails the 3–allylic intermediate I and relies
on the reversible formation of IMaj from Imin via I using
the elementary steps described previously in Figure 2. Since
Imin is 8.2 kcal mol-1 lower in energy than the reactants,
heating is required to overcome the exoergicity and pass
through the transition states and intermediates that link
Imin to IMaj. The high diastereoselectivity observed in this
transformation results from a dynamic thermodynamic
process in which heating increases the stereocontrol of the
reaction. Remarkably, this stereocontrolled remote func-
tionalization results from unselective C–H bond activations
and reversible cyclopropane ring opening thus enabling the
micro–reversibility of all events until the lowest energy
minimum is fully reached.
Having in hands this improved protocol, few representative
diastereomerically pure ω–ene–cyclopropanes 1e–f (for full
list of examples, see reference 17e) were successfully treated
with the Negishi reagent Cp2ZrC4H8, then electrophiles, to
produce the corresponding functionalized acyclic products
2e,f, bearing the original quaternary center and newly cre-
ated allylic tertiary stereogenic centers with excellent dia-
stereoselectivities (Scheme 5). In all cases, yields and dia-
stereomeric ratios remained excellent invariably of the
chain–length. It should be noted that the reaction is not
restricted to substrates with a terminal double bond as
internal olefin 1f provided also 2e as a single stereoisomer
using our standard conditions. Importantly, the final stere-
ochemical outcome of the double bond seems independent
of its initial geometry since both E– and Z–isomers of 1f
provide only the E–compound 2e. This last result thus clear-
ly assessed the regioconvergency of the Zr–walk process.
Despite these excellent results, we were puzzled to experi-
mentally observe that the thermal conversion of cis IIIb-cis
into trans–substituted allylzirconocene IIIb-trans (isomeriza-
tion at C2’) event proceeded without inducing any scram-
bling of the stereochemistry at the C1 position. This notable
high stereoelectronic control raised the question of its
origin since the formation of a single product requires a
large number of elementary steps during which stereo-
Figure 2. Dynamic processes
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Having now a better understanding of the overall sequential Scheme 7. Non diastereoselective reaction of aldehydes
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process, we decided to further increase the versatility and
scope of this approach by functionalizing the remaining sp3
carbon–zirconium bond with carbon electrophiles (while
fixing E1X as acetone). Although the ionic character of the
sp3 C–[Zr] bond is similar to a C–Mg bond, only readily
reactive electrophilic reagents such as H3O+ or I2 proved to
directly react with the sp3 C–[Zr] bond, presumably owing
to the steric shielding of the two cyclopentadienyl ligands.
To circumvent the lack of reactivity of this σ–carbon–metal
bond, we anticipated that its transmetalation into copper
species could solve this issue.28
with allylzirconocene originating from –ene cyclo-
propanes 1
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Scheme 6. Copper(I)–catalyzed subsequent modular
functionalization of the remaining sp3 C–[Zr] bond
Following the assessment of all electrophilic substitutions,
we then envisaged to selectively cleave 1,1,2,3–
tetrasubstituted cyclopropane such as 1h (Scheme 8). If
selective, we expected to obtain a secondary sp3 organozir-
conocene species XII,29 which in some cases was reported to
be configurationally stable30 (Scheme 8). However, all at-
tempts to promote the isomerization / selective C–C bond
cleavage sequence of 1h led to a complex reaction mixture.
Scheme 8. Attempt to extend the sequence to 1,1,2,3–
tetrasubstituted –ene cyclopropane 1h
Gratifyingly, after addition of the first electrophile (ace-
tone), the introduction of a catalytic amount of CuI2LiCl in
the reaction mixture allowed to considerably expand the
scope of the second functionalization.17e,28 For instance,
SN2’–type processes could be carried out with allyl or pro-
pargyl bromide to give 2g and 2h respectively. C(sp3)–C(sp2)
bonds were directly formed using acyl chlorides (2i and 2j),
or indirectly via a Pd–catalyzed cross–coupling reaction
with phenyl iodide (2k, Scheme 6). As our strategy led to
products bearing stereogenic centers in a highly stereode-
fined 1,4–relationship, we attempted to add another level of
stereochemical complexity by studying the addition of
prochiral substrates such as aldehydes or imines as first
electrophiles (E1X). Whereas N–(tosyl)benzylideneimine
and N–(diphenylphosphinyl)benzaldimine proved to be
unreactive towards the intermediate III (described in
Scheme 4), the use of aliphatic or aromatic aldehydes with
1d,g led to the linear products 2l–n in good yields but with
a disappointing diastereoisomeric ratio (Scheme 7). Exten-
sive efforts to improve this ratio by further tuning the ex-
perimental conditions turned out to be fruitless.
2.3. Reactivity of ω–ene–spiro[2.2]pentanes We were
then interested to extend our approach to –ene alkenyl
spiro[2.2]pentanes 3. These smallest encountered spirocar-
bocycles31 have a higher ring strain energy (63 kcal mol-1)
than two cyclopropanes taken separately (27.5 kcal mol-1)
suggesting an even higher propensity towards fragmenta-
tion.32 Moreover, unlike thermal, radical, ionic or carbene–
induced cleavage of spiro[2.2]pentanes, the transition–
metal assisted transformations of these entities usually lead
to selective outcomes, therefore potentially becoming of
synthetic use. For instance, selective single or double ring
opening procedures of spiro[2.2]pentanes were already
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reported, although the single–ring opening mode is less ratios (see Supplementary Material), we then focused on
encountered. For example, de Meijere initially showed the their behavior using our zirconocene–based methodology.
possibility of inducing a single ring–opening mode through When 3a was treated with the Negishi reagent, we were
the [Co2(CO)8]–catalyzed carbonylation of vinyl spi- gratified to observe a rapid and clean isomerization reaction
ro[2.2]pentanes33 and of 4–methylenespiro[2.2]pentanyl followed by a selective single C–C bond cleavage providing
methanols.34 In parallel, a double ring–opening of spi- after reaction with acetone and subsequent hydrolysis, 4a in
ro[2.2]pentanes was also reported to be involved in a Heck 64% yield as a single E–isomer without any trace of second
arylation,35 a Rh(I)–catalyzed carbonylation36 or a Ru(II)– C–C bond cleavage product (Scheme 9). Notably, the stere-
catalyzed full ring–opening followed by a subsequent [4+2] oselectivity of the conversion of 3a into 4a was high (ds >
dimerization reaction.37 Following the development of a 98:2), as the isolated mixture 4a (dr 95:5) presented almost
1
2
3
4
5
6
7
8
9
straightforward access38 to various –ene alkenyl spi-
ro[2.2]pentanes 3 in good to excellent diastereoisomeric
the same diastereomeric ratio than its precursor (3a).
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11
12
13
14
15
16
17
18
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22
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60
Scheme 9. Combined isomerization–selective mono C–C bond cleavage of –ene alkenyl spiro[2.2]pentanes 3a-e
1) Cp2ZrC4H8, Et2O,
-78 to 25 °C, 12 h
2) R3COR3, 0 °C, 2.5 h
3) E2-X, 0 °C, 2.5 h
4) H3O+
n-1
R3
R3
n
R1
R2
E2
HO
R2
R1
4a-h
3a-d
5
3
4
Me
Me
iBu
Me
Me
Me
Me
Me
3c
dr 95:5
3d
3a
dr 95:5
3b
dr 95:5
dr 65:35:5:0
Mechanistic hypothesis for n = 1
CH3
R3
CH3
HO
R1
R2
R3
R3
Cp2ZrBu2
R1
R2
E2-X
R1
R2
R3COR3
E2
[Zr]
R1
[Zr]
R3
O
[Zr]
R2
R1
R2
XV
4
XIII
Selective
XIV
Allylic C-H
mono C-C bond
cleavage
bond activation
[Zr] = Cp2Zr
Scope
Pr
Bu
Pr
Pr
Pr
Pr
Et
HO Et
Me
HO Me
D
H
Me
HO Me
Me
HO Me
Me
HO Me
Et
HO Et
H
D
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
4cd (from 3a)
79%
E1-X = EtCOEt
E2-X = D3O+
4d (from 3b)
4a (from 3a)
4ad (from 3a)
59%
E1-X = MeCOMe
E2-X = D3O+
4b (from 3a)
4c (from 3a)
76%
E1-X = EtCOEt
E2-X = H3O+
62%
64%
66%
E1-X = MeCOMe
E2-X = H3O+
E:Z = > 98:2, ds > 98:2
E1-X = MeCOMe
E2-X = H3O+
E:Z = > 98:2, ds > 98:2
E1-X = MeCOMe
E2-X = AllylBr
E:Z = > 98:2, ds 95:5
E:Z = > 98:2, ds 90:10
E:Z = > 98:2, ds > 98:2
E:Z = > 98:2, ds 95:5
Bu
Pent
Me
Me
Me
Me
Me
HO Me
Me
HO Me
H
H
HO Me
HO Me
Me
Me
Me
Me
Me
Me
iBu
iBu
4e (from 3b)
77%
4f (from 3c)
4g (from 3d)
82%
4h (from 3d)
79%
70%
E1-X = MeCOMe
E2-X = H3O+
E1-X = MeCOMe
E2-X = AllylBr
E1-X = MeCOMe
E2-X = H3O+
E1-X = MeCOMe
E2-X = AllylBr
E:Z = > 98:2, ds > 98:2
E:Z = > 98:2, ds 90:10
E:Z = > 98:2, ds 98:2
E:Z = > 98:2, ds > 98:2
The presence of the remaining sp3 carbon–zirconium bond strategies. As previously observed with alkenyl cyclopro-
enabled the subsequent functionalization by deuterolysis panes (see Scheme 7), the addition of aldehyde such as iso-
(formation of 4ad) or by an allylation reaction after butyraldehyde also proceeded smoothly, although without
transmetalation with a catalytic amount (10 mol%) of any diastereocontrol (stereochemistry at the carbinol center
CuI2LiCl (formation of 4b). This tandem sequence was is not controlled as already depicted in Scheme 7, com-
pound not reported in Scheme 9). Following the develop-
ment of this straightforward approach for a selective mono–
C–C bond cleavage, we then turned our attention to pro-
mote the second C–C bond cleavage to provide potentially
the diene (5). All our attempts to directly cleave the two
applied to various –ene alkenyl spiro[2.2]pentanes 3a–d
and as previously discussed, longer alkyl chain between the
strained ring –namely here the spiro[2.2]pentane unit– and
the unsaturation’s relative positioning did not hamper the
overall transformation. Yields resulting from the isomeriza-
tion followed by the selective mono– C–C bond cleavage of rings of the spiro[2.2]pentane failed as the ––zirconocene
3a, 3b and 3c (with n = 3, 4 and 5 respectively) were indeed complex XIV resulting from the first scission did not induce
comparable. This approach allowed the formation of 1,1,2,2– the desired second ring–cleavage, most probably due to
(E)–vinyltetrasubstituted cyclopropanes motifs seemingly rotational constraints. We presumed that a suitable solution
challenging to prepare otherwise via more conventional
would be to disengage the zirconocene complex from its –
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system after addition of the first electrophile. The gained
flexibility should then allow rotations over the C–Zr bond,
required to optimally perform the second C–C bond cleav-
age.
1
2
3
4
5
6
7
8
We initially observed that the reaction led to the expected
second ring–cleavage product 5a, albeit in very low yield,
when the complete sequence of isomerization – first C–C
bond fragmentation and reaction with acetone were per-
formed in THF (Table 1, entries 1 and 2). This result under-
lined that a more polar solvent might be required to weaken
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60
the presumed aggregate described in XV and induce the
second ring fragmentation. However, THF was clearly not
an appropriate solvent for the zirconium–walk reaction
(Table 1, entry 2) and Et2O was used as solvent for all subse-
quent studies. We then further screened the influence of
various parameters to promote the second ring–opening of
the intermediate XV (Table 1). Adding THF or 2-MeTHF as
cosolvent after the first ring–opening and heating the reac-
tion mixture slightly increased the ratio in favor of the dou-
ble–opening product (Table 1, entries 3 and 4). To further
weaken the O–[Zr] bond, we then opted for additives to
transmetalate the C–[Zr] bond. Addition of a Lewis base,
such as MeLi, in the reaction mixture to produce an expect-
edly more reactive “organozirconate” complex (Table 1, en-
try 5) or adding Zn(II) salts to promote a transmetalation
into an alkylzinc species (Table 1, entry 6) did not signifi-
cantly lead to the desired second cyclopropane ring–opening
reaction. Only the addition of a Lewis acid such as TMSCl at
room temperature proved to be beneficial (Table 1, entry 7).
Heating the reaction mixture to reflux over 12 hours led to a Various –ene spiro[2.2]pentanes 3a,b,d were then subject-
complete full ring–opening of the initial spiro[2.2]pentane ed to these optimized conditions (Scheme 10). As previously
substrate (Table 1, entry 8). Whereas TMSOTf induced the mentioned, the reaction proceeded invariably of the chain
elimination of the alcohol moiety in 5a (Table 1, entry 9), length (n = 1 to 4) affording adducts 5 after reaction with a
BF3OEt2 was eventually found to be the most efficient Lew-
is acid affording the desired 4,6–diene 5a in satisfactory
yields and with still an excellent E–selectivity (Table 1, en-
tries 10 and 11).
ketone followed by hydrolysis with excellent E/Z ratios.
Therefore, through the development of these two protocols
(see Schemes 9 and 10), spiro[2.2]pentane motifs could
modularly and selectively undergo either one or two ring–
opening events to respectively yield vinyl cyclopropanes (4)
or 1,3-dienes structure valuable for further reactions (5).
Table 1. Screening of experimental conditions for the
induction of the second ring–opening mode converting
ω–ene spiro[2.2]pentane 3a into diene 5a.
Scheme 10. Scope of the remote and selective double
ring–opening of ω– ene spiro[2.2]pentane
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2.4. Reactivity of ω–ene–cyclopropanes possessing a duce the isomerization of the double bond to release the
leaving group. Similar isomerization/carbocycle fragmen- strain. The resulting zirconacyclopropane would then un-
1
2
3
4
5
6
7
8
dergo a selective C1–C3 bond cleavage (Scheme 12) to give the
tation sequence could also be applied to –ene cyclopro-
previously mentioned intermediate III (Scheme 1) for the
pane possessing a strategically positioned leaving group (in
this case, a methoxy moiety), by taking advantage of the transformation of –ene cyclopropanes 1 into acyclic frag-
zirconocene inherent strong oxophilicity. When diastereo- ments 2. To further probe our mechanistic understanding,
pure cyclopropyl methyl ethers 6, also potentially obtained we used the allylic CD3–labelled 8e as starting ACP and the
enantiomerically enriched,15 were treated with the Negishi product resulting from this combined allylic C–H bond acti-
reagent, a sequence of isomerization followed by a C–C vation and C–C bond cleavage gave 2s in excellent yield
bond fragmentation39 as depicted in XVII gave the corre- possessing two deuterium atoms at the allylic and one deu-
sponding allylzirconocene species and after acetolysis, the terium atom at the vinylic positions supporting our mecha-
dienes 7 with an excellent E:Z ratio as described in Scheme nistic hypothesis. In all cases, the combined allylic C–H
11. Owing to the potential steric repulsions between the Cp bond activation followed by the selective C1–C3 bond cleav-
groups of the zirconocene and the quaternary stereocenter, age proceeded smoothly to afford a large variety of linear
we hypothesized that the allylzirconocene XVIII should be products 2o–2q in excellent yields. As enantiomerically en-
the predominant isomer among all the possible haptotropic riched ACPs are easily accessible41 and because the quater-
forms. Surprisingly, only acetolysis provided a good selectiv- nary carbon stereocenter is at no risk of epimerization dur-
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10
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60
ing the process, the optical purity of 2r was assumed to be
identical from its ACP precursor 8d. When enantiomerically
enriched 8d (er 98:2)41c-e was treated under our experimental
conditions, the acyclic product 2r possessing the quaternary
carbon stereocenter was indeed obtained in excellent yields
as unique E–isomer. The enantiomeric ratio of (2E,4R)–4–
ethyl–4–methyl–octene 2r was determined by correlation
with an authentic sample.46 As expected, 2r was obtained
with the same enantiomeric ratio (er 98:2) than the starting
material 8d confirming that the overall reaction proceeds
without altering the stereochemistry of the quaternary car-
bon stereocenter. By a hydrogenation reaction of the double
bond of 2r, the simplest crypto–optically active saturated
hydrocarbon 10 with a quaternary carbon stereocenter was
successfully prepared.47 Our strategy appears to be an ap-
pealing alternative to those previously reported in this re-
gard.47
ity for the protonation reaction at the–position as addition
of H3O+ gave a mixture of  and –isomers. A concerted
allylic protonation as depicted in Scheme 11 could potential-
ly explain the positional selectivity of the olefin. Several –
ene cyclopropyl carbinol methyl ethers 6 were subjected to
these conditions and in all cases unconjugated dienes 7a–d
were obtained with excellent positional selectivity of the
internal double bond.17g This reaction was not restricted to
short alkenyl chain (n = 1) as longer alkyl chain (n= 3) also
successfully led to the unconjugated diene 7d in a good yield
although with a slightly lower E/Z ratio.
Scheme 11. Remote and selective cleavage of C–C and
C–O bonds in cyclopropyl carbinol methyl ethers. Rep-
resentative examples are described. For the full list,
see reference 17g
Scheme 12. Isomerization followed by C–C bond cleav-
age of ACPs. Representative examples are described.
For the full list, see reference 17g
2.5. Reactivity of alkylidenecyclopropanes. We also ex-
tended this strategy to a different family of small strained
ring derivatives, namely alkylidenecyclopropane (ACPs)
species.40,41 These substrates should be excellent candidates
for this transformation as we have already reported the met-
al–catalyzed hydroboration,42 hydrostannylation,43 hydrosi-
lylation44 and hydroformylation45 reactions with selective
ring–opening of the cyclopropyl ring. Based on the high
reactivity of the exoalkylidene moiety of ACPs,44 we reck-
oned that the Negishi zirconocene species should first in-
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originate from a backward chain–walking process. However,
1
2
3
4
5
6
7
8
this hypothesis was also not supported by the calculations
as no difference was found between the two substrates.
Although it could not be fully computationally confirmed
due to the very large conformational space to consider for a
large number of isomers of similar energies involved in the
various isomerisations, the phenyl moiety most likely pre-
vented (or enabled) specific rotations to occur, allowing the
metal center to switch from one diastereotopic face to an-
other.48
9
10
11
12
13
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17
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60
Scheme 13. Diastereoselective reaction with ACPs
3. CONCLUSION
Finally, we were interested to use ACPs to create a new and
In summary, several approaches using organozirconocene
species for the remote cleavage of strained three–membered
ring carbocycles such as –ene polysubstituted cyclopro-
panes, alkylidenecyclopropanes, –ene spiro[2.2]pentanes
and –ene cyclopropyl methyl ethers, into stereodefined
organometallic intermediates were successfully developed to
access highly stereoenriched acyclic scaffolds in good yields.
All of these protocols formally enable the C–C or/and C–O
bonds activation distant from the original olefin through a
cascade of well–controlled chemical events.49 These result-
ing acyclic products including stereocenters were readily
obtained with excellent selectivities in most cases. DFT
calculations and isotopic labeling were performed to deline-
ate the nature of the organometallic intermediates and the
origin of the stereoselectivities. Remarkably, the large num-
ber of fast and reversible isomerizations involved in these
transformations contribute to a highly stereoselective reac-
tion which is in turn under thermodynamic control. This
was shown to be in the –ene cyclopropane and also sug-
gested for the alkylidenecyclopropanes. By showing the
extended scope and limitations of these zirconocene–based
transformations, we hope to further illustrate the power of
such cascade reactions, prospectively useful for the elabora-
tion of complex hydrocarbon acyclic scaffolds. Efforts to
develop similar conceptual synthetic strategies in a catalytic
distant stereogenic center (1,4–relationship from the initial
quaternary carbon stereocenter). When ACP 8a, possessing
two different alkyl groups at the quaternary stereocenter,
was treated in our experimental conditions, the product 2t
was obtained in excellent yield as a single E–isomer but as
two diastereoisomers in a 1:1 ratio (Scheme 13, path a).
Nonetheless, for substrates possessing a phenyl moiety at
the quaternary center of the alkylidenecyclopropane
(Scheme 13, path b), the reaction led to an excellent dia-
stereoselectivity as 2u was obtained in an excellent diaster-
eoisomeric ratio of above 98:2 (77% yield). Several acyclic
products 2v–2x were also remarkably produced with similar
excellent selectivities. The dramatic effect of the presence of
this phenyl moiety was computationally investigated. Con-
sidering the minimum steric difference between the two
alkyl groups (Me and Et) of 8a, one could hypothesized that
the two faces of the ACP were equally accessible for reac-
tion with the zirconocene complex while one of the two
faces of 8c was preferred when an aryl group was present.
However, this hypothesis was not supported by the DFT
calculations as the coordination of the two faces with the
zirconocene reagent for 8a as well as for 8b was found to be
energetically equivalent with ΔΔrG° ≤ 0.8 kcal mol-1. As the
coordination essentially proceeds equally on the two faces,
we then imagined that the lowest energy pathway could
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fashion are currently being carried out in our laboratory. indicator. All organomagnesium reagent solutions in dieth-
Most importantly, through this work, we hope to inspire yl ether were homemade and prepared according to stand-
other synthetic chemists to grasp all the potential of imple- ard procedures, except for methylmagnesium bromide solu-
menting remote disconnections in their retrosynthetic tion (3 M in diethyl ether) which was purchased from Al-
1
2
3
4
5
6
7
8
planning.
drich. Grignard solutions were regularly titrated under ar-
gon atmosphere by 1 M solution of 2-isobutanol in toluene,
using 2,2’-biquinoline as indicator. All the reagents used for
the preparation of starting materials were purchased from
commercial suppliers and used without further purification
except for oxalyl chloride which was distilled prior to use.
Ketone and aldehyde compounds, allyl bromide, benzoyl
chloride and iodobenzene were purchased from commercial
suppliers and distilled prior to use under an atmosphere of
argon as follows: acetone was distilled from CaSO4, diethyl
ketone was distilled from P2O5, cyclohexanone, cyclopenta-
none were distilled from MgSO4, allyl bromide, benzoyl
chloride, benzaldehyde, mesitaldehyde and iodobenzene
were distilled from CaCl2. Propargyl bromide solution (80
wt.% in toluene), 4-methylcyclohexanone, 4-tert-
butylcyclohexanone, N-(diphenylphosphinyl)benzaldimine
were commercially obtained and used as received.
EXPERIMENTAL SECTION
General comments
All reactions were carried out under an atmosphere of ar-
gon, with flame-dried flasks under positive pressure of argon
and with dry, oxygen-free solvents using standard Schlenk
techniques. All organometallic compounds, dry solvents and
other air or moisture sensitive reagents were transferred
using plastic single-use graduated syringes and oven-dried
stainless steel needles. Progress of the reactions was moni-
tored by analytical TLC using glass plates precoated with
silica gel with F254 indicator (Merck). Visualization of spots
was done using phosphomolybdic acid, p-anisaldehyde or
potassium permanganate stains followed by heating. Frontal
ratios (Rf) of synthesized compounds were determined from
the reaction crude by analytical TLC using glass plates pre-
coated with silica gel with F254 indicator (Merck). Purifica-
tion of crude mixtures was accomplished by column chro-
matography on silica gel 60 Å (GraceResolv) using gradients
mixture n-pentane / diethyl ether, n-hexane / diethyl ether
or pure pentane or hexane.
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Starting materials and products
ω-ene cyclopropanes 1a-h were prepared using previously
reported procedures.15n,17c,17e,17g ω-ene cyclopropyl methyl
ethers 6 were synthesized from their corresponding already
well-charaterized ω-ene cyclopropyl carbinol derivatives17a
through a standard nucleophilic substitution using NaH and
iodomethane. Alkylidenecyclopropanes 8a-d were obtained
according to a synthetic route previously reported.17c,17f,17j All
analytic data of the compounds 2a-c17g 2d-n,17e 2o-x17g and
7a-d17g, 1017g can be found in the literature.
13
1H and C NMR spectra were measured on Brucker Avance
AV200 (200 MHz H, 50 MHz 13C), Brucker Avance AV300
1
(300 MHz H, 75 MHz 13C), Brucker Avance AV400 (400
1
MHz 1H, 101 MHz C) spectrometer in CDCl3 and referenced
13
to TMS. Chemical shifts values (δ) are reported in ppm (cal-
ibration of spectra to the residual peak of CDCl3: δ = 7.26
Preparation of starting materials 3a-d
1
13
ppm (s) for H NMR; δ = 77.16 ± 0.06 ppm for C NMR). All
the proton spectra reported as following: δ value (multiplici-
ty, J coupling constant in Hz, number of nuclei). Multiplicity
contractions used: (bs) – broad singlet, (d) – doublet, (dd) –
doublet of doublet, (ddd) – doublet of doublets of doublets,
(ddt) - doublet of doublet of triplets, (dddt) – doublet of
doublets of doublets of triplets, (dt) – doublet of triplets,
(m) – multiplet, (t) – triplet, (td) – triplet of doublets, (tq) –
triplet of quartets, (tt) – triplet of triplets, (q) – quartet, (s) –
singlet, (p) – quintuplet. E/Z and diastereomeric ratios were
evaluated by 1H and 13C NMR analysis respectively.
General procedure for the synthesis of homoallenyl alcohols
IIa-c
Homoallenyl alcohols IIa,b were prepared from the corre-
sponding commercially available propargyl alcohols Ia,b
using a previously reported procedure.50
General procedure for the synthesis of 2-(spiro[2.2]pentan-1-
yl)ethanols IIIa,b
Into a flame-dried three-neck flask, equipped with a stir bar,
a low temperature thermometer, a rubber septum and an
inert gas inlet, a diethyl zinc solution 1.0 M in hexanes (4
equiv.) was added to anhydrous DCM (5 mL for 1 mmol of
II) at 0 °C under argon atmosphere and the resulting mix-
ture was stirred for 5 min at this temperature. Freshly dis-
tilled trifluoroacetic acid (TFA) was thereafter added drop-
wise (CAREFUL: exothermic and gas production) at that
temperature and the mixture was stirred at 0 °C for 30 min.
Diiodomethane (4 equiv.) was then added dropwise to the
reaction mixture while maintaining the internal tempera-
ture at 0 °C. After completion of the addition, the resulting
solution was stirred for an additional 30 min period at 0 °C.
A dry DCM solution of the homoallenyl alcohol II (1 equiv., 1
mL for 1 mmol of II) was then added via syringe while main-
taining the internal temperature under 0° C at all time. The
reaction mixture was allowed to warm-up slowly to room
temperature and was stirred for 12 h under an inert atmos-
phere. After completion of the reaction mixture, the reac-
Electrospray ionization mass spectrometry analyses were
obtained on a APCI instrument by Maxis Impact (Bruker)
and on a LCT Premier (Waters).
Solvents and reagents
THF and diethyl ether (HPLC grade, non-stabilized, BioLab)
were dried using Innovative Technology PureSolv PS-MD-2
solvent purifier (aluminum oxide columns) and kept under
positive pressure of nitrogen (99.9999% purity grade).
Bis(cyclopentadienyl)zirconium(IV) dichloride, copper(I)
iodide, copper(I) chloride and copper(I) bromide dimethyl
sulfide complex were purchased from ACROS, Aldrich or
Alfa Aesar and used as received. n-Butyllithium solution in
hexanes (1.6 M) was commercially obtained from Aldrich
and regularly titrated under argon atmosphere by 1 M solu-
tion of 2-isobutanol in toluene, using 1,10-phenantroline as
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The Journal of Organic Chemistry
tion was quenched with a 1 M HCl solution. The layers were at 0 °C and the resulting mixture was further stirred for
separated and the aqueous phase was extracted with DCM another 2 h period. The reaction was lastly quenched with a
(three times). The combined organic fractions were dried 0.1 M-HCl solution. The layers were separated and the aque-
over MgSO4, filtered and concentrated under reduced pres- ous layer was extracted with Et2O (twice). The combined
sure. The products IIIa,b were isolated by silica-gel chroma- organic fractions were washed with brine, dried over
1
2
3
4
5
6
7
8
tography (SiO2, n-hexane / EtOAc, 90:10).
MgSO4, filtered and concentrated under reduced pressure.
The product IVb was purified by silica-gel chromatography
(SiO2, or n-hexane / Et2O, 70:30) and directly engaged into
the next reaction.
Typical procedure for the synthesis of IVa
Into a flame-dried 250-mL three-neck flask, equipped with a
stir bar, a low temperature thermometer, a rubber septum
and an inert gas inlet, dry DMSO (2.1 mL, 30.1 mmol), dilut-
9
General procedure for the synthesis of 3a, 3b and 3c
10
11
12
13
14
15
16
17
18
19
20
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22
23
24
25
26
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35
36
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43
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47
48
49
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ed in dry DCM (5 mL), was added to a dry DCM solution A flame-dried three-neck flask equipped with a stir bar, a
(150 mL) of oxalyl chloride (1.9 mL, 22.5 mmol) at – 78 °C low temperature thermometer, a rubber septum and an
under an inert atmosphere. After a 10-min stirring period at inert gas inlet was charged with CuBr.DMS (0.1 equiv.) and a
-78 °C, a dry DCM solution (7 mL) of alcohol IIIa (2.770 g, dry Et2O solution (10 mL for 1 mmol of substrate) of the
15.03 mmol) was added dropwise while maintaining the mesylate compound IVb or IVc (1.0 equiv.). The reaction
stirred reaction mixture at -78 °C. After 15-min stirring peri- mixture was allowed to stir for 10 min at 0 °C (ice bath) un-
od at 78 °C, freshly distilled Et3N (11.53 mL, 82.67 mmol) was der an inert atmosphere. An Et2O solution of alkenylmagne-
added dropwise and the reaction mixture was stirred at -78 sium bromide (2 equiv.) was then added dropwise at 0 °C
°C for an additional 30-min period and then warmed-up to and the resulting black solution was stirred at room temper-
room temperature for 6 h. The reaction was lastly quenched ature for 2 h under an inert atmosphere. After completion of
with a saturated aqueous NaHCO3 solution. The layers were the reaction, it was quenched with a saturated aqueous
separated and the aqueous phase was extracted with Et2O NH4Cl solution at 0 °C. The layers were separated and the
(twice). The combined organic fractions were washed with aqueous phase was extracted with Et2O (twice). The com-
brine, dried over MgSO4, filtered and concentrated under bined organic fractions were washed with brine, dried over
reduced pressure. The crude was purified by silica-gel chro- MgSO4, filtered and concentrated under reduced pressure
matography (SiO2, n-hexane / Et2O, 90:10) to afford IVa, (CAUTION: the compounds are volatile). The products 3a,
which was rapidly engaged into the next reaction (decompo- 3b, 3c were isolated by silica-gel chromatography (SiO2, n-
sition over time).
pentane, 100%).
Typical procedure for the synthesis of 3d
Into a flame-dried 250-mL three-neck flask, equipped with a General procedure for the synthesis of 2 from ω-ene-
stir bar, a low temperature thermometer, a rubber septum cyclopropanes 1
and an inert gas inlet, a dry THF solution of t-BuOK (2.657
General procedure for the synthesis of 2a-b from 1a-b
g, 23.68 mmol) was added to a Ph3PMeBr (8.459 g, 23.68
A flame-dried 50-mL three-neck flask equipped with a stir
mmol) suspension in dry THF (240 mL) at -20 °C under an
bar, a low temperature thermometer, a rubber septum and
inert atmosphere. After 2 h-stirring period at a temperature
an
inert
gas
inlet
was
charged
with
between -20 and -5 °C, a dry THF solution of aldehydic
compound IVa (2.158 g, 11.84 mmol) was added dropwise at -
5 °C. The reaction mixture was allowed to warm-up to room
temperature and after 12 h, the reaction was quenched with
a saturated aqueous NaHCO3 solution. The layers were sepa-
rated and the aqueous phase was extracted with Et2O
(twice). The combined organic fractions were washed with
brine, dried over MgSO4, filtered and concentrated under
reduced pressure (CAUTION: the compound is volatile).
The crude was purified by silica-gel chromatography (SiO2,
n-pentane, 100%) to afford 3d as a colorless oil (1.309 g,
62%).
bis(cyclopentadienyl)zirconium dichloride (292.0 mg, 1.0
mmol) and dry Et2O (10 mL) under an inert atmosphere.
After cooling down the stirred reaction suspension to -78 °C,
a solution of n-butyllithium (1.6 M in hexanes, 1.25 mL, 2.0
mmol) was added dropwise at that temperature. After stir-
ring for 1 hour at -78 °C, a 2 mL dry Et2O solution of sub-
strate 1a-b (0.5 mmol) was added dropwise to the solution at
-78 °C and the resulting mixture was allowed to slowly
warm-up to room temperature overnight (12 h) at which
time the reaction mixture was a yellow-orange suspension.
An aqueous solution of 1M HCl (or DCl) was then added and
the phases were separated. The aqueous phase was extracted
with Et2O (5 times). The combined organic fractions were
General procedure for the synthesis of IVb
A flame-dried three-neck flask equipped with a stir bar, a washed with an aqueous saturated NaHCO3 solution and
low temperature thermometer, a rubber septum and an brine, dried over Na2SO4, filtered and concentrated under
inert gas inlet was charged with 4-(dimethylamino)pyridine reduced pressure. The products 2a-b were isolated by silica-
(0.25 equiv.) and a dry DCM (10 mL for 1 mmol of III) solu- gel chromatography (SiO2, n-pentane or n-hexane, 100%).
tion of the spiropentane alcohol IIIb (1.0 equiv.). The reac-
Typical procedure for the synthesis of 2c from 1c
tion mixture was allowed to stir for 15 min at 0 °C (ice bath)
A flame-dried 50-mL three-neck flask equipped with a stir
under an inert atmosphere. Freshly distilled Et3N (2 equiv.)
bar, a low temperature thermometer, a rubber septum and
was then added dropwise to the reaction mixture at 0 °C and
the resulting solution was stirred for 10 min at 0 °C. Me-
thanesulfonyl chloride (2.5 equiv.) was then added dropwise
an
inert
gas
inlet
was
charged
with
bis(cyclopentadienyl)zirconium dichloride (292.0 mg, 1.0
13
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The Journal of Organic Chemistry
mmol) and dry Et2O (10 mL) under an inert atmosphere. an inert
Page 14 of 23
with
gas
inlet
was
charged
1
After cooling down the stirred reaction suspension to -78 °C, bis(cyclopentadienyl)zirconium dichloride (496.9 mg, 1.7
a solution of n-butyllithium (1.6 M in hexanes, 1.25 mL, 2.0 mmol) and dry Et2O (10 mL) under an inert atmosphere.
mmol) was added dropwise at that temperature. After stir- After cooling down the stirred reaction suspension to -78 °C,
ring for 1 hour at -78 °C, a 2 mL dry Et2O solution of sub- a solution of n-butyllithium (1.6 M in hexanes, 2.13 ml, 3.4
strate 1h (97.2 mg, 0.5 mmol) was added dropwise to the mmol) was added dropwise at that temperature. After stir-
solution at -78 °C and the resulting mixture was allowed to ring for 45 min at -78 °C, a 2 mL dry Et2O solution of 1e-f (1
slowly warm-up to room temperature overnight (12 h). The mmol) was added dropwise to the solution at -78 °C and the
first electrophile, freshly distilled acetone (57 µL, 1.25 mmol) resulting mixture was allowed to slowly warm-up to room
was added dropwise after cooling down the reaction mixture temperature over 5.5 12 hours at which time the reaction
to -30 °C and the resulting solution was allowed to stir for 1 mixture was a yellow-orange suspension. Dry THF (40 mL)
hour at that temperature. The second electrophile, iodine was then added to the reaction mixture and the resulting
(634.5 mg, 2.5 mmol) in dry Et2O (5 mL) was then added at 0 solution was heated at 55 °C for 3 hours. The freshly distilled
°C and the reaction mixture was stirred for additional 1 hour first electrophile (3.0 mmol) was added dropwise after cool-
at that temperature. Finally, the reaction mixture was hy- ing down the reaction mixture to 0 °C and the resulting
drolyzed with an aqueous solution of 1M HCl. The layers solution was allowed to stir for 2 hours at that temperature.
were separated and the aqueous phase was extracted with Finally, the reaction mixture was hydrolyzed with an aque-
Et2O (5 times). The combined organic fractions were washed ous solution of 1M HCl. The layers were separated and the
with a saturated aqueous solution of Na2S2O3, brine, dried aqueous phase was extracted with Et2O (3 times). The com-
over Na2SO4, filtered and concentrated under reduced pres- bined organic fractions were washed with brine, dried over
sure. Purification by silica-gel chromatography using gradi- MgSO4, filtered and concentrated under reduced pressure.
ent mixtures of ethyl acetate and n-hexane as eluents af- Products 2e-f were isolated by silica-gel chromatography
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
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26
27
28
29
30
31
32
33
34
35
36
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39
40
41
42
43
44
45
46
47
48
49
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53
54
55
56
57
58
59
60
forded 2c as a colorless oil (101 mg, 53% yield).
(SiO2, n-pentane / Et2O, 80:20 – 90:10).
Typical procedure for the synthesis of 2d from 1d
Typical procedure for the synthesis of 2g from 1g
A flame-dried 100-mL three-neck flask equipped with a stir A flame-dried 100-mL three-neck flask equipped with a stir
bar, a low temperature thermometer, a rubber septum and bar, a low temperature thermometer, a rubber septum and
an
inert
gas
inlet
was
charged
with an
inert
gas
inlet
was
charged
with
bis(cyclopentadienyl)zirconium dichloride (496.9 mg, 1.7 bis(cyclopentadienyl)zirconium dichloride (496.9 mg, 1.7
mmol) and dry Et2O (10 mL) under an inert atmosphere. mmol) and dry Et2O (10 mL) under an inert atmosphere.
After cooling down the stirred reaction suspension to -78 °C, After cooling down the stirred reaction suspension to -78 °C,
a solution of n-butyllithium (1.6 M in hexanes, 2.13 ml, 3.4 a solution of n-butyllithium (1.6 M in hexanes, 2.13 ml, 3.4
mmol) was added dropwise at that temperature. After stir- mmol) was added dropwise at that temperature. After stir-
ring for 45 min at -78 °C, a 2 mL dry Et2O solution of sub- ring for 45 min at -78 °C, a 2 mL dry Et2O solution of 1g
strate 1d (180.4, 1 mmol) was added dropwise to the solution (180.3 mg, 1 mmol) was added dropwise to the solution at -
at -78 °C and the resulting mixture was allowed to slowly 78 °C and the resulting mixture was allowed to slowly warm-
warm-up to room temperature (over 5.5 hours if n = 1 and 12 up to room temperature over 5.5 hours at which time the
hours if n = 3) at which time the reaction mixture was a reaction mixture is a yellow-orange suspension. Dry THF
yellow-orange suspension. Dry THF (40 mL) was then added (40 mL) was then added to the reaction mixture and the
to the reaction mixture and the resulting solution was heat- resulting solution was heated at 55 °C for 3 hours. Freshly
ed at 55 °C for 3 hours. Freshly distilled acetone (220 µL, 3.0 distilled acetone (220 µL, 3.0 mmol) was added dropwise
mmol) was added dropwise after cooling the reaction mix- after cooling down the reaction mixture to 0 °C and the
ture to 0 °C and the resulting solution was allowed to stir for resulting solution was allowed to stir for 2 hours at that
2 hours at that temperature. The second electrophile, iodine temperature. The second electrophile, freshly distilled allyl
(1.269 g, 5.0 mmol) in dry THF (5 mL) was then added at 0 bromide (5.0 mmol, 433 µL), was added to the solution to 0
°C and the resulting mixture was stirred for additional 2 °C, followed by the addition at that temperature of a dry
hours at that temperature. Finally, the reaction mixture was THF solution (3 mL) of CuI (19.1 mg, 0.1 mmol) and flame-
hydrolyzed with an aqueous solution of 1M HCl. The layers dried LiCl (8.5 mg, 0.2 mmol). The resulting mixture was
were separated and the aqueous phase was extracted with allowed to stir at 55 °C for 2 hours at which time it was
Et2O (3 times). The combined organic fractions were washed quenched with an aqueous solution of 1M HCl. The layers
with a saturated aqueous solution of Na2S2O3, brine, dried were separated and the aqueous phase was extracted with
over MgSO4, filtered and concentrated under reduced pres- Et2O (3 times). The combined organic fractions were washed
sure. Purification by silica-gel chromatography (SiO2, n- with brine, dried over MgSO4, filtered and concentrated
pentane / Et2O, 90:10) afforded 2d as a yellow oil (208 mg, under reduced pressure. The crude was purified by silica-gel
57%).
chromatography (SiO2, n-pentane / Et2O, 80:20) to afford 2g
as a light yellow oil (157 mg, 56% yield).
Typical procedure for the synthesis of 2h from 1d
General procedure for the synthesis of 2e-f from 1e-f
A flame-dried 100-mL three-neck flask equipped with a stir
bar, a low temperature thermometer, a rubber septum and
A flame-dried 100-mL three-neck flask equipped with a stir
bar, a low temperature thermometer, a rubber septum and
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The Journal of Organic Chemistry
charged with fied by silica-gel chromatography (SiO2, n-pentane / Et2O,
an
inert
gas
inlet
was
1
2
3
bis(cyclopentadienyl)zirconium dichloride (447.3 mg, 1.53 80:20-60:40).
mmol) and dry Et2O (10 mL) under an inert atmosphere.
Typical procedure for the synthesis of 2i from 1g
After cooling down the stirred reaction suspension to -78 °C,
a solution of n-butyllithium (1.6 M in hexanes, 1.91 ml, 3.06
mmol) was added dropwise at that temperature. After stir-
ring for 45 min at -78 °C, a 2 mL dry Et2O solution of 1d
(153.3 mg, 0.85 mmol) was added dropwise to the solution at
-78 °C and the resulting mixture was allowed to slowly
warm-up to room temperature over 12 hours at which time
the reaction mixture was a yellow-orange suspension. Dry
THF (40 mL) was then added to the reaction mixture and
the resulting solution was heated at 55 °C for 3 hours. Fresh-
ly distilled acetone (315 µL, 4.25 mmol) was added dropwise
after cooling down the reaction mixture to 0 °C and the
resulting solution was allowed to stir for 2 hours at that
temperature. The second electrophile, propargyl bromide
(80wt% in toluene, 0.48 mL, 4.25 mmol) was added to the
solution at 0 °C, followed by the addition at that tempera-
ture of a dry THF solution (3 mL) of CuI (16.2 mg, 0.085
mmol) and flame-dried LiCl (7.2 mg, 0.17 mmol). The result-
ing mixture was allowed to stir at 55 °C for 3 hours at which
time it was quenched with an aqueous solution of 1M HCl.
The layers were separated and the aqueous phase was ex-
tracted with Et2O (3 times). The combined organic fractions
were washed with brine, dried over MgSO4, filtered and
concentrated under reduced pressure. The crude was puri-
fied by silica-gel chromatography (SiO2, n-pentane / Et2O,
80:20) to afford 2h as a yellow oil (126 mg, 53%).
A flame-dried 100-mL three-neck flask equipped with a stir
bar, a low temperature thermometer, a rubber septum and
4
5
6
7
8
9
an
inert
gas
inlet
was
charged
with
bis(cyclopentadienyl)zirconium dichloride (496.9 mg, 1.7
mmol) and dry Et2O (10 mL) under an inert atmosphere.
After cooling down the stirred reaction suspension to -78 °C,
a solution of n-butyllithium (1.6 M in hexanes, 2.13 ml, 3.4
mmol) was added dropwise at that temperature. After stir-
ring for 45 min at -78 °C, a 2 mL dry Et2O solution of 1g
(180.3 mg, 1 mmol) was added dropwise to the solution at -
78 °C and the resulting mixture was allowed to slowly warm-
up to room temperature over 5.5 hours at which time the
reaction mixture is a yellow-orange suspension. Dry THF
(40 mL) was then added to the reaction mixture and the
resulting solution was heated at 55 °C for 3 hours. Freshly
distilled acetone (220 µL, 3.0 mmol) was added dropwise
after cooling down the reaction mixture to 0 °C and the
resulting solution was allowed to stir for 2 hours at that
temperature. A dry THF solution (3 mL) of CuI (19,1 mg, 0.1
mmol) and flame-dried LiCl (8.5 mg, 0.2 mmol) was then
added, followed by the addition of iodobenzene (1.1 mmol,
123 µL) and Pd(PPh3)4 (115.5 mg, 0.1 mmol) solubilzed in dry
THF respectively at that temperature. The resulting mixture
was allowed to stir at 58 °C for 3.5 hours at which time it was
quenched with an aqueous solution of 1M HCl. The layers
were separated and the aqueous phase was extracted with
Et2O (3 times). The combined organic fractions were washed
10
11
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19
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45
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48
49
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55
56
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60
General procedure for the synthesis of 2i –j from 1g
A flame-dried 100-mL three-neck flask equipped with a stir with brine, dried over MgSO4, filtered and concentrated
bar, a low temperature thermometer, a rubber septum and under reduced pressure. The crude was purified by silica-gel
an
inert
gas
inlet
was
charged
with chromatography (SiO2, n-pentane / Et2O, 80:20) to afford 2i
bis(cyclopentadienyl)zirconium dichloride (496.9 mg, 1.7 as an orange oil (158 mg, 50%).
mmol) and dry Et2O (10 mL) under an inert atmosphere.
Typical procedure for the synthesis of 2l from 1g
After cooling down the stirred reaction suspension to -78 °C,
a solution of n-butyllithium (1.6 M in hexanes, 2.13 ml, 3.4
mmol) was added dropwise at that temperature. After stir-
ring for 45 min at -78 °C, a 2 mL dry Et2O solution of 1g
(180.3 mg, 1 mmol) was added dropwise to the solution at -
78 °C and the resulting mixture was allowed to slowly warm-
up to room temperature over 5.5 hours at which time the
reaction mixture is a yellow-orange suspension. Dry THF
(40 mL) was then added to the reaction mixture and the
resulting solution was heated at 55 °C for 3 hours. Freshly
distilled acetone (220 µL, 3.0 mmol) was added dropwise
after cooling down the reaction mixture to 0 °C and the
resulting solution was allowed to stir for 2 hours at that
temperature. A dry THF solution (3 mL) of CuI (19.1 mg, 0.1
mmol) and flame-dried LiCl (8.5 mg, 0.2 mmol) was then
added at 0 °C, followed by the addition of the corresponding
acid chloride (2.0 mmol) at that temperature. The resulting
mixture was allowed to stir at 55 °C for 3 hours at which
time it was quenched with an aqueous solution of 1M HCl.
The layers were separated and the aqueous phase was ex-
tracted with Et2O (3 times). The combined organic fractions
were washed with brine, dried over MgSO4, filtered and
concentrated under reduced pressure. The crude was puri-
A flame-dried 100-mL three-neck flask equipped with a stir
bar, a low temperature thermometer, a rubber septum and
an
inert
gas
inlet
was
charged
with
bis(cyclopentadienyl)zirconium dichloride (496.9 mg, 1.7
mmol) and dry Et2O (10 mL) under an inert atmosphere.
After cooling down the stirred reaction suspension to -78 °C,
a solution of n-butyllithium (1.6 M in hexanes, 2.13 ml, 3.4
mmol) was added dropwise at that temperature. After stir-
ring for 45 min at -78 °C, a 2 mL dry Et2O solution of 1g
(180.3 mg, 1 mmol) was added dropwise to the solution at -
78 °C and the resulting mixture was allowed to slowly warm-
up to room temperature over 5.5 hours at which time the
reaction mixture is a yellow-orange suspension. Dry THF
(40 mL) was then added to the reaction mixture and the
resulting solution was heated at 55 °C for 3 hours. Freshly
distilled propionaldehyde (215.1 µL, 3 mmol), used as first
electrophile, was added at -50 °C and the mixture was al-
lowed to stir for 2 h at that temperature. The reaction mix-
ture was quenched with an aqueous solution of 1M HCl. The
layers were separated and the aqueous phase was extracted
with Et2O (3 times). The combined organic fractions were
washed with a saturated aqueous solution of Na2S2O3, brine,
dried over MgSO4, filtered and concentrated under reduced
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The Journal of Organic Chemistry
Page 16 of 23
pressure. The crude was purified by silica-gel chromatog- A flame-dried 100-mL three-neck flask equipped with a stir
raphy (SiO2, n-pentane / Et2O, 90:10) to afford 2l as two bar, a low temperature thermometer, a rubber septum and
1
2
3
4
5
6
7
8
separated diastereomers (121 mg, 50%).
an
inert
gas
inlet
was
charged
with
bis(cyclopentadienyl)zirconium dichloride (496.5 mg, 1.7
mmol) and dry Et2O (45 mL) under an inert atmosphere.
After cooling down the stirred reaction suspension to -78 °C,
a solution of n-butyllithium (1.40 M in hexane, 2.4 mL, 3.4
mmol) was added dropwise at that temperature. After stir-
ring for 1 hour at -78 °C, a 5 mL dry Et2O solution of the
substrate 8c (172.3 mg, 1.0 mmol) was added dropwise to the
solution at -78 °C and the resulting mixture was allowed to
slowly warm-up to 10 °C overnight (13 h). Freshly distilled
acetone (184 µL, 2.5 mmol), serving as first electrophile was
added dropwise at 0 °C and the resulting solution was al-
lowed to stir for 6 hours at that temperature. The second
electrophile, iodine (1.02 g, 4.0 mmol) was then added at 10
°C and stirred for additional 3 hours at that temperature.
Finally, the reaction mixture was quenched at 0 °C with an
aqueous solution of 1M HCl. The layers were separated and
the aqueous phase was extracted with Et2O (twice). The
combined organic fractions were washed with a saturated
aqueous solution of Na2S2O3, brine, dried over MgSO4, fil-
tered and concentrated under reduced pressure. The crude
was purified by silica-gel chromatography (SiO2, n-hexane /
EtOAc, 95:5) to afford 2q as a yellow oil (258 mg, 72%).
General procedure for the study of the influence of the alde-
hyde on the dr
A flame-dried 100-mL three-neck flask equipped with a stir
bar, a low temperature thermometer, a rubber septum and
an
inert
gas
inlet
was
charged
with
bis(cyclopentadienyl)zirconium dichloride (496.9 mg, 1.7
mmol) and dry Et2O (10 mL) under an inert atmosphere.
After cooling down the stirred reaction suspension to -78 °C,
a solution of n-butyllithium (1.6 M in hexanes, 2.13 ml, 3.4
mmol) was added dropwise at that temperature. After stir-
ring for 45 min at -78 °C, a 2 mL dry Et2O solution of 1d
(180.3 mg, 1 mmol) was added dropwise to the solution at -
78 °C and the resulting mixture was allowed to slowly warm-
up to room temperature over 12 h hours at which time the
reaction mixture is a yellow-orange suspension. Dry THF
(40 mL) was then added to the reaction mixture and the
resulting solution was heated at 55 °C for 3 hours. The fresh-
ly distilled aldehyde (3 mmol), used as first electrophile, was
added at -50 °C and the mixture was allowed to stir for 2 h.
The second electrophile, iodine (1.269 g, 5.0 mmol) in dry
THF (5 mL) was then added at 0 °C and stirred for addition-
al 2 hours at that temperature. The reaction mixture was
quenched with an aqueous solution of 1M HCl. The layers
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
General procedure for the synthesis of 2u and 2x
were separated and the aqueous phase was extracted with A flame-dried 100-mL three-neck flask equipped with a stir
Et2O (3 times). The combined organic fractions were washed bar, a low temperature thermometer, a rubber septum and
with a saturated aqueous solution of Na2S2O3, brine, dried an
inert
gas
inlet
was
charged
with
over MgSO4, filtered and concentrated under reduced pres- bis(cyclopentadienyl)zirconium dichloride (496.5 mg, 1.7
sure. The diastereomeric ratios of 2m and 2n were finally mmol) and dry THF (45 mL) under an inert atmosphere.
determined on their respective crude by 13C NMR analyses. After cooling down the stirred reaction suspension to -78 °C,
a solution of n-butyllithium (1.4 M in hexanes, 2.4 mL, 3.4
mmol) was added dropwise at that temperature. After stir-
General procedure for the synthesis of 2 from alkyli-
ring for 1 hour at -78 °C, a 5 mL dry THF solution of the
denecyclopropanes 8
substrate 8a (R1 = Et) or 8e (R1 = Pr) (1.0 mmol) was added
General procedure for the synthesis of 2o-p from 8a-b
dropwise to the solution at -78 °C and the resulting mixture
was allowed to slowly warm-up to room temperature over-
night (13 h). The reaction was then heated at 60-65 °C for 5-
6 hours. Freshly distilled acetone (367.0 µL, 5.0 mmol), serv-
ing as first electrophile, was added dropwise to the reaction
mixture after cooling down the reaction at 10 °C and the
resulting solution was allowed to stir for 40 min at that
temperature. Finally, the reaction mixture was quenched at
10 °C with an aqueous solution of 1M HCl and the resulting
mixture was stirred for 1 hour. The layers were separated
and the aqueous phase was extracted with Et2O (twice). The
combined organic fractions were successively washed with
water, an aqueous saturated NaHCO3 solution and brine,
dried over MgSO4, filtered and concentrated under reduced
pressure. The products were isolated by silica-gel chroma-
tography (SiO2, n-hexane / EtOAc, 95:5 – 97:3) as unique
diastereomers.
A flame-dried 100-mL three-neck flask equipped with a stir
bar, a low temperature thermometer, a rubber septum and
an
inert
gas
inlet
was
charged
with
bis(cyclopentadienyl)zirconium dichloride (496.5 mg, 1.7
mmol) and dry Et2O (45 mL) under an inert atmosphere.
After cooling down the stirred reaction suspension to -78 °C,
a solution of n-butyllithium (1.4 M in hexanes, 2.4 mL, 3.4
mmol) was added dropwise at that temperature. After stir-
ring for 1 hour at -78 °C, a 5 mL dry Et2O solution of corre-
sponding substrate 8a-b (1.0 mmol) was added dropwise to
the solution at -78 °C and the resulting mixture was allowed
to slowly warm-up to 10 °C overnight (13 h). The reaction
mixture was thereafter quenched with an aqueous solution
of 1M-HCl at rt or DCl (1 M in D2O, 30 mL) at 0 °C. After
stirring for 2 hours, the layers were separated and the aque-
ous phase was extracted with Et2O (twice). The combined
organic fractions were successively washed with water, an
aqueous saturated NaHCO3 solution and brine, dried over
MgSO4, filtered and concentrated in vacuo. The products
were isolated by silica-gel chromatography (SiO2, n-hexane,
100%).
Typical procedure for the synthesis of 2v from 8e
A flame-dried 100-mL three-neck flask equipped with a stir
bar, a low temperature thermometer, a rubber septum and
an
inert
gas
inlet
was
charged
with
bis(cyclopentadienyl)zirconium dichloride (496.5 mg, 1.7
Typical procedure for the synthesis of 2q from 8c
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The Journal of Organic Chemistry
mmol) and dry THF (45 mL) under an inert atmosphere. Typical procedure for the synthesis of 10 from 2r
1
2
3
4
5
6
7
8
After cooling down the stirred reaction suspension to -78 °C,
a solution of n-butyllithium (1.4 M in hexanes, 2.4 mL, 3.4
In an autoclave, 2r (154.3 mg, 1 mmol) was dissolved in 5 mL
of Et2O. 1 mol% of Pd/C (10%) was added to the solution and
mmol) was added dropwise at that temperature. After stir-
the hydrogenation was performed under 3 atm of H2 over-
ring for 1 hour at -78 °C, a 5 mL dry THF solution of sub-
night. The solution was filtered over celite and the solvent
strate 8e (R1 = Pr) (186.3 mg, 1.0 mmol) was added dropwise
was evaporated. Compound 10 was obtained as colorless oil
to the solution at -78 °C and the resulting mixture was al-
lowed to slowly warm-up to room temperature overnight (13
h). The reaction was then heated at 60 °C for 6 hours. Para-
formaldehyde (124.1 mg, 4.0 mmol) as first electrophile was
added to the reaction mixture after cooling down the reac-
tion at 10 °C and the resulting solution was allowed to stir
for 2 hours at that temperature. Finally, the reaction mixture
was quenched at 10 °C with an aqueous solution of 1M HCl
and the resulting mixture was stirred for 1 hour. The layers
were separated and the aqueous phase was extracted with
Et2O (twice). The combined organic fractions were succes-
sively washed with water, an aqueous saturated NaHCO3
solution and brine, dried over MgSO4, filtered and concen-
trated under reduced pressure. The crude was purified by
silica-gel chromatography (SiO2, n-hexane / EtOAc, 96:4) to
afford 2v as a yellow oil (144 mg, 62%).
in 90% yield. All spectroscopic data of 10 was in agreement
with those previously reported.47
9
General procedure for the synthesis of 4 and 5 from ω-
ene-spiropentanes 3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
General procedure for the synthesis of 4a, 4ad, 4c, 4cd, 4d,
4f, 4g
A flame-dried 50-mL three-neck flask equipped with a stir
bar, a low temperature thermometer, a rubber septum and
an
inert
gas
inlet
was
charged
with
bis(cyclopentadienyl)zirconium dichloride (467.7 mg, 1.6
mmol) and dry Et2O (5 mL) under an inert atmosphere.
After cooling down the stirred reaction suspension to -78 °C,
a solution of n-butyllithium (1.0 M in hexanes, 3.2 mL, 3.2
mmol) was added dropwise at that temperature. After stir-
ring for 1 hour at -60 °C, a 5 mL dry Et2O solution of sub-
strate 3 (1.0 mmol) was added dropwise to the solution at -
78 °C and the resulting mixture was allowed to slowly warm-
up to room temperature overnight (12 h). The freshly dis-
tilled first electrophile (2.5 mmol) was added dropwise after
cooling down the reaction mixture to 0 °C and the resulting
solution was allowed to stir for 2.5 hour at that temperature.
Finally, the reaction mixture was hydrolyzed at 0 °C with an
aqueous solution of 1M HCl or DCl. The layers were separat-
ed and the aqueous phase was extracted with Et2O (3 times).
The combined organic fractions were washed with brine,
dried over MgSO4, filtered and concentrated under reduced
pressure. The products were isolated by silica-gel chroma-
tography (SiO2, n-hexane / EtOAc, 90:10).
Typical procedure for the synthesis of 2w from 8e
A flame-dried 100-mL three-neck flask equipped with a stir
bar, a low temperature thermometer, a rubber septum and
an
inert
gas
inlet
was
charged
with
bis(cyclopentadienyl)zirconium dichloride (496.5 mg, 1.7
mmol) and dry THF (45 mL) under an inert atmosphere.
After cooling down the stirred reaction suspension to -78 °C,
a solution of n-butyllithium (1.40 M in hexane, 2.4 mL, 3.4
mmol) was added dropwise at that temperature. After stir-
ring for 1 hour at -78 °C, a 5 mL dry THF solution of sub-
strate 8e (R1 = Pr) (186.3 mg, 1.0 mmol) was added dropwise
to the solution at -78 °C and the resulting mixture was al-
lowed to slowly warm-up to 10 °C overnight (13 h). Freshly
distilled acetone (294 µL, 4.0 mmol), serving as first electro-
phile was added dropwise at 10 °C and the resulting solution
was allowed to stir for 40 min at that temperature. The sec-
ond electrophile, iodine (1.269 g, 5.0 mmol) in dry THF (5
mL) was then added at 10 °C and stirred for additional 3
hours at that temperature. Finally, the reaction mixture was
quenched at 0 °C with an aqueous solution of 1M HCl. The
layers were separated and the aqueous phase was extracted
with Et2O (twice). The combined organic fractions were
washed with a saturated aqueous solution of Na2S2O3, brine,
dried over MgSO4, filtered and concentrated under reduced
pressure. The crude was purified by silica-gel chromatog-
raphy (SiO2, n-hexane / EtOAc, 97:3) to afford 2w as a yellow
oil (239 mg, 62% yield).
General procedure for the synthesis of 4b, 4e and 4h
A flame-dried 100-mL three-neck flask equipped with a stir
bar, a low temperature thermometer, a rubber septum and
an
inert
gas
inlet
was
charged
with
bis(cyclopentadienyl)zirconium dichloride (467.7 mg, 1.6
mmol) and dry Et2O (5 mL) under an inert atmosphere.
After cooling down the stirred reaction suspension to -78 °C,
a solution of n-butyllithium (1.0 M in hexanes, 3.2 ml, 3.2
mmol) was added dropwise at that temperature. After stir-
ring for 1 hour at -60 °C, a 2 mL dry Et2O solution of 3 (1
mmol) was added dropwise to the solution at -78 °C and the
resulting mixture was allowed to slowly warm-up to room
temperature overnight (13 h). The first electrophile, freshly
distilled acetone (184 µL, 2.5 mmol) was added dropwise
after cooling the reaction mixture to 0 °C and the resulting
solution was allowed to stir for 3 hours at that temperature.
The second electrophile, freshly distilled allyl bromide (5.0
mmol, 433 µL), was added to the solution to 0 °C, followed
by the addition at that temperature of a dry THF solution (3
mL) of CuI (19.1 mg, 0.1 mmol) and flame-dried LiCl (8.5
mg, 0.2 mmol). The resulting mixture was allowed to stir at
55 °C for 2 hours at which time it was quenched at 0 °C with
an aqueous solution of 0.1M HCl. The layers were separated
Determination of the enantiopurity of 2r via an ozonolysis
derivatization
Substrate 8d was prepared enantioenriched using a previ-
ously reported procedure.17g41c-e Enantioenriched compound
2r was synthesized using the same conditions as for 2o. An
ozonolysis reaction afforded the corresponding aldehyde
whose measured specific rotation was compared to the liter-
ature ([α]25 = + 5.00 (c = 10 mg/mL, CDCl3), er evaluated =
D
98:02).46
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The Journal of Organic Chemistry
Page 18 of 23
and the aqueous phase was extracted with Et2O (3 times). Characterization data of previously unreported com-
The combined organic fractions were washed with brine, pounds
1
2
3
4
5
6
7
8
dried over MgSO4, filtered and concentrated under reduced
pressure. The products were isolated by silica-gel chroma-
tography (SiO2, n-hexane / EtOAc, 90:10).
(3R*,6R*,E)-6-butyl-2,6-dimethyl-3-propyldeca-4,8,9-
trien-2-ol (2h). Yellow oil; 126 mg, 53%; E/Z > 98:2; dr =
1
98:2; Rf = 0.69 (n-pentane / Et2O, 80:20); H NMR (300
General procedure for the synthesis of 5a-d
MHz, CDCl3) δ 0.87 (td, J = 7.2, 2.3 Hz, 6H), 0.97 (s, 3H), 1.11
(s, 3H), 1.13 – 1.16 (m, 2H), 1.17 (s, 3H), 1.19 – 1.37 (m, 8H), 1.68
(s, 1H), 1.89 – 1.96 (m, 1H), 1.99 – 2.06 (m, 2H), 4.60 (dt, J =
6.6, 2.5 Hz, 2H), 4.93 – 5.09 (m, 2H), 5.39 (d, J = 15.7 Hz, 1H).
13C NMR (75 MHz, CDCl3) δ 13.9, 14.0, 21.1, 23.3, 23.3, 26.4,
26.7, 26.8, 31.6, 39.5, 40.5, 40.6, 54.9, 71.9, 73.4, 86.2, 127.7,
142.9, 209.4. HRMS (ESI-TOF) m/z: calcd for C19H34ONa+ [M
+ Na]+ 301.2507, found 301.2507.
A flame-dried 50-mL three-neck flask equipped with a stir
bar, a low temperature thermometer, a rubber septum and
an
inert
gas
inlet
was
charged
with
9
bis(cyclopentadienyl)zirconium dichloride (356.6 mg, 1.2
mmol) and dry Et2O (5 mL) under an inert atmosphere.
After cooling down the stirred reaction suspension to -78 °C,
a solution of n-butyllithium (1.0 M in hexanes, 2.4 mL, 2.4
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
mmol) was added dropwise at that temperature. After stir- (4R*,7S*,E)-4,7-dimethyl-7-propylundec-5-en-3-ol
(2l).
ring for 1 hour at -60 °C, a 5 mL dry Et2O solution of sub- Yellow oil; 121 mg, 50%; E/Z > 98:2; dr = 52:48; Rf = 0.33 and
strate 3 (0.6 mmol) was added dropwise to the solution at - 0.44 (n-pentane / Et2O, 90:10).
78 °C and the resulting mixture was allowed to slowly warm-
up to room temperature overnight (12 h). The freshly dis-
tilled first electrophile (2.5 mmol) was added dropwise after
cooling down the reaction mixture to 0 °C and the resulting
1
 For Rf = 0.33: H NMR (300 MHz, CDCl3) δ 0.83 – 0.88 (m,
6H), 0.91 (s, 3H), 0.93 – 1.00 (m, 6H), 1.09 – 1.28 (m, 10H),
1.31 – 1.43 (m, 1H), 1.58 (dtd, J = 21.3, 7.5, 3.8 Hz, 1H), 1.69
(bs, 1H), 2.07 – 2.19 (m, 1H), 3.23 (ddd, J = 8.0, 6.7, 3.7 Hz,
solution was allowed to stir for 2.5 hours at that tempera-
1H), 5.11 (dd, J = 15.8, 8.7 Hz, 1H), 5.38 (d, J = 15.8 Hz, 1H).
ture. Anydrous BF3.Et2O (212.9 µL, 1.5 mmol) was then added
at 0 °C and the resulting mixture was heated at 40 °C for 5
hours. Finally, the reaction mixture was hydrolyzed at 0 °C
with an aqueous solution of 1M HCl or DCl (0.1 M in D2O).
The layers were separated and the aqueous phase was ex-
tracted with Et2O (3 times). The combined organic fractions
were washed with brine, dried over MgSO4, filtered and
concentrated under reduced pressure. The products were
isolated by silica-gel chromatography (SiO2, n-hexane /
EtOAc, 95:05).
13C NMR (75 MHz, CDCl3) δ 9.8, 14.0, 14.8, 17.1, 17.2, 23.1,
23.4, 26.3, 26.8, 38.7, 41.0, 43.2, 43.7, 75.9, 128.2, 142.1.
HRMS (ESI-TOF) m/z: calcd for C16H33O+ [M + H]+
241.2531, found 241.2531.
 For Rf = 0.44: 1H NMR (300 MHz, CDCl3) δ 0.83 – 0.89 (m,
6H), 0.90 (s, 3H), 0.92 – 1.00 (m, 1H), 1.11 – 1.42 (m, 1H), 1.48
– 1.61 (m, 2H), 3.34 (ddd, J = 8.9, 5.4, 3.8 Hz, 1H), 5.15 (dd, J
= 15.9, 7.7 Hz, 1H), 5.33 (dd, J = 15.9, 0.7 Hz, 1H). 13C NMR
(75 MHz, CDCl3) δ 10.2, 14.0, 14.8, 15.3, 17.2, 23.1, 23.4, 26.3,
26.7, 38.5, 41.1, 42.4, 43.7, 76.5, 128.7, 140.5. HRMS (ESI-
TOF) m/z calcd for C16H33O+ [M + H]+ 241.2531, found
241.2527.
General procedure for the synthesis of 7 from ω-ene-
(methoxymethyl) cyclopropane 6
2-((3S*,4R*)-4-isobutyl-4-methylspiro[2.2]pentan-1-
yl)ethan-1-ol (IIIa). Pale yellow oil; 1.041 g, 38%; dr =
65:30:5:0; 1H NMR (400 MHz, CDCl3) (mixture of
diastereomers) δ 0.28-0.37 (m, 1H), 0.44-0.60 (m, 2H), 0.75-
1.06 (m, 10H), 1.16-1.33 (m, 4H), 1.43-1.51 (m, 1H), 1.57-1.64 (m,
1H), 1.68-1.79 (m, 1H), 3.60-3.73 (m, 2H). 13C NMR (50 MHz,
CDCl3) (mixture of diastereomers) δ 10.29, 11.4, 12.3, 13.3, 17.8,
17.9, 18.5, 20.7, 21.0, 22.7, 23.3, 23.5, 26.2, 26.3, 36.1, 46.2, 46.6,
62.8. HRMS (ESI-TOF) m/z: calcd for C12H23O [M + H]+
183.1749, found 183.1731.
A flame-dried 50-mL three-neck flask equipped with a stir
bar, a low temperature thermometer, a rubber septum and
an
inert
gas
inlet
was
charged
with
bis(cyclopentadienyl)zirconium dichloride (584.6 mg, 2.0
mmol) and dry Et2O (10 mL) under an inert atmosphere.
After cooling down the stirred reaction suspension to -78 °C,
a solution of n-butyllithium (1.5 M in hexanes, 2.7 mL, 4.0
mmol) was added dropwise at that temperature. After stir-
ring for 1 hour at temperature between -78 °C and -50 °C, a 1
mL dry Et2O solution of substrate 6 (1.0 mmol) was added
dropwise to the solution at -50 °C and the resulting mixture
was allowed to slowly warm-up to room temperature over-
night (5 h). The reaction mixture was then cooled down to -
78 °C and acetic acid or AcOD (0.5 mL) was added. After
warming up the reaction to room temperature, the reaction
was quenched with an aqueous solution of 1M HCl. The
layers were separated and the aqueous phase was extracted
with Et2O (twice). The combined organic fractions were
washed with an aqueous saturated solution Na2CO3, dried
over MgSO4, filtered and concentrated in vacuo. The prod-
ucts 7a-d were isolated by silica-gel chromatography (SiO2,
n-hexane or n-hexane, 100%).
2-((1S*,3R*)-4,4-dimethylspiro[2.2]pentan-1-yl)ethan-1-ol
(IIIb). Colorless oil; 1804 mg, 50%; dr = 95:05; H NMR (400
1
MHz, CDCl3) δ 0.34 (t, J = 4.1 Hz, 1H), 0.46 (d, J = 4.5 Hz,
1H), 0.53 (d, J = 3.9 Hz, 1H), 0.78-0.91 (m, 1H), 0.92-1.19 (m,
6H), 1.43-1.57 (m, 2H), 3.60-3.75 (m, 4H). 13C NMR (100 MHz,
CDCl3) δ 10.8, 12.9, 16.1, 18.0, 23.4, 23.7, 27.0, 36.3, 63.1. HRMS
(ESI-TOF) m/z: calcd for C9H17O+ [M + H]+ 141.1279, found
141.1275.
2-((3S*,4R*)-4-ethyl-4-propylspiro[2.2]pentan-1-
yl)ethan-1-ol (IIIc). Colorless oil; 437 mg, 48%; dr =
55:45:0:0 (unknown configuration at the quaternary center);
both diastereomers are described as a mixture): 1H NMR (400
MHz, CDCl3) δ 0.27-0.36 (m, 1H), 0.38-044 (m, 1H), 0.46-0.53
(m, 1H), 0.76-0.91 (m, 7H), 0.96-1.06 (m, 1H), 1.16-1.37 (m,
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The Journal of Organic Chemistry
6H), 1.40-1.51 (m, 1H), 1.53-164 (m, 2H), 3.58-3.73 (m, 2H). 13C oil; 132 mg, 59%; E/Z > 98:2; dr = 95:05; H NMR (400 MHz,
NMR (100 MHz, CDCl3) δ 10.4, 10.7, 10.7, 12.4, 12.6, 14.7, 14.8, CDCl3) δ 0.34 (d, J = 4.4 Hz, 1H), 0.55 (d, J = 4.4 Hz, 1H), 0.85
16.0, 19.6, 24.4 & 24.4, 26.6, 26.7, 27.3, 27.6, 36.3, 36.4, 36.8, (t, J = 7.0 Hz, 3H), 1.03 (s, 3H), 1.10 (s, 6H), 1.12-1.23 (m, 7H),
63.2. HRMS (ESI-TOF) m/z: calcd for C12H23O+ [M + H]+ 1.28-1.38 (m, 1H), 1.40-1.50 (m, 1H), 1.72 (s, 1H), 1.89 (td, J =
1
1
2
3
4
5
6
7
8
183.1749, found 183.1738.
9.6, 2.8 Hz, 1H), 5.09 (dd, J = 15.6, 9.6 Hz, 1H), 5.47 (d, J =
15.6 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 14.3, 19.2 (d, J =
19.1 Hz), 21.6, 22.1, 22.4, 23.3, 26.0, 26.7, 27.9, 28.1, 32.2, 55.2,
72.1, 128.4, 140.7. HRMS (ESI-TOF) m/z: calcd for C15H28DO+
[M + H]+ 226.2281, found 226.2288.
(3S*,4R*)-1,1-dimethyl-4-(pent-4-en-1-
yl)spiro[2.2]pentane (3a). Colorless oil; 660 mg, 62%; dr =
95:5 (relative configuration of the major isomer determined
by NOESY experiments); H NMR (400 MHz, CDCl3) δ 0.26
1
9
(dd, J = 4.4, 3.9 Hz, 1H), 0.42 (d, J = 4.4 Hz, 1H), 0.53 (d, J = (R*)-3-((E)-2-((S*)-1-(but-3-en-1-yl)-2,2-
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4.0 Hz, 1H), 0.78 (dd, J = 8.3, 3.8 Hz, 1H), 0.86-0.96 (m, 1H), dimethylcyclopropyl)vinyl)-2-methylhexan-2-ol
(4b).
1
0.95-1.14 (m, 6H), 1.20-1.34 (m, 2H), 1.36-1.49 (m, 2H), 2.04 Colorless oil; 174 mg, 66%; E/Z > 98:2; dr = 90:10; H NMR
(m, 2H), 4.82-5.07 (m, 2H), 5.70-5.88 (m, 1H). 13C NMR (100 (400 MHz, CDCl3) δ 0.26 (d, J = 4.5 Hz, 1H), 0.54 (d, J = 4.5
MHz, CDCl3) δ 10.9, 15.7, 15.9, 17.6, 23.3, 23.5, 27.3, 28.8, 32.6, Hz, 1H), 0.85 (t, J = 7.1 Hz, 3H), 0.99 (s, 3H), 1.02-1.53 (m,
+
33.8, 114.2, 139.2. HRMS (ESI-TOF) m/z: calcd for C12H21 [M 14H), 1.58-1.70 (m, 2H), 1.95 (ddd, J = 10.6, 9.2, 2.5 Hz, 1H),
+ H]+ 165.1643, found 165.1663.
2.00-2.16 (m, 2H), 4.83-5.01 (m, 2H), 5.11 (dd, J = 15.4, 9.7 Hz,
1H), 5.51 (d, J = 15.5 Hz, 1H), 5.80 (ddt, J = 17.1, 10.2, 6.8 Hz,
1H). 13C NMR (100 MHz, CDCl3) δ 14.2, 21.5, 21.9, 22.1, 23.5,
25.2, 27.2, 31.4, 32.1, 32.3, 33.8, 55.1, 114.2, 131.2, 137.5, 139.4.
HRMS (ESI-TOF) m/z: calcd for C18H33O+ [M + H]+ 265.2531,
found 265.2543.
(3S*,4R*)-4-(hex-5-en-1-yl)-1,1-
dimethylspiro[2.2]pentane (3b). Colorless oil; 252 mg,
1
78%; dr = 95:5; H NMR (400 MHz, CDCl3) δ 0.25 (t, J = 4.1
Hz, 1H), 0.42 (d, J = 3.9 Hz, 1H), 0.53 (d, J = 3.9 Hz, 1H), 0.77
(dd, J = 7.7, 4.3 Hz, 1H), 0.86-0.95 (m, 1H), 0.95-1.15 (m, 6H),
1.17-1.48 (m, 6H), 1.97-2.09 (m, 2H), 4.86-5.02 (m, 2H), 5.70- (R*)-3-ethyl-4-((E)-2-((S*)-1,2,2-
5.89 (m, 1H). 13C NMR (100 MHz, CDCl3) δ 11.06, 15.9, 16.2, trimethylcyclopropyl)vinyl)heptan-3-ol (4c). Colorless
17.8, 23.5, 23.7, 27.5, 29.1, 33.1, 34.0, 114.34, 139.4. HRMS (ESI- oil; 191 mg, 76%; E/Z > 98:2; dr = 90:10; (both diastereomers
+
1
TOF) m/z: calcd for C13H23 [M + H]+ 179.1800, found: are described as a mixture): H NMR (400 MHz, CDCl3) δ
179.1827.
0.33 (t, J = 4.4 Hz, 1H), 0.54 (d, J = 4.4 Hz, 1H), 0.79-0.89 (m,
9H), 0.96-1.69 (m, 18H), 2.06 (ddd, J = 11.8, 9.6, 2.0 Hz, 1H),
5.16 (dd, J = 15.5, 9.7 Hz, 1H), 5.43 (d, J = 15.5 Hz, 1H). 13C
NMR (100 MHz, CDCl3) δ 7.7, 7.8, 14.3, 19.6, 21.4, 21.5, 22.1,
22.4, 23.3, 26.1, 28.1 & 28.2, 28.5, 28.6, 28.9, 29.1, 31.1 & 31.2,
50.3, 50.4, 75.4, 75.6, 128.4, 139.8. HRMS (ESI-TOF) m/z:
calcd for C17H33O+ [M + H]+ 253.2531, found 253.2542.
(3S*,4R*)-4-(hept-6-en-1-yl)-1,1-
dimethylspiro[2.2]pentane (3c). Colorless oil; 261 mg, 81%;
dr =95:5; 1H NMR (400 MHz, CDCl3) δ 0.25 (t, J = 4.1 Hz, 1H),
0.39-0.47 (m, 1H), 0.53 (d, J = 3.9 Hz, 1H), 0.61-0.80 (m, 1H),
0.86-0.95 (m, 1H), 0.95-1.13 (m, 6H), 1.17-1.44 (m, 8H), 1.97-
2.08 (m, 2H), 4.86-5.03 (m, 2H), 5.72-5.86 (m, 1H). 13C NMR
(100 MHz, CDCl3) δ 11.0, 15.9, 16.3, 17.8, 23.5, 23.7, 27.5, 29.2, (R*)-4-((E)-2-((S*)-2,2-dimethyl-1-(methyl-
29.4, 29.5, 33.2, 34.0, 114.3, 139.4. HRMS (ESI-TOF) m/z: d)cyclopropyl)vinyl)-3-ethylheptan-3-ol (4cd). Colorless
calcd for C14H25+ [M + H]+ 193.1956, found: 193.1973.
oil; 200 mg, 79%; E/Z > 98:2; dr = 85:15; (both diastereomers
are described as a mixture): H NMR (400 MHz, CDCl3) δ
1
(3S*,4R*)-4-allyl-1-isobutyl-1-methylspiro[2.2]pentane
(3d). Colorless oil; 1.309 g, 62%; dr = 65:30:5:0 (relative con-
figuration of the major isomer determined by NOESY experi-
0.32 (d, J = 4.3 Hz, 1H), 0.54 (d, J = 4.3 Hz, 1H), 0.75-0.93 (m,
9H), 1.03 (s, 3H), 1.09 (s, 3H), 1.12-1.25 (m, 3H), 1.26-1.65 (s,
8H), 2.06 (ddd, J = 11.1, 9.6, 2.4 Hz, 1H), 5.15 (dd, J = 15.5, 9.6
Hz, 1H), 5.41 (minor) & 5.43 (major) (d, J = 15.5 Hz, 1H). 13C
NMR (100 MHz, CDCl3) δ 7.7, 7.8, 14.3, 14.3, 19.3 (t, J = 19.1
Hz), 21.4, 21.5, 22.0, 22.4, 23.3, 23.4, 26.0, 28.1, 28.2, 28.5, 28.6,
28.9, 29.1, 31.2, 31.2, 50.3, 50.4, 75.4, 75.6, 128.1, 128.4, 139.9.
HRMS (ESI-TOF) m/z: calcd for C17H30OD [M – OH]+
236.2483, found 236.2490.
1
ments); : H NMR (400 MHz, CDCl3) δ 0.32-0.38 (m, 1H),
0.47-0.51 (m, 1H), 0.60-0.64 (m, 1H), 1.13-1.45 (m, 2H), 1.45-
1.84 (m, 12H), 2.04 (t, J = 6.5 Hz, 2H), 4.95 (d, J = 10.1 Hz, 1H),
5.06 (d, J = 17.1 Hz, 1H), 5.86 (ddt, J = 16.8, 10.2, 6.5 Hz, 1H).
13C NMR (100 MHz, CDCl3) δ 10.4, 11.5, 15.0, 16.0, 17.8, 17.9,
18.6, 18.7, 20.8, 21.0, 22.8, 23.4, 26.4, 26.4, 26.9, 27.0, 37.5,
46.6, 46.8, 114.5, 138.4. HRMS (ESI-TOF) m/z: calcd for
C13H23O [M + H2O]+ 195.1749, found 195.1758.
(R*)-2-methyl-3-((E)-2-((S*)-1,2,2-
trimethylcyclopropyl)vinyl)heptan-2-ol (4d). Colorless
(R*)-2-methyl-3-((E)-2-((S*)-1,2,2-
trimethylcyclopropyl)vinyl)hexan-2-ol (4a). Colorless oil;
143 mg, 64%; E/Z > 99:1; dr = 95:05; H NMR (400 MHz,
oil; 147 mg, 62%; E/Z > 98:2; dr = 80:20; (both diastereomers
1
1
are described as a mixture): H NMR (400 MHz, CDCl3) δ
0.33 (t, J = 4.4 Hz, 1H), 0.54 (d, J = 4.3 Hz, 1H), 0.84 (t, J = 6.8
Hz, 3H), 1.02 (s, 3H), 1.04-1.18 (m, 13H), 1.18-1.36 (m, 4H),
1.45-1.56 (m, 1H), 1.74 (s, 1H), 1.88 (ddd, J = 10.9, 9.6, 2.5 Hz,
1H), 5.10 (dd, J = 15.4, 9.7 Hz, 1H), 5.46 (m, 1H). 13C NMR (100
MHz, CDCl3) δ 14.3, 19.6, 22.1, 22.4, 22.8, 22.8, 23.3, 23.4, 26.0
& 26.1, 26.8 & 26.9, 27.2, 28.1, 28.4, 29.5, 29.6, 30.5, 30.7, 55.4,
72.1, 72.4, 128.2, 128.4, 140.7. HRMS (ESI-TOF) m/z: calcd for
C16H31O+ [M + H]+ 239.2375, found: 239.2382.
CDCl3) δ 0.33 (d, J = 4.4 Hz, 1H), 0.55 (d, J = 4.4 Hz, 1H), 0.85
(t, J = 7.2 Hz, 3H), 1.03 (s, 3H), 1.07-1.25 (m, 14H), 1.26-1.51 (m,
2H), 1.73 (s, 1H), 1.92 (ddd, J = 11.1, 9.7, 2.5 Hz, 1H), 5.11 (dd, J
= 15.5, 9.7 Hz, 1H), 5.47 (d, J = 15.5 Hz, 1H). 13C NMR (100
MHz, CDCl3) δ 14.3, 19.5, 21.6, 22.1, 22.4, 23.3, 26.1, 26.8, 27.3,
28.1, 32.2, 55.2, 72.1, 128.4, 140.7. HRMS (ESI-TOF) m/z: calcd
for C15H29O+ [M + H]+ 225.2218, found 225.2225.
(R*)-3-((E)-2-((S*)-2,2-dimethyl-1-(methyl-
d)cyclopropyl)vinyl)-2-methylhexan-2-ol (4ad). Colorless
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(E)-3-butyl-2,7,7-trimethyl-6-methyleneoct-4-en-2-ol
Page 20 of 23
(R*)-3-((E)-2-((S*)-1-(but-3-en-1-yl)-2,2-
1
1
2
3
4
5
6
7
8
dimethylcyclopropyl)vinyl)-2-methylheptan-2-ol (4e).
(5b). Colorless oil; 87 mg, 61%; E/Z > 98:2; H NMR (400
MHz, CDCl3) δ 0.85 (t, J = 6.8 Hz, 3H), 1.06 (s, 9H), 1.11-1.38
(m, 11H), 1.51-1.65 (m, 2H), 1.96 (ddd, J = 11.0, 9.9, 2.7 Hz, 1H),
4.73 (s, 1H), 4.95 (s, 1H), 5.56 (dd, J = 15.2, 9.9 Hz, 1H), 6.11 (d,
J = 15.3 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 14.3, 22.9, 27.1,
27.5, 29.3, 29.5, 30.6, 35.2, 55.5, 72.6, 107.0, 131.9, 133.8, 156.6.
HRMS (ESI-TOF) m/z calcd for C16H31O+ [M + H]+ 239.2375,
found: 239.2386.
1
Colorless oil; 214 mg, 77%; E/Z > 98:2; dr = 95:05; H NMR
(400 MHz, CDCl3) δ 0.26 (d, J = 4.5 Hz, 1H), 0.55 (d, J = 4.5
Hz, 1H), 0.84 (t, J = 6.9 Hz, 3H), 0.99 (s, 3H), 1.04-1.46 (m,
15H), 1.47-1.57 (m, 1H), 1.59-1.69 (m, 2H), 1.92 (ddd, J = 10.9,
9.7, 2.7 Hz, 1H), 1.99-2.20 (m, 2H), 4.82-5.01 (m, 2H), 5.11 (dd,
J = 15.4, 9.7 Hz, 1H), 5.51 (d, J = 15.5 Hz, 1H), 5.80 (ddt, J =
17.2, 10.2, 6.7 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 14.3, 22.0,
9
22.1, 22.8, 23.5, 25.2, 27.2, 28.5, 30.7, 31.4, 32.4, 33.8, 55.3, 72.3, (E)-2,3,7,7,9-pentamethyl-6-methylenedec-4-en-2-ol
1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
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59
60
114.2, 131.3, 137.5, 139.4. HRMS (ESI-TOF) m/z: calcd for (5c). Colorless oil; 103 mg, 72%; E/Z > 98:2; H NMR (400
C19H35O+ [M + H]+ 279.2688, found 279.2689.
MHz, CDCl3) δ 0.74-0.89 (m, 6H), 1.00-1.10 (m, 9H), 1.12-1.23
(m, 6H), 1.27 – 1.32 (m, 2H), 1.54 (m, 2H), 1.70 (bs, 1H), 2.18-
2.25 (m, 1H), 4.71 (d, J = 1.4 Hz, 1H), 5.03 (s, 1H), 5.72-5.80 (m,
1H), 6.09 (d, J = 15.3 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ
15.7, 25.0, 25.1, 27.0, 27.1, 28.4, 28.5, 38.8, 48.8, 50.1, 72.8,
108.4, 131.8, 133.0, 155.1. HRMS (ESI-TOF) m/z: calcd for
C16H30O [M + H]+ 238.2296 found 238.2307.
(R*)-2-methyl-3-((E)-2-((S*)-1,2,2-
trimethylcyclopropyl)vinyl)octan-2-ol (4f). Colorless oil;
176 mg, 70%; E/Z > 98:2; dr = 85:15; (both diastereomers are
described as a mixture): 1H NMR (400 MHz, CDCl3) δ 0.33 (t,
J = 4.4 Hz, 1H), 0.56 (d, J = 4.4 Hz, 1H), 0.84 (t, J = 6.8 Hz,
3H), 0.98-1.12 (m, 9H), 1.12-1.35 (m, 13H), 1.43-1.54 (m, 1H),
1.72 (s, 1H), 1.89 (ddd, J = 10.9, 9.7, 2.5 Hz, 1H), 5.10 (dd, J = (E)-3-ethyl-4,8,8,10-tetramethyl-7-methyleneundec-5-
15.4, 9.6 Hz, 1H), 5.43 (m, 1H). 13C NMR (100 MHz, CDCl3) δ en-3-ol (5d). Colorless oil; 108 mg, 68%; E/Z > 98:2; 1H NMR
14.3, 19.5, 19.6, 22.1, 22.4, 22.5, 22.8, 22.9, 23.3, 23.4, 26.1, 26.8, (400 MHz, CDCl3) δ 0.79-0.91 (m, 12H), 0.96-1.09 (m, 9H),
26.9, 27.3, 27.9, 28.0, 28.1, 28.4, 29.8, 29.9, 31.9, 32.0, 55.4, 1.12-1.31 (m, 3H), 1.41-1.60 (m, 5H), 2.26-2.40 (m, 1H), 4.71 (d, J
72.1, 72.4, 128.2, 128.5, 140.7. HRMS (ESI-TOF) m/z calcd for = 1.0 Hz, 1H), 5.03 (s, 1H), 5.74-5.88 (m, 1H), 6.05 (d, J = 15.4
C17H33O+ [M + H]+ 253.2531, found 253.2543.
Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 7.8, 7.9, 14.9, 25.0,
25.0, 25.1, 28.4, 28.4, 28.5, 28.9, 38.9, 44.0, 50.2, 108.2, 131.1,
133.1, 155.2. HRMS (ESI-TOF) m/z: calcd for C18H34O+ [M +
H]+ 266.2610, found 266.2613.
(E)-5-((1S*,2R*)-2-isobutyl-1,2-dimethylcyclopropyl)-2,3-
dimethylpent-4-en-2-ol (4g). Colorless oil; 195 mg, 82%;
E/Z > 98:2; dr = 60:40; (both diastereomers are described as a
1
mixture): H NMR (400 MHz, CDCl3) δ, , 0.33 (d, J = 4.5 Hz,
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: XXXX.
0.4H), 0.35 (d, J = 4.5 Hz, 0.6H), 0.57 (d, J = 4.4 Hz, 0.4H),
0.61 (d, J = 4.4 Hz, 0.6H), 0.80 – 1.30 (m, 22H), 1.58 – 1.70 (m,
3H), 2.11 – 2.23 (m, 1H), 5.28 (m, 1H), 5.48 (d, J = 6.0 Hz,
0.6H) 5.52 (d, J = 6.0 Hz, 0.4H). 13C NMR (100 MHz, CDCl3)
δ 15.9, 16.0, 19.3, 19.5, 19.8, 20.1, 22.6, 22.7, 22.7, 22.9, 24.7,
24.8, 25.4, 25.5, 26.0, 26.2, 26.2, 26.3, 26.9, 27.1, 27.2, 27.5,
43.9, 44.3, 48.6, 48.6, 72.2, 72.3, 129.2, 129.7, 138.5, 138.5.
HRMS (ESI-TOF) m/z: calcd for C16H30O [M + H]+ 238.2295,
found 238.2314.
Overview of the adopted strategy for the preparation of starting
materials, computational details and Cartesian coordinates,
1
mechanistic experimental details, and H and 13C NMR spectra
of all new products.
AUTHOR INFORMATION
Corresponding Author
(E)-5-((1S*,2R*)-1-(but-3-en-1-yl)-2-isobutyl-2-
methylcyclopropyl)-2,3-dimethylpent-4-en-2-ol
(4h).
* E-mail: chilanm@technion.ac.il; Tel: +972-4-8293709.
Email: Odile.Eisenstein@univ-montp2.fr
Email: lionel.perrin@univ-lyon1.fr
Colorless oil; 219 mg, 79%; E/Z > 98:2; dr = 60:40; (both
diastereomers are described as a mixture): H NMR (400
1
MHz, CDCl3) δ 0.20-0.32 (m, 1H), 0.53-0.65 (m, 1H), 0.77-1.48
(m, 20H), 1.52-1.84 (m, 3H), 1.94-2.28 (m, 3H), 4.83-5.06 (m,
2H), 5.18-5.35 (m, 1H), 5.45-5.60 (m, 1H), 5.71-5.92 (m, 1H).
13C NMR (100 MHz, CDCl3) δ 16.1, 16.1, 19.2, 20.3, 22.7, 23.0,
23.0, 23.1, 24.4, 24.4, 24.7, 26.3, 26.9, 26.9, 27.1, 27.1, 31.0, 31.0,
32.3, 32.4, 33.5, 33.8, 43.7, 44.4, 48.7, 48.7, 72.5, 72.6, 114.1,
114.2, 132.1, 132.6, 135.5, 135.5, 139.4, 139.5. HRMS (ESI-TOF)
m/z: calcd for C19H34O [M + H]+ 278.2610, found 278.2599.
Author Contributions
‡ These authors have contributed equally.
ACKNOWLEDGMENT
This research is supported by the European Research Council
under the European Community’s Seventh Framework Program
(ERC agreement no. 338912). S.S. thanks the Planning and
Budgeting Committee (PBC) of the Council for Higher Educa-
tion for providing financial support. LP thanks CCIR of ICBMS
and CALMIP for providing computational resources and tech-
(E)-2,7,7-trimethyl-6-methylene-3-propyloct-4-en-2-ol
1
(5a). Colorless oil; 79 mg, 59%; E/Z > 98:2; H NMR (400
MHz, CDCl3) δ 0.87 (t, J = 7.2 Hz, 3H), 1.06 (s, 9H), 1.11-1.55
(m, 10H), 1.62 (s, 1H), 1.99 (ddd, J = 11.2, 10.1, 2.5 Hz, 1H), 4.73 nical support. I.M. holds the Sir Michael and Lady Sobell Aca-
demic Chair.
(s, 1H), 4.95 (s, 1H), 5.57 (dd, J = 15.2, 9.9 Hz, 1H), 6.11 (d, J =
15.3 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 14.3, 21.5, 27.2,
27.5, 29.6, 31.9, 35.2, 55.3, 72.6, 107.0, 131.9, 133.8, 156.6.
HRMS (ESI-TOF) m/z: calcd for C15H29O+ [M + H]+ 225.2218,
found 225.2215.
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