Regioselective pinacol rearrangement of unsymmetrical cyclobutane-1,2-diols

Article abstract of DOI:10.1246/bcsj.20170335

Hydroxy-sulfone 34b, prepared as a mixture of trans and cis isomers by condensing the O-silyl derivative 18c of 2-hydroxy-2-methyl-cyclobutanone 18b-the Norrish II photocyclisation product of 2,3-pentanedione 21- and methyl phenyl sulfone 33 was found to rearrange selectively either to the cyclo-propanic β-ketosulfone 37 or the isomeric methyl ketone 38 by using, respectively, the tosyl fluoride/DBU and the DAST reagent. The potential of this methodology has been illustrated by a synthesis of phytal 1 from geranylacetone 46, and by the preparation from 3,4-hexanedione 51 and prenol 56-via the cyclopropanic β-ketosulfone 54 (X-ray)-of an advanced fragment of the juvenile hormone molecule 59.

Full text of DOI:10.1246/bcsj.20170335

Advance Publication Cover Page
Regioselective Pinacol Rearrangement of Unsymmetrical Cyclobutane-1,2-diols
Vincent Gembus, Lydia Karmazin, Sylvain Pira, and Daniel Uguen*
Advance Publication on the web December 4, 2017
doi:10.1246/bcsj.20170335
©
2017 The Chemical Society of Japan

Regioselective Pinacol Rearrangement of Unsymmetrical Cyclobutane-1,2-diols
1
2
1
1 #
Vincent Gembus, Lydia Karmazin, Sylvain Pira, and Daniel Uguen *
1Laboratoire de Synthèse Organique (associé au CNRS; UMR 7509), Ecole Européenne de Chimie, Polymères et Matériaux, Université de
Strasbourg, 25 rue Becquerel, 67087 Strasbourg, France
2Service de Radiocristallographie, Université de Strasbourg, BP296/R8, 67008 Strasbourg, France
E-mail: uguen@unistra.fr
Received: October 20, 2017
Daniel Uguen
Daniel Uguen obtained the Doctorat-ès-Sciences Physiques degree from Pierre et Marie Curie (Paris 6) University in
1
1
977 (Prof. Marc Julia). After postdoctoral work with Prof. Sir John Cornforth at Sussex University, UK (1978.10 to
979.9), he worked at Ecole Normale Supérieure (Paris), at first as research associate (with Prof. Marc Julia), and then as
Directeur de Recherche (CNRS). In 1990, he took Professor position at the University of Strasbourg (present status:
emeritus). He spent his sabbatical as Visiting Professor at the University of Tokyo (three trimesters, in 2005-2007; Prof.
Kazuhiko Saigo), and at the Science University of Tokyo (one trimester, in 2011; Prof. Isamu Shiina).
Abstract
Hydroxy-sulfone 34b, prepared as a mixture of trans and cis
isomers by condensing the O-silyl derivative 18c of 2-hydroxy-
-methyl-cyclobutanone 18b — the Norrish II photocyclisation
product of 2,3-pentanedione 21 — and methyl phenyl sulfone
was found to rearrange selectively either to the
cyclopropanic β-ketosulfone 37 or the isomeric methyl ketone
8 by using, respectively, the tosyl fluoride/DBU and the
possibility of unveiling at a late stage of the synthesis the C1-
C4 (red-coloured) residue of this aldehyde via homoallylic
rearrangement of alcohol 2 had been studied (Scheme 1).3
To this end, ester 3, prepared in four steps from
acetobutyrolactone 4,4a had been reacted with 2-methyl-
2
5
3
3
glutaronitrile 5 — a facility of the Nylon 6-6 industry — in
basic conditions. Refluxing the keto-dinitrile 6 thus produced in
conc. HCl, and then treating the resulting chloro-ketone 7 with
KOH afforded the keto-acid 8. Next, diol 9a, formed by
treatment of 8 with an excess of LAH, was sequentially reacted
with tosyl chloride (TsCl) and triethylsilyl chloride (TESCl) to
give tosylate 9b, the Wurtz coupling of which with
tetrahydrogeranylmagnesium chloride 10, followed by
hydrolysis of the silyl ether, furnished the cyclopropyl carbinol
3
DAST reagent. The potential of this methodology has been
illustrated by a synthesis of phytal 1 from geranylacetone 46,
and by the preparation from 3,4-hexanedione 51 and prenol 56
—
via the cyclopropanic β-ketosulfone 54 (X-ray) — of an
advanced fragment of the juvenile hormone molecule 59.
2
. The latter was then converted into bromide 11 using PBr
3
1
. Introduction
under Johnson conditions.1a Finally, exchanging the bromine
atom to an acetoxy group, hydrolyzing the acetate 12a with
KOH, and then oxidizing the resulting alcohol 12b under
Swern conditions afforded isophytal 13, which was next
isomerized to phytal (1) using diluted sodium hydroxide.
Although our strategy was validated, in addition to the number
As exemplified in the polyprenol and the insect pheromone
series, the conversion of cyclopropyl carbinols into homoallylic
bromides in acid (Lewis or protic) conditions — i.e., the
homoallylic rearrangement — has evolved as an efficient
methodology to synthesize compounds with trisubstituted
1
carbon-carbon double bonds. With a view to designing a new
2
access to phytal (1), a key intermediate to tocopherols, the

of steps and the lack of convergence, another concern was the
limited availability of ester 3. Although various preparative
procedures have been designed,4b-d this compound is very
expensive and, clearly, a more practical approach to the C20
alcohol 2 was desirable. To this end, the possibility of
accessing this cyclopropyl carbinol by the ring-contraction
process depicted in Scheme 2 was investigated, and our
progress and observations along this line are reported in this
publication.
rearrangement of the tetrahedral intermediate;6d,9 acceleration
of this rearrangement process by added silver ion has been
shown not to result from pre-dissociation of the carbon-
halogen bond, thus excluding a cationic intermediate,6f and
the rearrangement of acetal 16 into ester 15b by treatment
with p-toluenesulfonic acid (PTSA) is thought to proceed
similarly.7d Interestingly, a related “pull-push” mechanism
has been proposed for the formation of ketone 17 by reacting
14 with methyllithium (or the corresponding Grignard
reagent);6h results obtained in the rearrangement in basic
conditions of 2-chlorocyclobutanols with blocked
configuration strongly supported this view, with only those
chlorohydrins in which the chlorine atom occupies a pseudo-
2
. Results and discussion
As exemplified in Scheme 2A, the Favorskii reaction of 2-
halocyclobutanones (and related acetals) is well
documented.6-8 Whatever the pH conditions used,
experiments in D O have shown that the rearrangement of 2-
equatorial
orientation
rearranging
to
a
cyclopropanecarboxaldehyde.10 Keeping these observations
in mind with a view to designing a convenient access to
cyclopropyl carbinol 2, the tosylate 18a of the known11
hydroxycyclobutanone 18b was targeted in the hope, as
depicted, that the alkoxide anion 19 formed by condensing
18a and a hexahydrofarnesyl organometallic species would
rearrange to ketone 20, resulting in a straightforward access
2
bromo-cyclobutanone 14 to cyclopropanecarboxylic acid 15a
does not proceed by the classical mechanism — i.e., the
Loftfield cyclopropanone mechanism — but, more likely, by
2
nucleophilic addition of D O (or the deuteroxide anion) to the
carbonyl group followed, as indicated, by semibenzylic

to this alcohol, and thence to phytal 1 (another possibility
being an access to ester 3 by methanolysis of 18a).
by treating the corresponding lithium (or potassium) alkoxide
with TsCl in THF,12c or attempting to exchange the oxygen to
a chlorine (or bromine) atom using conventional reagent
conditions. The use of tosyl fluoride associated with DBU
(TsF•DBU) as a reagent, and of an O-silyl derivative of 18b
as substrate was then considered. Nonaflyl fluoride (NFF)
has proved to be a useful reagent for converting hindered
alcohols into alkyl fluorides (via nonaflates) when DBU was
used as a base13 and, independently, conversion of O-TMS
derivatives of various alcohols and enols to corresponding
nonaflates has been efficiently realized by reacting these
ethers with NFF in presence of tetraalkylammonium (or
cesium) fluoride.14 Although covalent catalysis was not
probed in the former conditions, it could be envisioned, as
depicted in Scheme 2B, that the N-tosylpyrimidoazepinium
fluoride that TsF should
Ketone 18b was prepared according to literature by
irradiating a solution of 2,3-pentadione 21 in EtOAc (used in
place of benzene11a) with a mercury lamp for ca. 30 h to
obtain, after elimination of the solvents, a 92:8 mixture (GC)
of ketone 18b and its dimer 2211b in virtually quantitative
yield. Although purifying this mixture by column
chromatography did furnish pure 18b, only freshly-prepared
1
8b/22 mixtures were used owing to pronounced tendency of
this ketone to give 22 on standing. Reacting 18b with TsCl in
standard conditions (in pyridine, alone or with added DMAP)
resulted only in decomposition and the same observation was
made using either the N-tosyl-N–methylimidazolium
triflate12a or the TsCl•DABCO reagent,12b as recommended in
case of hindered alcohols; no more success was encountered

form with DBU would cleave the silyl ether, resulting in a
fast tosylation process owing to conjunction of base and
covalent catalysis. Indeed, reacting the O-TMS ether 23 with
hydrolysis of the ester. This led us to modify our plan, with
the pinacol rearrangement preferred to the preceding quasi-
Favorskii reaction process (Scheme 3).
excess TsF and DBU in CDCl
3
(NMR tube experiment)
Consonant
with
observations
made
with
2-
afforded within a few minutes the tosylate 24 in virtually
quantitative yield.15 Accordingly, the alcohol function of 18b
was protected with a TES group (preferred to TMS owing to
a better stability) by using TES chloride and added 2,4,6-
collidine in DMF to obtain, after purification by column
chromatography, the silyl ether 18c in fair yield (overall 65%,
from 21); notably, using other base and solvent conditions
failed to give 18c and, in most cases, decomposition was
observed. Deceptively, however, reacting 18c with the
TsF•DBU reagent in acetonitrile for a prolonged period failed
to give tosylate 18a. Attempted esterification of 18b with
carboxylic acids was no more rewarding: decomposition was
observed either by reacting 18b with p-nitrobenzoyl chloride
or trifluroacetic anhydride and added DMAP in pyridine and,
although ester 18d could be obtained in low yield (30%) by
reacting 18b with p-nitrobenzoic acid and added DCC,
treating this ester with NaOMe in methanol resulted in
halocyclobutanones (vide supra), 1,2-cyclobutanediols
rearrange in acidic conditions (Lewis or protic) to
cyclopropylcarbonyl compounds.6j,16,17 Except in case of
phenyl substitution,16b and as illustrated in Scheme 3A by the
formation of a 7:3 mixture of, respectively, 1-methyl-
cyclopropanecarboxaldehyde 25 and cyclopropyl methyl
ketone 26 by refluxing 1- methycyclobutane-1,2-diol 27 with
PTSA in benzene,17 controlling the regioselectivity of this
rearrangement in case of unsymmetrical substitution was a
potential problem. In addition, though of less significance,
the rate of these rearrangements is dependent on
stereoelectronic factors — the trans-diol trans-28 rearranges
to 29 faster than its cis-isomer cis-28 — and controlling the
stereoselectivity of the cyclobutanediol preparation process
might have been desirable. As depicted in Scheme 3B, owing
to strong electron-withdrawing property of the sulfonyl group,
it could be surmised that the diol 30 formed by

condensing 18b and hexahydrofarnesyl phenyl sulfone 31
would rearrange selectively in acidic conditions into the β-
ketosulfone 32, potentially convertible into 20 by
hydrogenolysis of the sulfone.
fold excess) in THF, although the yield was low (35%). A
better result was registered by using the O-silylated ketone
18c and a stoichiometric amount of this anion in otherwise
the same conditions to obtain in good yield (83%) a 28:72
1
Model experiments were realized using methyl phenyl
sulfone 33 (Scheme 4). Syn-selectivity (with regard to the
methyl group) has previously been observed by reacting 1,2-
cyclobutanedione with excess MeLi (or MeMgBr) in ether
mixture (GC, H NMR) of sulfones cis-34b and trans-34b,
respectively; a ratio not significantly affected by varying the
solvent, the metal, the temperature and the time conditions.
Treating this silyl ether mixture with HF•pyridine afforded in
high yield (99%) a mixture of the diol-sulfones cis-34a and
trans-34a (same diastereomeric ratio).
(or THF) to obtain, via the lithium (or magnesium) alkoxide
of hydroxy-ketone 18b, the diol cis-28,6j,17 and indeed the cis
diol-sulfone cis-34a was found to be the main product (cis-
Owing to their similar polarity in TLC, either separating the
cis-34a/trans-34a or the cis-34b/trans-34b mixture by
column chromatography proved unfeasible, a difficulty that
3
4a:trans-34a = 4:1; these structures were determined later)
by reacting 18b with the lithium anion of sulfone 33 (two-

was overcome by reacting 18c with the lithio derivative of
thioanisole 35 in similar conditions. After 1 h, TLC showed
two new products, and these were efficiently separated by
chromatography. Although NMR analysis strongly suggested
that the minor product (15%) was cis-36, the major one
(cis-34b/trans-34b = 28:72), and that using hydroxyketone
18b resulted in reversal of this selectivity, with formation of
the cis-sulfone cis-34a as main product.
At contrast with results previously obtained with
dimethylcyclobutanediol 28 (vide supra), no reaction was
observed in TLC by reacting the preceding 28:72
(35%) thus being trans-36, a more rigorous structure
assignment was secured by reacting the latter compound with
3 2 3
diastereomeric diol-sulfone mixture with BF •Et O in CHCl
m-CPBA to obtain sulfone trans-34b (80%, mp 64 °C),
at room temperature. However, bringing the reaction mixture
to reflux resulted in the formation of a new product, and 3 h
later, when decomposition was visible, hydrolysis followed
by column chromatography afforded successively the β-
ketosulfone 37 (75%) as a white solid (mp 78 °C) and the
pure cis-sulfone cis-34a (25%), the same result being
obtained by using the silylated sulfone 34b in place of 34a
(Scheme 5). In the same way, reacting the 4:1 diol-sulfone
mixture in these conditions afforded 37 (24%), and cis-34a
1
identified (by GC, H NMR) to the main product of the 18c-
3
3 condensation, and whose treatment by TBAF afforded a
crystalline sulfone (90%, mp 73 °C), similarly identified as
the minor component of the 18b-33 condensation product,
and to which structure trans-34a was assigned by X-ray
diffraction analysis. It thus follows that the main product of
the 18c-35 condensation was the trans-sulfide trans-36, that
the 18c-33 condensation proceeded with same anti-selectivity

(
65%). The apparent lack of reactivity of the cis-isomer was
temperature for 2 h. However, adding excess reagents (3
equiv. of each) to the reaction mixture resulted in the smooth
formation of a new product, and 16 h later, when the reaction
was completed, brief purification by chromatography of the
product then isolated afforded the ketosulfone 37 in good
yield (92%).
confirmed either by refluxing cis-34a with BF •Et O in
3
2
chloroform or PTSA in benzene: in each case, only partial
decomposition was observed.
The lower reactivity of sulfone 34a, as compared to
dimethylcyclobutanediol 28 deserves a few comments. As
pointed out by Conia,17 in contrast with the cis isomer, in one
conformation, the two OH groups of the trans-diol trans-28
occupy a pseudoequatorial position and, accordingly, this diol
should react faster, as observed. In the present case, owing to
the negative inductive effect of the sulfonyl group, only the
OH at C2 is displaced and sulfone trans-34a should not react
as fast as trans-28, as observed. As to the observed
dichotomy in reactivity of the trans- and the cis-isomer, in
the solid state, the torsion angle formed by the C2-O and the
C1-C4 bond of trans-34a approximates 145 °, compared with
the indicated 91 ° value suggested by a modelling study of
the corresponding torsion angle in cis-34a. Although the
Although our goal was achieved, the possibility of reversing
the regioselectivity of this rearrangement was studied.
Previously, cyclobutanone cyanohydrin has been shown to
rearrange, via a cyclobutonium ion, into a fluorinated
cyclopropanecarbonitrile when reacted with DAST,19 thus
illustrating the remarkable ability of this reagent to amplify
the leaving group ability of deactivated OH groups. Keeping
in mind the preceding observations, this result strongly
suggested that the sulfiminium fluoride 34d which should
form by reacting hydroxysulfone 34b with DAST would
evolve by intramolecular nucleophilic attack of the fluoride
ion onto the silicon atom, with the result of a fast “push-pull”
rearrangement to the methyl ketone 38 (Scheme 5B). This
would extend a concept previously conceived to access the
3
latter value rises to ca. 135 ° by linking the oxygen to BF , it
is likely that anchimeric assistance of the C1-C4 sigma-bond
electrons would hardly contribute in this case, thus
explaining the lack of reactivity of cis-34a under these
conditions.18
quadrone skeleton by pinacol rearrangement of
a
tricycloundecanediol,20 and has now been verified in practice.
As evidenced by TLC analysis, adding DAST to a solution of
With control of the stereochemical fate of the 18c-33
condensation having proved difficult (vide supra), the only
2 2
34b in CH Cl at room temperature resulted within a few
minutes in the formation of a new product and 30 min later,
when the reaction was completed, a solid product (mp 78 °C)
assigned by NMR as 38 was isolated in good yield (81%).
The significant role of the silyl protection was evidenced by
reacting the diol-sulfone 34a with DAST to obtain, after
separation by column chromatography, the β-ketosulfone 37
(74%) and the isomeric methyl ketone 38 (20%). Although of
no immediate interest given the preceding result with TsF and
DBU, the possibility to orient this rearrangement towards
sulfone 37 was studied by reacting the lithium alkoxide
formed in the 18c/33 condensation with t-butyldimethylsilyl
triflate (TBDMSOTf); selective hydrolysis of the bis-silyl
ether 34e would have provided 34f, potentially convertible
into 37 by treatment with DAST. Although the planned
quenching experiment did not succeed, this was realized
stepwise by reacting 34b with TBDMSOTf and added
possibility for ensuring
a
full conversion of this
diastereomeric mixture was to convert the OTES substituent
into a good leaving group — “pull effect”— and, if possible,
to increase the “push” ability of the C1 oxygen. To this end,
the use of the TsF•DBU reagent was reconsidered. With
failure to sulfonylate the hydroxyketone 18b being imputable
to strong deactivating effect (possibly electronic and steric)
of the carbonyl group, it could be envisioned, as depicted in
Scheme 5A, that 34b would react with the putative N-tosyl-
pyrimidoazepinium fluoride intermediate more easily than
1
8b and, irrespective of the sulfone stereochemistry, that a
fast rearrangement of the resulting tosylate 34c would occur
owing to anionisation of the C1 alcohol by DBU (pKBH+
2
4.3). No reaction was observed by TLC upon reacting 34b
with an equivalent of TsF and DBU in acetonitrile at room

collidine in DMF to obtain 34e (52%). Hydrolyzing
selectively the TES ether of 34e proved delicate and, using
the best conditions founded so far, the O-TBDMS derivative
diastereomers (GC). Establishing the configuration of each
component by 1H NMR proved difficult owing to the
multiplicity of signals in a narrow range of chemical shifts
and, without further analyses, this alcohol product was
reacted with TsF and DBU as above. NMR analysis of the
complex product (TLC) thus obtained suggested it to be
constituted of tosylate 39b, alongside various unidentified
3
4f was obtained in moderate yield (54%), alongside diol-
sulfone 34a (44%) by using TBAF at low temperature in THF.
As expected, treating 34f by DAST under the preceding
conditions afforded the β-ketosulfone 37 (77%).
The application of these results to phytal (1) synthesis was
then investigated (Scheme 6). Although it was later to prove
otherwise, recourse to a sulfonyl group to control the
selectivity of the pinacol reaction seemed unnecessary since
condensing 18c and a hexahydrofarnesyl organometallic
species, and then reacting the resulting alcohol with the
TsF•DBU reagent would have afforded, via alkoxide 19
4 2 3
impurities. Treating this product with NBu F SiPh (NMR
tube experiment) afforded a still more complex mixture, in
which a methyl ketone also observed (by NMR) in the
impure product issued from treatment of 39a with DAST and
to which the structure 40 was tentatively assigned by 13C
NMR. Modelling study revealed severe hindrance of the TES
residue by the isopentyl substituent and it is likely that this
discrepancy originates from the greater reactivity of the free
OH as compared to the OTES substituent.
(M=DBUH, in Scheme 2), the ketone 20. This was tested by
reacting 18c with isopentylmagnesium chloride to obtain, in
low yield (29%), the alcohol 39a as a 65:35 mixture of two
Results obtained with sulfone 41a, which was prepared in

good yield (86%) as a mixture of only two diastereomers
GC-MS, NMR; relative configuration of the C-SO Ph
sulfone 44 as a white solid (mp 57 °C). Hydrogenating 44
(H , 5% Pd/C) then afforded 43 (96%).
[
2
2
carbon atom was not determined] by condensing the lithium
anion of isopentyl phenyl sulfone 42 and 18c, also suggest
that the steric factor is critical in this series. Practically no
reaction was observed in TLC on reacting 41a with the
TsF•DBU reagent for a prolonged period. The desired
Next, homologation of 37 to phytal (1) was realized as
indicated. Oxirane 45, prepared in three steps (overall 77%)
from geranylacetone 46 by a hydrogenation, a methylenation,
and an epoxidation (see experimental), was heated under
3
reflux with Al(O-i-Pr) in toluene for 5 h. Treating the
ketosulfone 43 could be obtained by using BF
3
•Et
2
O as a
resulting alcohol mixture (2:1 by GC and NMR) with ethyl
chloroformate in ether with added pyridine then afforded the
carbonates exo-47a and endo-47a (overall 86%, from 45;
exo:endo = 2:1). Surprisingly, reacting this carbonate product
with 37 under Tsuji conditions as above afforded in high yield
(92%) the sulfone 48 as the sole product; this is possibly the
result of equilibration of the π-allylpalladium intermediates,
owing to reversibility of the palladation process.23
reagent, however. Notably, the rearrangement proceeded in
this case at room temperature and after a few hours,
separation by column chromatography afforded unreacted
diol-sulfone cis-41b (36%) and 43 (55%, mp 113 °C), as
3 2
established by NMR; reacting further cis-41b with BF •Et O
resulted in decomposition. Finally, an attempt was made to
condense 18c with the lithium anion of hexahydrofarnesyl
phenyl sulfone 31 but, as previously observed with long-
chain alkyl sulfones,21 only decomposition of this sulfone
was observed. A convenient solution to these difficulties was
found by homologating the ketosulfone 37, which was first
reacted with ethyl methallyl carbonate under Tsuji allylation
Although removing the sulfonyl group using aluminium
would have been more appropriate (vide infra),
straightforward conversion of 48 to ketone 20 was attempted
by heating this sulfone with Raney nickel in EtOH.24 This
gave an over-hydrogenated product with the same polarity as
20 in TLC, later identified as 49 by GC-mass. Reducing this
hydrogenation product with LAH, and then separating the
conditions22 (with added [Pd
2
3 3 3
dba •CHCl ] and PPh in THF)
for 2 h at room temperature to obtain in good yield (90%) the

resulting two-component mixture (TLC) by column
chromatography afforded successively the alcohol 50 (29%)
and the cyclopropyl carbinol 2 (69%; identified by GC-mass
and NMR), which was subsequently converted into phytal (1)
by using the same sequence as depicted in Scheme 1 (overall
sulfonyl group, another key feature being the protection of
the remote alcohol with a TES group. Thus, reacting sulfone
34b with the TsF•DBU reagent has afforded the β-
ketosulfone 37 with a perfect selectivity, which could be
reversed simply by using DAST in place of this reagent.
Although not explicitly probed, in each case this efficiency is
likely to result from the conjunction of base and covalent
catalysis, facilitated by the use of a fluorinated reagent and a
silyl protection.
5
2% from 2).
Finally, the scope of this emerging methodology was briefly
explored by irradiating a solution of 3,4-hexanedione 51 in
EtOAc (Scheme 7). As previously observed,11c owing to the
symmetry of the molecule, the reaction proceeded faster as
compared with dione 21, and on completion after 16 h (TLC),
elimination of the solvent afforded quantitatively the ketone
More straightforward conversion of cyclopropyl alcohol 2 to
isophytal (1) — not investigated in this study — would be
desirable. Nevertheless, the results presented in this
publication are not without interest. In addition to being
transposable to the synthesis of an advanced fragment of
juvenile hormone 59 from dione 51, the strategy we used to
prepare the key cyclopropyl-carbinol intermediate 2 should
be applicable to the synthesis of a variety of cyclopropane
derivatives and of unsaturated compounds. The ready
availability of diones 21 and 51 combined with the mildness
of the conditions used in the allylation step, and in the
elimination of the sulfonyl group, makes β-ketosulfones 37
and 54 a valuable alternative to the commonly-used pathway
5
2a, which was silylated with TESOTf to give, after
purification by column chromatography, the pure (by NMR)
ketone 52b in good yield (overall 72%, from 51). Reacting
5
2b with the lithium anion of sulfone 33 then gave the
hydroxysulfone 53 (91%) as a mixture of two diastereomers
by NMR). Without further purification, this condensation
(
product was reacted with the TsF•DBU reagent in acetonitrile.
Though proceeding more slowly, as compared with 34b, after
1
6 h heating at ca. 35 °C the reaction was completed (by
TLC) and the usual processing, followed by recrystallization
from Et O/hexane afforded 54 (65%) as white crystals whose
2
starting from γ-butyrolactone
4 and proceeding via
structure 54 was confirmed by X-ray analysis. Reacting this
sulfone with the carbonate 55a of alcohol 55b (prepared in
corresponding β-ketoesters, thereby improving significantly
the already valuable olefination methodology developed by
Johnson.
2
5
three steps from prenol 56 as described ) under Tsuji
conditions, and then treating the resulting sulfone 57 (78%)
with aluminium in moist THF26 furnished in good yield
Finally, ironically, since gem-diones are accessible by
oxidation of 2-alkenes,27 as illustrated below (Scheme 8), the
Norrish II/pinacol/homoallylic rearrangement sequence that
has been used in present work makes 2-pentene 60 a formal
synthetic equivalent of an isopentene residue, an analogy that
suggests possible applications in the isotopic labelling of
isoprenyl derivatives.
(75%) the C1-C9 fragment 58 of Hyalophora cecropia
juvenile hormone (59).
3
. Conclusion
Initially conceived for the use of dinitrile 5 in the synthesis of
phytyl derivatives, this study has evolved into a convenient
synthesis of aldehyde 1 from 2,3-pentanedione 21 and
geranylacetone 46. Crucial in this approach was the selective
pinacol rearrangement of an unsymmetrical cyclobutane
glycol, a challenging task that was solved by taking
advantage of the electron-withdrawing properties of the

CaH
Pyridine, triethylamine and 2,4,6-collidine were distilled
from CaH . CH was stirred for 2 d with K CO and added
copper bronze, filtered on neutral alumina, and then distilled
from CaH (Bp 55-60 °C at 10 Torr). Tosyl chloride and PPh
were re-crystallized from hexane. Methallyl alcohol, ethyl
chloroformate, oxalyl chloride, thioanisole, TiCl and
2 4 3 4 3
, then P O10 (CH CN); P O10 (pentane, hexane, CHCl )].
2
2
I
2
2
3
2
3
4
3 2 2
BF •Et O were distilled from CaH . Tosyl fluoride was
prepared using a protocol adapted from literature.28 In an
argon atmosphere, KF (“spray dried” grade; 11.6 g, 200
mmol) was added to a solution of TsCl (19.06 g, 100 mmol)
4
. Experimental
in CH
rt for 30 h. The residue left by evaporation of the solvents in
a vacuum was diluted with CH Cl and the solids were
3
CN (100 mL) and the resulting mixture was stirred at
General. Infrared (IR) spectra were recorded in KBr pellets
on a Perkin Elmer Spectrum One apparatus. Excepted
otherwise indicated H and 13C NMR spectra were recorded
on a Bruker Avance-300 apparatus at 300 and 75 MHz,
respectively; Bruker DPX-400 for 400 MHz 1H NMR
experiments. Chemical shifts (δ) are reported in parts per
million relative to the solvent resonance as the internal
2
2
eliminated by filtration on a sintered funnel. Concentration of
the filtrate in a vacuum then afforded TsF (16.4 g, 94%) as a
1
2 3 3
white solid (mp 40 °C). [Pd dba •CHCl ] was freshly
prepared from PdCl as described in Ref. 29. Ethyl methallyl
2
3
0
carbonate (prepared according to literature ) was distilled
before use (Bp 59 °C at 10 Torr). Diones 21 and 51,
geranylacetone 46, prenol 56, t-butyldimethylsilyl chloride, t-
3
standard [CD(H)Cl , 7.26 and 77 ppm respectively]. Signal
multiplicity is described as s, singlet; d, doublet; t, triplet; m,
multiplet; br, broad. Melting points (mp) have been measured
on an Electrothermal apparatus. Elemental analyses were
realized at the laboratory of analyses of the Faculty of
Chemistry of the University of Strasbourg. GC-MS analyses
were performed on a Shimadzu-QP5050 GCMS apparatus.
GC analyses were performed on a HP 6890 apparatus
equipped with a HP-5 crosslinked 5% Ph-Me Siloxane (30 m
x 0.32 m x 0.25 mm). TLC analyses were performed on silica
gel (60 GF254 Merck); with spot visualisation by exposure to
butyldimethylsilyl triflate,
trietylsilyl triflate, DBU,
were used as
diethylaminosulfur trifluoride, Al(O-i-Prop)
3
received (all reagents from Fluka-Sigma-Aldrich). All other
reagents were available. n-BuLi solutions (in hexane; only
freshly opened bottles were used) were titrated with N-
pivaloyl-o-toluidine.31 Aluminium (ca. 4xcm2 pieces of
aluminium foil) was activated just before use by treatment
with 2% aqueous HgCl
2
as described in Ref. 26b. Raney®
nickel was activated in situ by stirring vigorously the
commercial slurry (in water) in EtOH for a few hours and
then siphoning off the supernatant, these operations being
repeated twice. Zinc powder was activated in situ by
treatment with TMSCl as previously reported.32 pH 2 tartaric
buffer was prepared by adding NaOH pellets to 0.7 M tartaric
acid (Universal paper as an indicator). For all hydrogenation
experiments, 5% Pd/C (ca. 4-5 mg/mmol) was added to a
2 4
UV light (254 nm) or treatment with the H SO /vanillin
reagent, alkaline KMnO or iodine vapour. Column
4
chromatography refers to the Stille method using Merck 60H
silica gel; unless it is otherwise stated, a slow gradient of
solvents was realized. All experiments were performed in
dried glassware, under an argon atmosphere with magnetic
stirring. All solvents used were freshly distilled from an
appropriate reagent [Na.benzophenone (ether, THF, toluene);
degassed solution of the substrate in EtOAc (ca.
mL/mmol). The resulting mixture was stirred at rt in a H
atmosphere, and then filtered on a bed of Celite® (washings
4
2
2 2 2 2 3
Mg (MeOH, EtOH), CaH (CH Cl , DMF); K CO (EtOAc);

with CH
2
Cl
2
). The residue left by evaporation of the solvents
cooling (ice bath), TESCl (5.8 mL, 35 mmol) and the
preceding 18b/22 mixture (2 g, 20 mmol), diluted with DMF
(10 mL) were added sequentially with a syringe. The cooling
bath was removed and the reaction mixture was further
stirred at rt for 2 d before being diluted with 1 M HCl (40
mL) and hexane (30 mL). After vigorous stirring, the aqueous
layer was extracted with hexane (3 x 15 mL) and the pooled
organic phases were washed with brine (3 x 20 mL), and
was purified by column chromatography. Irradiations were
performed using a Philipps HPK-125 UV lamp. X-ray
analyses: the crystals were placed in oil, and a single crystal
was selected, mounted on a glass fibre and placed in a low-
temperature N
carried out on a Nonius Kappa-CCD diffractometer equipped
with an Oxford Cryosystem liquid N device, using Mo-Kα
radiation (λ = 0.71073 Å). The crystal-detector distance was
6 mm. The cell parameters were determined (Denzo
software33a) from reflections taken from one set of 10 frames
1.0° steps in phi angle), each at 20 s exposure. The structures
were solved by Direct methods using the program SHELXS-
7.33b The refinement and all further calculations were
2
stream. X-ray diffraction data collection was
2
4
dried (MgSO ). The coloured residue left by evaporation of
3
the solvents was purified by column chromatography
(hexane/EtOAc) to give, after thorough elimination of the
solvents in a vacuum, 18c as a colourless oil (2.79 g, overall
(
f
65% from 21); TLC (hexane:ether = 4:1) R = 0.58; IR (neat,
-1
9
cm ): 1956, 1877, 1790, 1270, 1214, 1039, 1013, 816, 744;
carried out using SHELXL-2013.33c The H-atoms were
included in calculated positions and treated as riding atoms
using SHELXL default parameters. The non-H atoms were
refined anisotropically, using weighted full-matrix least-
1H NMR (CDCl
1.43 (s, 3H), 2.02-2.09 (m, 2H), 2.66-2.87 (m, 2H); 13C NMR
3
): δ 0.57-65 (m, 6H), 0.91-0.96 (m, 9H),
(CDCl
3
2 3 2
): δ 5.9 (CH Si), 6.8 (CH CH ), 23.9 (CH3), 29.4
(C3H ), 38.8 (C4H
2
2
3
), 89.3 (C2), 210.5 (C=O); MS (CI-NH ):
+
+
2
m/z 232 (M + NH ), 215 (M + H ), 185, 157, 131, 115, 102;
squares on F .
4
Anal. Found: C, 61.87; H, 10.25 %. Calcd for C11
22 2
H O Si:
2
-Hydroxy-2-methylcyclobutan-1-one 18b: In a 1-L round-
C, 61.63; H, 10.34 %
bottom flask connected to an argon/vacuum line, and
equipped with a 10 cm-long Pyrex finger containing the lamp,
EtOAc (950 mL) was thoroughly degassed (two
freeze/pump/thaw cycles). Dione 21 (10 g, 100 mmol),
diluted with EtOAc (ca. 30 mL) was added with a syringe
and, after the flask was tightly wrapped in a foil of
aluminium, the resulting yellow solution was irradiated with
gentle stirring until the reaction was complete (30 h), as
indicated by disappearance of the yellow colour, almost as a
titration. The solvents were eliminated in a vacuum to give a
1-Methyl-2-oxocyclobutyl 4-nitrobenzoate 18d: In a flask
connected to an argon line, with stirring, DMAP (425 mg,
6.96 mmol) and DCC (718.4 mg, 6.96 mmol) were added
sequentially to a cooled (ice bath) solution of hydroxyketone
18b (232.6 mg, 2.32 mmol) and p-nitrobenzoic acid (426.0
mg, 2.55 mmol) in CH
2
Cl
2
(5 mL). After a further 6 h stirring
Cl (10
at 0 °C, the reaction mixture was diluted with CH
2
2
mL) and 0.2 M HCl (6 mL). The organic phase was washed
with 0.2 M HCl (2 x 6 mL), brine (3 x 7 mL), and dried
4
(MgSO ). The solvents were evaporated and the coloured
9
2/8 mixture (GC) of 18b and 22 respectively as a pale-
residue was chromatographed on silica gel (hexane/EtOAc)
yellow oil (10 g, 100%); IR (neat, cm ): 3418, 1788; 13C
NMR (CDCl ): δ 22.1, 28.1, 39.2, 88.3, 212.2; MS (CI-NH ):
m/z 118 (M + NH ), 101 (M + H ), 83, 72, 55. Dimer 22:
-1
to give ester 18d (176.2 mg, 30%) as a white solid; TLC
-1
3
3
(hexane:ether = 1:1) R
f
= 0.56; mp 141 °C; IR (KBr, cm ):
+
+
1
4
1791, 1728, 1346, 1284, 1207, 1103, 1013, 843, 716; H
+
+
MS (CI-NH
3
): m/z 218 (M + NH
27, 116, 99.
-Methyl-2-[(triethylsilyl)oxy]cyclobutan-1-one 18c: In a
4
), 201 (M + H ), 183, 141,
NMR (CDCl
2.75 (m, 1H), 2.91-3.03 (m, 1H), 3.23-3.35 (m, 1H), 8.16-
8.19 (m, 2H), 8.26-8.29 (m, 2H); 13C NMR (CDCl
): δ 20.3
(CH ), 26.4 (C3H ), 39.8 (C4H ), 90.2 (C2),
123.8/131.1/134.5/150.9 (Carom), 163.6 [C=O(O)], 205.5
3
3
): δ 1.63 (s, 3H, CH ), 2.12-2.21 (m, 1H), 2.65-
1
2
3
flask connected to an argon line, 2,4,6-collidine (4.6 mL, 35
mmol) was diluted with DMF (10 mL) and, with stirring, and
3
2
2

(
C=O); Anal. Found: C, 57.72; H, 4.80%. Calcd for
hydroxycyclobutanone 18b (1 g, 10 mmol) and sulfone 33
(3.12 g, 20 mmol). Isolated: 4:1 mixture (GC, NMR) of,
respectively, sulfones cis-34a and trans-34a (914 mg, 35%)
12 5
C H11NO
: C, 57.83; H, 4.45%.
General protocol for cyclobutanone/sulfone condensation
experiments. All these experiments were similarly realized
and only that with ketone 18c and methyl phenyl sulfone 33
is described.
as a thick colourless oil; TLC (hexane:ether = 1:1) R
1H NMR (CDCl
): δ 1.35 (s, 2.4 H, CH ), 1.45 (s, 0.6H,
CH ), 1.62-2.32 (m, 4H), 3.32-3.70 (m, 2H),
2.47/3.22/3.86/4.15 (4 s, 2H, 2 OH), 7.54-7.70 (m, 3H), 7.91-
7.97 (m, 2H); 13C NMR (CDCl
, signals of the trans isomer
in red): δ 22.5/22.7 (CH ), 27.7/28.4 (CH ), 29.1/34.5 (CH ),
60.6/60.9 (SO CH ), 74.5/75.8 (C2), 76.7/77.2 (C1),
127.6/127.7 (Carom), 129.3/129.4 (Carom),133.9/134.0 (Carom),
f
= 0.08;
3
3
3
2
-Methyl-1-[(phenylsulfonyl)methyl]-2-
[(triethylsilyl)oxy]cyclobutan-1-ol 34b: In a flask connected
3
to an argon/vacuum line, a solution of sulfone 33 (156 mg, 1
mmol) in THF (4 ml) was thoroughly degassed (three
freeze/pump/thaw cycles). The flask was immersed in a dry-
ice/acetone bath and, with stirring, 1.6 M (in hexane) n-BuLi
3
2
2
2
2
3 4
140.6/140.8 (Carom); MS (CI-NH ): m/z 274 (M + NH
+), 257
+
(625 µL) was added with a syringe. After 30 min stirring, a
(M + H ), 256, 239, 216, 174, 132, 115, 97. By hydrolysis of
sulfone 34b: In an argon atmosphere, HF.pyridine (20 µL,
0.588 mmol) was added to a stirred solution of the 28/72
mixture of cis-34b and trans-34b (219 mg, 0.590 mmmol) in
degassed solution of ketone 18c (92.5 mg, 0.43 mmol) in
THF (2 mL) was added with a cannula. The temperature was
then allowed to rise gradually to -50 °C. After 30 min
stirring, the cooling bath was removed and the reaction
mixture was diluted with ether (3 mL) and water (4 mL). The
aqueous layer was extracted with ether (3 x 5 mL) and the
pooled organic phases were washed with water (6 mL), brine
CH
2
Cl
2
(2 mL). After 5 min stirring at rt, the reaction mixture
Cl (5 mL). The
was diluted with 1 M HCl (2 mL) and CH
2
2
aqueous layer was extracted with CH
pooled organic phases were washed with brine (3 x 3 mL),
and dried (K CO ). Purification of the residue left by
2 2
Cl (3 x 5 mL) and the
(2 x 6 mL), and dried (MgSO
4
). The solvents were
2
3
evaporated in vacuum and the solid residue was
a
evaporation of the solvents by column chromatography
(hexane/EtOAc) afforded, after thorough elimination of the
solvents in a good vacuum, a 28/72 (GC, NMR) mixture of,
respectively, cis-34a and trans-34a as a thick colourless oil
(150 mg, 99%).
chromatographed on silica gel (hexane/EtOAc) to give, after
thorough elimination of the solvents in a good vacuum, a
2
8:72 (GC) mixture of, respectively, cis-34b and trans-34b
(133 mg, 83%) as a white solid; TLC (hexane:ether = 1:1) R
f
1
=
0.33; mp 64 °C; H NMR (CDCl
), 0.85-0.95 (m, 9H, SiCH CH
), 1.56-2.35 (m, 4H, CH ), 3.32-3.86 (m, 3H, SO
OH), 7.50-7.70 (m, 3H), 7.91-7.98 (m, 2H); 13C NMR
3
): δ 0.47-0.62 (m, 6H,
Trans-2-methyl-1-[(phenylthio)methyl]-2-
SiCH
2
2
3
), 1.33/1.35 (2 s, 3H,
CH
[(triethylsilyl)oxy]cyclobutan-1-ol trans-36 and cis-2-
methyl-1-[(phenylthio)methyl]-2-
CH
3
2
2
2
,
[(triethylsilyl)oxy]cyclobutan-1-ol cis-36: In
a
flask
(
CDCl
.9/7.0 (SiCH
1.2/34.9 (CH
9.5/79.5 (C1), 127.7/128.5 (Carom), 129.0/129.3 (Carom),
33.5/133.81 (Carom), 141.2/141.3 (Carom); MS (CI-NH ): m/z
3
, signals of the trans isomer in red): δ 6.1/6.3 (SiCH
CH ), 22.4/23.7 (CH ), 27.5/28.1 (CH
), 60.0/62.1 (SO CH
2
),
connected to an argon/vacuum line, a solution of thioanisole
35 (62 µL, 0.54 mmol) in THF (1.2 mL) was thoroughly
degassed and then cooled to –78 °C (dry ice/acetone bath).
With stirring, 1.6 M (in hexane) n-BuLi (337 µL, 0.81 mmol)
was added with a syringe and the resulting mixture was
stirred 2 h at –78 °C, and then 20 h at rt before being cooled
to ca. 0 °C (ice bath). A solution of ketone 18c (77.5 mg, 0.36
mmol) in THF (1.5 mL) was added with a syringe and, after
stirring 1 h at rt, the reaction mixture was diluted with ether
(2 mL) and water (3 mL). The aqueous layer was extracted
6
3
7
1
3
9
1
3
2
3
3
2
),
2
2
2
), 77.9/77.9 (C2),
3
+
+
38 (M + NH
4
), 371 (M + H ), 256, 239, 229, 216, 173, 132,
7.
-Benzenesulfonylmethyl-2-methyl-cyclobutane-1,2-diol
4a: General protocol for cyclobutanone/sulfone
condensation experiments. In THF (80 mL). From

with ether (3 x 3 mL) and the pooled organic phases were
washed with 1 M HCl (3 mL), brine (3 x 4 mL), and dried
0.88 (t, J = 8.0 Hz, 9H), 1.35 (s, 3H), 1.56-1.82 (m, 3H),
2.20-2.30 (m, 1H), 3.44 (dd, J = 14.0, 1.1 Hz, 1H), 3.54 (d, J
= 15.0 Hz, 1H), 3.84 (s, 1H, OH), 7.55-7.69 (m, 3H), 7.93-
(
MgSO
solvents in vacuo was chromatographed on silica gel
hexane/ether) to give successively the trans cyclobutanol
4
). The coloured residue left by evaporation of the
7.96 (m, 2H); 13C NMR (CDCl
): δ 6.3 (SiCH
), 31.2 (CH ), 60.0
3
2
), 7.0
(
(CH CH ), 22.4 (CH ), 27.5 (CH
2
3
3
2
2
trans-36 (42 mg, 35%) and the cis isomer cis-36 (18 mg,
5%). trans-36: TLC (hexane:ether = 1:1) R
= 0.74; 1
NMR (CDCl ): δ 0.56 (q, J = 7.8 Hz, 6H), 0.91 (t, J = 7.8 Hz,
H), 1.32 (s, 3H), 1.60-1.89 (m, 3H), 2.03-2.15 (m, 1H), 3.05
d, J = 1.2 Hz, 2H), 3.73 (s, 1H, OH), 7.05-7.10 (m, 1H),
(SO
2
CH
2
), 77.9 (C2), 79.5 (C1), 127.7 (Carom), 129.3 (Carom),
): m/z 388 (M +
4
NH ), 371 (M + H ), 256, 239, 229, 216, 173, 132, 97; Anal.
1
f
H
133.8 (Carom), 141.2 (Carom); MS (CI-NH
3
+
+
3
9
Found: C, 58.23, H, 8.38 %. Calcd for C18
C, 58.34; H, 8.16 %.
30 4
H O SSi:
(
7
.16-7.21 (m, 2H), 7.31-7.35 (m, 2H); 13C NMR (CDCl
3
): δ
Trans-1-methyl-2-[(phenylsulfonyl)methyl]cyclobutane-
1,2-diol trans-34a: In a flask connected to an argon line, with
6
.2 (SiCH ), 6.9 (CH CH ), 23.3 (CH ), 28.9 (CH ), 33.4
2
2
3
3
2
(
CH
2
), 41.4 (SCH
2
), 78.3 (C2), 79.1 (C1), 125.7 (Carom),
2
stirring, TBAF.3 H O (22 mg, 0.067 mmol) was added to a
1
28.7 (Carom), 129.3 (Carom), 137.9 (Carom); MS (CI-NH
3
): m/z
cooled (ice bath) solution of sulfone trans-34b (25 mg, 0.067
mmol) in THF (200 µL). After 5 min stirring, the reaction
+
3
39 (M + H ), 229, 207, 173, 132, 115, 97. cis-36: TLC
1
(hexane:ether = 1:1) R
f
= 0.65; H NMR (CDCl
3
): δ 0.54 (q, J
4
mixture was diluted with ether (2 mL) and 1 M KHSO (1
=
8.0 Hz, 6H), 0.90 (t, J = 8.0 Hz, 9H), 1.30 (s, 3H), 1.56-
mL). The aqueous phase was extracted with ether (3 x 1 mL)
and the pooled organic phases were washed with brine (3 x 2
1
3
.80 (m, 4H), 2.70 (s, 1H, OH), 3.12 (d, J = 13.4 Hz, 1H),
.45 (dd, J = 13.4, 1.0 Hz, 1H), 7.06-7.23 (m, 3H), 7.32-7.37
4
mL), and dried (MgSO ). The residue left by evaporation of
(
m, 2H); 13C NMR (CDCl
3
): δ 6.3 (SiCH
2
), 7.0 (CH
2
CH
3
),
the solvents was purified by column chromatography
(hexane/EtOAc) to give, after elimination of the solvents in a
vacuum, diol-sulfone trans-34a as a white solid (15.4 mg,
2
7
3.1 (CH
3
), 27.7 (CH
2
), 31.0 (CH ), 42.6 (SCH
2
2
), 78.7 (C2),
9.1 (C1), 128.1 (Carom), 128.9 (Carom), 129.5 (Carom), 137.9
+
(C
arom); MS (CI-NH
3
): m/z 339 (M + H ), 229, 207, 173, 132,
f
90%); TLC (hexane:EtOAc = 1:1) R = 0.08; mp 73 °C
115, 97.
[monocrystals obtained by slow diffusion (in a NMR tube) of
1
Trans-2-methyl-1-[(phenylsulfonyl)methyl]-2-
(triethylsilyl)oxy]cyclobutan-1-ol trans-34b: With stirring,
NaHCO (60 mg, 0.71 mmol) and m-CPBA (62 mg, 0.472
mmol) were added sequentially to a cooled (ice bath) solution
of sulfide trans-36 (40 mg, 0.118 mmol) in CH Cl (350 µL).
The resulting mixture was further stirred for 40 min at 0 °C,
cyclohexane into a solution of trans-34a in CDCl
(CDCl
3
]; H NMR
[
3
): δ 1.45 (s, 3H), 1.70-1.94 (m, 3H), 2.14-2.22 (m,
3
1H), 2.48 (s, 1H, OH), 3.52 (d, J = 14.1 Hz, 1H), 3.67 (d, J =
14.1 Hz, 1H), 3.86 (s, 1H, OH), 7.54-7.70 (m, 3H), 7.91-7.97
(m, 2H); 13C NMR (CDCl
2
2
3
3 2
): δ 22.5 (CH ), 28.4 (CH ), 29.1
(CH ), 60.6 (SO CH ), 74.5 (C2), 76.7 (C1), 127.6 (Carom),
2
2
2
and then 1 h at rt before being diluted with CH
2
Cl
2
(5 mL)
3
129.4 (Carom), 134.0 (Carom), 140.6 (Carom); MS (CI-NH ): m/z
+
+
and 0.25 M Na
2
S
2
O
3
(2 mL). The aqueous layer was
(3 x 5 mL) and the pooled organic
274 (M + NH
4
), 257 (M + H ), 256, 239, 216, 174, 132, 115,
extracted with CH
2
Cl
2
97; crystal data C12H O
16 4
S, MW= 256.31, 0.06 x 0.04 x 0.04
phases were washed with 10% NaHCO
3
(6 mL), brine (6
mm, Monoclinic, space group P 2
1
/c, T = 173 K, a =
mL), and dried (MgSO ). The solid residue left by
4
9.3097(2), b = 16.8291(5), c = 7.8017(2) Å, β = 90.234(5)°,
3
-1
evaporation of the solvents was purified by column
chromatography (hexane/EtOAc) to give, after elimination of
the solvents in a vacuum, sulfone trans-34b (34.9 mg, 80%)
V = 1222.31(5) Å , λ (Mo-Kα) = 0.71073 Å, µ = 0.265 mm .
A total of 6370 reflections were measured and 3562 were
independent. Final = R1 = 0.0469, wR2 = 0.1361 (2677 refs; I
> 2σ(I)), and GOF = 1.074 (for all data, R1 = 0.0687, wR2
= 0.1543).
f
as a white solid; TLC (hexane:ether = 1:1) R = 0.33; mp 64
1
°
C; H NMR (CDCl
3
, 400 MHz): δ 0.53 (q, J = 8.0 Hz, 6H),

General protocol for BF
3
-mediated rearrangement
65%) as a thick oil.
experiments. All these experiments were similarly realized
and only that with sulfone 34a is described.
General protocol for TsF•DBU-mediated rearrangement
experiments. All these experiments were similarly realized
and only that with hydroxysulfone 34b is described.
1-(1-Methylcyclopropyl)-2-(phenylsulfonyl)ethan-1-one
37: In a flask connected to an argon line, the 28:72 cis-
34b/trans-34b mixture (157 mg, 0.423 mmol) and tosyl
1
3
-(1-Methylcyclopropyl)-2-(phenylsulfonyl)ethan-1-one
7: In a flask equipped with a condenser connected to an
3 2
argon line, BF .Et O (73 µL, 0.57 mmol) was added with a
syringe to a stirred solution of the 28:72 mixture of diol-
sulfones cis-34a and trans-34a (178 mg, 0.48 mmol) in
3
fluoride (296 mg, 1.7 mmol) were diluted with CH CN (1.6
CHCl
stirring at 70 °C (oil bath) for 3 h before being cooled, and
poured into a stirred mixture of 10 M NH Cl (2 mL) and
3
(415 µL). The reaction mixture was heated with
mL). With stirring, DBU (245 µL, 1.7 mmol) was added with
a syringe. Within a few minutes, the yellow colour initially
developed changed to orange. After 18 h stirring at rt, when
the reaction was completed in TLC, the reaction mixture was
4
CH
2
2
Cl
Cl
2
2
(3 mL). The aqueous phase was extracted with
(2 x 4 mL) and the pooled organic extracts were
CH
diluted with CH
aqueous phase was extracted with CH
pooled organic extracts were washed with 0.1 M HCl (7 mL),
brine (2 x 7 mL), and dried (MgSO ). The solvents were
2
Cl
2
(11 mL) and 0.1 M HCl (8 mL). The
washed with 10 M NH
4
Cl (4 x 1 mL), brine (2 x 4 mL), and
2
2
Cl (3 x 5 mL) and the
dried (MgSO ). The residue left by elimination of the
4
solvents was chromatographed on silica gel (hexane/EtOAc)
to give successively ketosulfone 37 (89.4 mg, 75%) as a
white solid, and a thick colourless oil identified as cis-34a by
4
evaporated and the coloured residue was purified by column
chromatography (hexane/EtOAc) to give, after thorough
elimination of the solvents in a good vacuum, a white solid
(mp 78 °C) identified as ketosulfone 37 by NMR (92.7 mg,
92%).
GC-mass and NMR (30 mg, 25%); TLC (hexane:EtOAc =
1
2
:1) R
f
= 0.43; mp 78 °C; H NMR (CDCl
3
): δ 0.84 (m, 2H, 2
), 4.17 (s, 2H,
), 7.55-7.70 (m, 3H), 7.89-7.92 (m, 2H; 13C NMR
): δ 19.0 (2 CH ), 19.4 (CH ), 28.1 (CCH ), 61.8
CH ), 128.9 (Carom), 129.3 (Carom), 134.1 (Carom), 139.1
CHH), 1.30 (m, 2H, 2 CHH), 1.35 (s, 3H, CH
3
SO
2
CH
CDCl
SO
2
General protocol for DAST-mediated rearrangement
experiments. All these experiments have been realized using
the same protocol and only that with hydroxysulfone 34b is
described.
(
(
(
3
2
3
3
2
2
3 4
arom), 199.3 (C=O); MS (CI-NH ): m/z 256 (M + NH
+),
C
+
2
39 (M + H ), 116, 99, 72; Anal. Found: C, 60.53; H, 5.88%.
1-{1-[(Phenylsulfonyl)methyl]cyclopropyl}ethan-1-one 38:
In a plastic tube capped with a septum, and connected to an
argon line, the 28:72 mixture of sulfones cis-34b and trans-
1
Calcd. for C12
H
14
O
3
S: C, 60.48; H 5.92%. cis-34a: H NMR
(
CDCl
H), 2.16-2.29 (m, 1H), 3.26 (brs, 1H, OH), 3.36 (d, J = 14.4
Hz, 1H), 3.47 (d, J =14.4 Hz, 1H), 4.15 (brs, 1H, OH), 7.54-
.68 (m, 3H), 7.90-7.95 (m, 2H); 13C NMR (CDCl
): δ 22.7
CH ), 27.7 (CH ), 34.5 (CH ), 60.9 (SO CH ), 75.8 (C2),
3
): δ 1.34 (s, 3H), 1.65-1.83 (m, 2H), 1.85-1.95 (m,
1
2 2
34b (46 mg, 0.124 mmol) was diluted with CH Cl (400 µL)
and, with stirring, DAST (17 µL, 0.136 mmol) was added
7
3
with a syringe. The resulting orange mixture was stirred 30
(
3
2
2
2
2
min at rt before being diluted with CH
aqueous NaHCO (2 mL). The aqueous layer was extracted
with CH Cl (3 x 2 mL) and the pooled organic phases were
washed with brine (2 x 3 mL), and dried (MgSO ). The
2 2
Cl (1 mL) and 10%
7
7.2 (C1), 127.7 (Carom), 129.3 (Carom), 133.9 (Carom), 140.8
arom); MS (CI-NH ): m/z 274 (M + NH
+), 257 (M + H+),
56, 239, 216, 174, 132, 115, 97; Anal. Found: C, 56.37; H,
.42%. Calcd for C12 S: C, 56.23; H, 6.29%. Using the
:1 cis-34a/trans-34a mixture: In CHCl (1 mL), with added
3
(C
3
4
2
2
2
6
4
4
H
16
O
4
residue left by elimination of the solvents in a vacuum was
purified by column chromatography (hexane/EtOAc) to give
3
BF
3
.Et
2
O (107 µL, 0.84 mmol). From 34a (145 mg, 0.565
ketone 38 (24 mg, 81%) as a white solid; TLC (1:1
1
mmol). Isolated: ketosulfone 37 (39 mg, 24%) as a white
solid (mp 78 °C), and the cis diol-sulfone cis-34a (94 mg,
hexane:EtOAc) R
f
= 0.23; mp 78 °C; H NMR (CDCl
3
): δ
1.19-1.23 (m, 2H, 2 CHH), 1.35-1.40 (m, 2H, 2 CHH), 1.90

(
s, 3H, CH
3
), 3.58 (s, 2H, SO
.92 (m, 2H); 13C NMR (CDCl
7.5 (C), 59.9 (SO CH ), 128.5 (Carom), 129.2 (Carom), 133.9
2
CH
2
), 7.52-7.68 (m, 3H), 7.89-
4
with 1 M KHSO (1 mL) and ether (2 mL). The aqueous
7
2
3
): δ 15.2 (2 CH
2
), 23.9 (CH
3
),
phase was extracted with ether (3 x 1 mL) and the pooled
organic extracts were washed with brine (3 x 2 mL), and
2
2
(
C
arom), 139.7 (Carom), 204.2 (C=O); MS (CI-NH
3
): m/z 256
), 239 (M + H ), 125, 97, 77; Anal. Found: C,
0.51; H, 5.99%. Calcd for C12 S: C, 60.48; H, 5.92%.
DAST-mediated rearrangement of diol-sulfone 34a:
General protocol. In CH Cl (900 µL), with added DAST (39
µL, 0.295 mmol). From the 28:72 diastereomeric mixture
75.4 mg, 0.294 mmol). Isolated: β-ketosulfone 37 (52 mg,
4%; mp 78 °C) and methyl ketone 38 (13.8 mg, 20%; mp 78
C), both identified by GC and NMR.
t-Butyldimethyl{2-methyl-1-[(phenylsulfonyl)methyl]-2
4
dried (MgSO ). The residue left by elimination of the
+
+
(
M + NH
4
solvents in a vacuum was chromatographed on silica gel
6
H
14
O
3
(hexane/EtOAc) to give, successively: the sulfone 34f (39.1
mg, 54%) as a white solid and the diol-sulfone 34a (22 mg,
1
2
2
44%); TLC (hexane/EtOAc = 3 :1) R
f
= 0.25; mp 115 °C; H
NMR: δ 0.17/0.18 (2 s, 3H, 2 SiCH
1.42 (s, 3H, C2CH ), 1.80-2.17 (m, 4H, 2 CH
13.8, 1H), 3.68 (d, J = 13.8 Hz, 1 H), 3.87 (s, 1H, OH), 7.52-
7.67 (m, 3H), 7.92-7.98 (m, 2H); 13C NMR (CDCl
): δ -0.7
(SiCH ), 0.0 (SiCH ), 20.2 [C(CH )], 25.3 (C2CH ), 27.9
3 3
), 0.93 [s, 9H, C(CH )],
(
3
2
), 3.48 (d, J =
7
°
3
3
3
3
3
[(triethylsilyl)oxy]cyclobutoxy}silane 34e: With stirring,
3 2 2 2 2
[C(CH )], 30.6/30.9 (C3H /C4H ), 64.8 (SO CH ), 80.6 (C1),
TBDMS triflate (204 µL, 0.890 mmol) and 2,4,6-collidine
83.2 (C2), 129.4/131.3/135.5/143.8 (Carom); MS (CI-NH
3
):
(197 µL, 1.485 mmol) were added sequentially to a cooled
(ice bath) solution of the 28:72 cis-34b/trans-34b mixture
(220 mg, 0.593 mmol) in DMF (600 µL). After 3 h stirring at
m/z 353 (M – OH), 313, 255, 229, 199, 185, 171, 135, 73;
Anal. Found: C, 58.60; H, 7.97%. Calcd for C18
58.34; H, 8.16%.
30 4
H O SSi: C,
rt, the reaction mixture was processed as usual to give, after
purification by column chromatography (hexane/EtOAc)
followed by elimination of the solvents in a good vacuum,
sulfone 34e (same diastereomeric ratio as 34b; by GC) as a
1-(1-Methylcyclopropyl)-2-(phenylsulfonyl)ethan-1-one
37 by DAST-mediated rearrangement of sulfone 34f:
2 2
General protocol (see above). In CH Cl (322 µL), with
added DAST (13 µL, 0.093 mmol). From the O-TBDMS
derivative 34f (30 mg, 0.085 mmol). Isolated: β-ketosulfone
37 (15.6 mg, 77%) as a white solid (mp 78 °C).
thick colourless oil (150 mg, 52%); TLC (hexane:EtOAc =
1
1
7:3) R
f
= 0.46; H NMR (CDCl
3
): δ 0.21/0.29 (2 s, 6H, 2
), 0.82-0.89 (m, 9H, 3
], 1.30/1.32 (2 s, 3H,
2
), 3.23/3.35 (2 dd, J = 14.8,
SiCH
3
2
), 0.47-0.56 (m, 6H, 3 SiCH
CH ), 0.93 [s, 9H, C(CH
), 1.60-2.95 (m, 4H, 2 CH
2
2-Methyl-1-[3-methyl-1-(phenylsulfonyl)butyl]-2-
SiCH
3
3
)
3
[(triethylsilyl)oxy]cyclobutan-1-ol 41a: General protocol
for cyclobutanone/sulfone condensation experiments. In THF
(8 mL); -78 °C to rt (1 h). From ketone 18c (230 mg, 1.07
mmol) and isopentyl phenyl sulfone 42 (394.5, 1.86 mmol).
Isolated: 41a (62/38 mixture of the cis- and the trans-isomer
by GC and NMR) as a white solid (402.3 mg, 86%); TLC
C2CH
3
1
2
.2 Hz, 1H, SO CHH), 3.64/3.81 (2 d, J = 14.8 Hz, 1H,
SO
2
CHH), 7.51-7.65 (m, 3H), 7.90-7.96 (m, 2H); 13C NMR
(
CDCl
3
): δ -2.3 (SiCH
.0/7.2 (CH CH ), 20.2 [C(CH
6.1/26.2 [C(CH )], 28.2/28.3 (C3H
3
), -2.0 (SiCH
)], 25.6/25.7 (C2CH
), 34.9/35.2 (C4H
3
), 6.3/6.4 (SiCH
2
3
2
),
),
),
7
2
6
1
2
3
3
(hexane:EtOAc = 2:1) R
= 0.33; mp 94 °C; 1H NMR
f
3
2
2.6/62.7
(SO
2
CH
2
),
79.4/79.7
(C2/C3),
(CDCl ): δ 0.50-1.06 (2m, 22H), 1.35 (s, 1.8H), 1.51 (s,
3
27.5/129.2/133.3.141.5 (Carom); MS (CI-NH
3
): m/z 485 (M +
1.2H), 1,55-2,25 (m, 6H), 3.25 (dd, J = 10.5, 2.2 Hz, 0.6H),
3.31 (s, 0.6H), 3.66 (s, 0.4H), 3.89 (dd, J = 7.7, 3.3 Hz,
0.4H), 7.48-7.66 (m, 3H), 7.86-7.98 (m, 2H); 13C NMR
+
H ), 455, 427, 353, 227, 211, 199, 115, 104, 87, 59.
2
-[(t-Butyldimethylsilyl)oxy]-1-methyl-2-
(phenylsulfonyl)methyl]cyclobutan-1-ol 34f: With stirring,
TBAF.3 H O (62 mg, 0.19 mmol) was added to a cooled (ice
[
(CDCl
3
): δ 6.0/6.3 (SiCH
2
), 6.9/7.2 (SiCH
2
CH
), 25.9/26.5 (CH),
), 64.5/68.4
81.1/84.2 (C1),
3
), 21.3/21.5
2
(CH ), 22.6/23.2 (C2CH
3
3
), 24.1/24.8 (CH
3
bath) solution of sulfone 34e (94.5 mg, 0.19 mmol) in THF (3
29.2/30.6 (CH
2
), 31.3/34.3 (CH
2 2
), 34.3/35.8 (CH
mL). After 5 min stirring, the reaction mixture was diluted
(CHSO ),
2
76.8/79.6 (C2),

1
27.8/128.5/129.0/129.5/133.5/133.9/141.2/141.3 (Carom).
3
PPh and, with a syringe, a degassed solution of ketosulfone
4
-Methyl-1-(1-methylcyclopropyl)-2-
37 (43 mg, 0.18 mmol) and ethyl methallyl carbonate (52 mg,
0.36 mmol) in THF (300 µL). After 2 h stirring at rt, when
(phenylsulfonyl)pentan-1-one 43: General protocol for BF
3
-
mediated pinacol rearrangement experiments. In CHCl (200
3
the reaction was completed in TLC, the reaction mixture was
®
µL), with added BF
1a (96.2 mg, 0.225 mmol). Isolated: ketosulfone 43 (36.4
mg, 55%) as a white solid, and the cis diol-sulfone cis-41b
3
.Et
2
O (34 µL, 0.27 mmol). From sulfone
filtered on Celite (washings with CH
2
Cl
2
). The filtrates were
4
concentrated in a vacuum and the residue was purified by
column chromatography (hexane/EtOAc) to give a white
solid (47 mg, 90%) identified as 44 by NMR; TLC
(25.3 mg, 36%) as a thick oil; TLC (hexane:EtOAc = 1:1) R
f
1
= 0.37; mp 57 °C; 1H NMR
f
=
0.53; mp 113 °C; H NMR (CDCl
3
): δ 0.83 (d, J = 6.6 Hz,
(hexane:EtOAc = 3:1) R
(CDCl ): δ 0.76 (m, 1H, CHH), 0.86 (m, 1H, CHH), 1.28 (m,
1H, CHH), 1.38 (m, 1H, CHH), 1.41 (s, 3H, C(O)CCH ),
1.65 (s, 3H, C=CCH ), 2.47-2.62 (m, 2H, SO CHCH ), 4.58
(dd, J = 10.2, 4.3 Hz, 1H, SO CH), 4.59 (m, 1H, C=CHH),
4.76 (m, 1H, C=CHH), 7.52-7.59 (m, 2H), 7.64-7.71 (m, 1H),
3
3
7
H), 0.88 (d, J = 6.6 Hz, 3H), 1.24-1.44 (m, 4H), 1.45 (s,
3
H), 1.64-1.84 (m, 2H), 4.55 (dd, J = 10.5, 3.6 Hz, 1H), 7.51-
3
.58 (m, 2H), 7.64-7.70 (m, 3H); 13C NMR (CDCl
), 20.5 (2 CH ), 21.9 (CHCH ), 23.2 (CHCH
CHMe ), 28.4 (C), 37.3 (SO CHCH ), 67.7 (SO
): δ 20.1
), 26.1
CH),
):
3
3
2
2
(CH
3
2
3
3
2
(
2
2
2
2
7.76-7.80 (m, 2H); 13C NMR (CDCl
): δ 19.9 (C=CCH
], 28.6 [C(O)CCH
),
],
1
28.8/129.9/134.2/136.7 (Carom), 204.2 (C=O); MS (CI-NH
3
3
3
+
m/z 295 (M + H ), 171, 153, 143, 127, 109, 95, 77, 55; Anal.
20.0 (CH ), 20.1 (CH ), 22.6 [C(O)CCH
2
2
3
3
Found: C 65.41; H 7.38%. Calc for C16
.53%. cis-1-Methyl-2-[3-methyl-1-
phenylsulfonyl)butyl]cyclobutane-1,2-diol cis-41b: TLC
hexane:EtOAc = 1:1) R , 400
= 0.35; 1H NMR (CDCl
H
22
O
3
S: C 65.28; H,
36.5 (SO
2 2 2 2
CHCH ), 67.7 (SO CH), 114.3 (C=CH ), 128.9
7
(Carom), 130.0 (Carom), 134.3 (Carom), 136.7 (C=CH
2
), 139.9
+
(
(Carom), 203.3 (CO); MS (CI-NH
3
): m/z 293 (M + H ), 151,
(
f
3
95, 83, 55; Anal. Found: C, 66.02; H, 7.14%. Calcd for
MHz): δ 0.78 (d, J = 6.4 Hz, 3H), 0.86 (d, J = 8 Hz, 3H),
C
16
H
20
O
3
S: C, 65.73; H, 6.89%. Hydrogenation (5% Pd/C, 1
1
1
7
2
.29 (s, 3H), 1.45-2.25 (m, 7H), 3.39 (dd, J = 10.0, 1.8 Hz,
atm H ) of sulfone 44 (26 mg, 88.9 mmol) in EtOAc
2
H) 3.48 (s, 1H, OH), 3.91 (s, 1H, OH), 7.56-7.61 (m, 2H),
afforded, after the usual processing, sulfone 43 (25.1 mg,
96%) as a white solid (mp and mixed mp: 113 °C).
2,6,10-Trimethylundec-1-ene 61: Wittig methylenation of
tetrahydrogeranylacetone 62 to 61 has previously been
reported.34 An improved procedure using Hoshima reagent
conditions35 is described below.
.65-7.70 (m, 1H), 7.88-7.92 (m, 2H); 13C NMR (CDCl
): δ
3
1.5 (2 CH ), 23.8 (C2CH ), 25.6 (CHMe ), 29.4
3
3
2
(SO
2 2 2 2 2
CHCH ), 34.1 (CH ), 36.8 (CH ), 67.1 (SO CH), 75.7
(C2), 80.5 (C1), 128.5 (Carom), 129.5 (Carom), 134.1 (Carom),
3 4
40.4 (Carom); MS (CI-NH ): m/z 330 (M + NH
+), 313 (M +
1
+
H ), 295, 171, 151, 143, 127, 114, 99; Anal. Found: C, 61.19;
Geranylacetone 46 was hydrogenated to 62 (5% Pd/C,
1
H, 8.02%. Calcd for C16
H
24
O
4
S: C, 61.51; H, 7.74%.
EtOAc, 1 atm H
RMN (CDCl
Hz, 6H); 1.00-1.66 (m, 12H); 2.13 (s, 3H); 2.39 (t, J = 7.5
Hz, 2H); 13C RMN (CDCl
): δ 19.4, 21.4, 22.4, 22.5, 24.6,
27.9, 29.5, 32.6, 36.5, 37.1, 39.3, 208.3; MS (CI-NH ): m/z
), 199 (M + H ), 140, 124, 109, 95, 85, 71, 58.
2
); TLC (hexane:ether = 3:1) R
f
= 0.45; H
General protocol for Tsuji allylation experiments. All
these experiments were similarly realized and only the
homolagation of ketosulfone 37 to 44 using ethyl methallyl
carbonate is described.
3
): δ 0.76 (d, J = 6.4 Hz, 3H); 0.86 (d, J = 6.6
3
3
+
+
4
-Methyl-1-(1-methylcyclopropyl)-2-
phenylsulfonyl)pent-4-en-1-one 44: With stirring, in a flask
equipped with a tube containing PPh (11 mg, 36.0 mmol),
216 (M + NH
4
(
In a flask connected to an argon/vacuum line, activated zinc
powder (5.9 g, 90.7 mmol) was covered with THF (120 mL)
and the resulting mixture was thoroughly degassed (three
3
2 3 3
and connected to an argon/vacuum, [Pd dba .CHCl ] (6.4
mg, 5.4 mmol) was diluted with THF (450 µL). The resulting
2 2
freeze/pump/thaw cycles). With stirring, CH I (4.1 mL, 50.4
solution was thoroughly degassed before adding sequentially
mmol) was added dropwise with a syringe and, 30 min later,

2.57 (d, J = 5.2 Hz, 1H); 13C NMR (CDCl
): δ 19.6 (CH
), 24.8 (CH
the flask was immersed in a dry ice/methanol bath. With
good stirring, TiCl (4.45 mL, 440.3 mmol) was added
3
3
),
2
),
2
),
4
20.9 (CH ), 22.6 (CH ), 22.7 (CH ), 22.7 (CH
3
3
3
2
progressively with a syringe. The cooling bath was removed
and after 30 min stirring a degassed solution of 62 (2 g, 10.08
mmol) in THF (20 mL) was transferred dropwise into the
flask with a cannula. The reaction mixture was stirred at rt for
a further 1 h before being diluted with ether (50 mL) and 1 M
HCl (100 mL). The solids were eliminated by filtration on a
sintered funnel (washings with ether) and the aqueous layer
was extracted with ether (3 x 40 mL). The pooled organic
phases were washed with water (2 x 50 mL), brine (50 mL),
27.8 (CH), 32.7 (CH), 37.0 (CH
2
), 37.1 (CH
2
), 37.2 (CH
39.3 (CH
2
), 53.9 (CH
2
), 57.0 (C); MS (CI-NH
3
): m/z 230 (M
+
+
+ NH
4
), 213 (M + H ), 180, 169, 137, 123, 109, 95, 85, 72,
55; Anal. Found: C, 79.22; H, 13.07%. Calcd for C14
79.18; H 13.29%.
H28O: C,
6,10-Dimethyl-2-methyleneundecan-1-ol exo-47b and
(E/Z)-2,6,10-trimethylundec-2-en-1-ol endo-47b: Epoxide
45 (1g, 4.7 mmol) was refluxed with aluminium isopropoxide
(2.88 g, 14.1 mmol) in toluene (24 mL) for 5 h. After cooling
to rt, the reaction mixture was poured into a stirred mixture of
ether (50 mL) and pH 2 tartaric buffer (100 mL). The
aqueous layer was extracted with ether (3 x 20 mL) and the
pooled organic phases were washed with pH 2 tartaric buffer
4
and dried (MgSO ). The residue left by evaporation of the
solvents was purified by column chromatography (hexane) to
give, after thorough elimination of the solvents in a vacuum,
6
9
0
1
1 as a colourless oil (1.404g, 71%); TLC (hexane:ether =
1
:1) R
f
= 0.9; H NMR (CDCl
3
): δ 0.86 (d, J = 6.5 Hz, 3H),
4
(30 mL), brine (2 x 30 mL), and dried (MgSO ). Purification
.87 (d, J = 6.6 Hz, 6H), 1.05-1.50 (m, 12H), 1.72 (m, 3H),
.99 (t, J = 7.6 Hz, 2H), 4.66-4.69 (m, 2H); 13C NMR
of the residue left by evaporation of the solvents by column
chromatography (hexane/EtOAc) afforded, after elimination
of the solvents in a good vacuum, a 2:1 mixture (by GC and
(
CDCl
3
): δ 19.7 (CH
3
), 22.4 (CH
), 25.1 (CH ), 28.0 (CH), 32.7 (CH), 36.7 (CH
), 38.2 (CH
3
), 22.6 (CH
3
), 22.7 (CH
3
),
),
2
3
4.8 (CH
2
2
2
2
1H NMR) of alcohols exo-47b and endo-47b as a colourless
1
7.3 (CH
2
), 39.4 (CH
2
), 109.5 (C=CH
2
), 146.3
oil (971 mg, 97%); TLC (hexane:ether = 4:1) R
f
= 0.32; H
+
+
(
C); MS (CI-NH
3
): m/z 214 (M + NH
38, 123, 109, 95, 81, 71, 59.
-(4,8-Dimethylnonyl)-2-methyloxirane 45: With stirring,
4
), 197 (M + H ), 179,
NMR (CDCl
3
): δ 0.83-0.87 (4 s, 13.5H, CH
3
), 1.02-1.58 (m,
), 1.97-2.05
1
18.5H), 1.65/1.77 (2 s, 1H, E and Z-CH=CCH
3
2
2 2 2 3
(m, 2H, CH C=CH and CH CH=CCH ), 3.98/4.05/4.12 (3 s,
m-CPBA (2.05 g, 9.15 mmol) was added progressively to a
cooled (ice bath) solution of olefin 61 (1.2 g, 6.11 mmol) in
2H, CH
2
O), 4.85/5.00 (2 s, 1.3H, C=CH
2
), 5.28/5.38 (2 t, J =
):
7.1 Hz/J = 8.0 Hz, 0.4H, E- and Z-CH=CMe); MS (CI-NH
3
+
+
CH
2
Cl
2
(60 mL). After 30 min, the cooling bath was removed
m/z 230 (M + NH
4
), 213 (M + H ), 194, 179, 165, 151, 139,
and the reaction mixture was stirred for a further 30 min
123, 109, 95, 81, 69.
before being poured into 10% NaHCO
3
(60 mL). Na
2
SO
3
Ethylcarbonates exo-47a and endo-47a: Pyridine (408 µL,
5 mmol) and ethyl chloroformate (444 µL, 4.62 mmol) were
added sequentially with a syringe to a cooled (ice bath)
solution of the preceding alcohol mixture (901 mg, 4.2
mmol) in ether (10 mL). The bath was removed and the
reaction mixture was further stirred for 3.5 h at rt before
(0.4 g) was added and the resulting mixture was vigorously
2
stirred 10 min. The aqueous layer was extracted with CH Cl
2
(
3 x 30 mL) and the pooled organic phases were washed with
0% NaHCO (2 x 20 mL), brine (20 mL), and dried
MgSO ). The residue left by evaporation of the solvents was
diluted with CH Cl and then filtered on silica gel (washings
1
3
(
4
2
2
4
being poured into 10% NH Cl. The aqueous phase was
with CH
2
Cl
2
) to give, after thorough elimination of the
extracted with ether (3 x 5 mL) and the pooled organic
extracts were washed with water (2 x 6 mL), brine (6 mL),
solvents in a good vacuum, epoxide 45 (1.102 g, 85%) as a
1
colourless oil; TLC (hexane:ether = 9:1) R
f
= 0.47; H NMR
and dried (MgSO
the solvents was purified by column chromatography
(hexane/EtOAc) to give 2:1 mixture (by GC) of,
4
). The oily residue left by elimination of
(CDCl
3
): δ 0.84 (d, J = 6.5 Hz, 3H), 0.86 (d, J = 6.6 Hz, 6H),
1
.01-1.65 (m, 14H), 1.29 (s, 3H), 2.55 (d, J = 4.9 Hz, 1H),
a

respectively, exo-47a and endo-47a as a colourless oil (1.07
nickel (ca. 3 g) for 5 h. After cooling, the reaction mixture
was filtered on Celite® (washings with ethanol) and the
1
g, 89%); TLC (hexane:EtOAc) R
f
= 0.47; H NMR (CDCl
3
):
δ 0.82-0.87 (4 s, 13.5H, CH
2 s, 1 H, CH C=CH), 1.97-2.10 (m, 2H, CH
CH CH=C), 4.09/4.19 (2 q, J = 7.1Hz, 2H), 4.49/4.55/4.63 (3
3
), 1.08-1.53 (m, 23H), 1.66/1.77
4
filtrates were dried (MgSO ), and concentrated in a vacuum.
(
3
2
C=CH
2
,
The residue was purified by column chromatography
(hexane/EtOAc) to give, after evaporation of the solvents in a
vacuum, an oily product (377.3 mg) constituted of ketones 20
2
2 2
s, 2H, CH O), 4.94/5.04 (2 s, 1.4H, C=CH ), 5.39/5.48 (2 t, J
=
7.1 Hz/J = 7.0 Hz, 0.4H, E- and Z-CH=C(Me); 13C NMR
3
and 49, as estimated by GC-mass; 20: MS (CI-NH ): m/z 295
+
(
CDCl
3
): δ 14.2 (CH
2.6 (CH ), 24.9 (CH
), 36.4 (CH
O), 66.4 (CH
3
), 19.6 (CH
), 25.0 (CH
), 36.6 (CH
3
), 21.8 (CH
3
), 22.5 (CH
3
),
),
(M + H ), 266, 125, 111, 98, 83, 69, 55. 49: MS (CI-NH
3
)
+
+
2
3
6
3
2
2
), 27.9 (CH), 32.6 (CH),
4
m/z 315 (M + NH ), 297 (M + H ), 196, 165, 126, 113, 95,
3.3 (CH
2
2
2
2
), 37.2 (CH
2
), 39.3 (CH
2
85, 72, 57. In an argon atmosphere, with stirring, LAH (42
mg, 1.1 mmol) was added to a cooled (ice bath) solution of
the desulfonylation product (294.5 mg, 1.0 mmol) in ether
(4.5 mL). After 1 h stirring at ca. 0 °C, the reaction mixture
3.9 (CH
2
O), 70.0 (CH
2
2
O), 72.8 (CH O), 73.7
(CH
2
O), 112.6 (C=CH
2
), 129.0 (CH=C), 129.1 (CH=C),
1
1
1
8
31.1 (CH=C), 132.0 (CH=C), 143.7 (C=CH ), 153.1 (C=O),
2
+
55.3 (C=O); MS (CI-NH
23, 109, 95, 81, 69, 55.
3
): m/z 285 (M + H ), 194, 179, 152,
2 4
was diluted with ether (1 mL) and 10% aqueous Na SO was
added progressively until formation of a past (ca. 1 mL). The
solids were eliminated by filtration on a sintered funnel
(washings with ether) and the filtrates were washed with 0.1
,12-Dimethyl-1-(1-methylcyclopropyl)-4-methylene-2-
(
phenylsulfonyl)tridecan-1-one 48: General protocol for
Tsuji-allylation experiments. In THF (3.7 mL), with added
Pd dba .CHCl ] (46 mg, 25.9 mmol) and PPh (80.2 mg,
06 mmol). From ketosulfone 37 (365 mg, 1.53 mmol) and
4
M HCl (5 mL), brine (2 x 6 mL), and dried (MgSO ). The
[
2
3
3
3
residue left by elimination of the solvents was
chromatographed on silica gel (hexane/ether) to give,
successively: the alcohol 50 (88 mg, 29%) and the
3
the exo-47a/endo-47a carbonate mixture (825 mg, 3.06
mmol). Isolated: ketosulfone 48 (612.3 mg, 92%) as a
cyclopropyl carbinol 2 (207 mg, 69%), both as clear
1
1
colourless oil. TLC (hexane:EtOAc = 3:1) R
f
= 0.5; H NMR
colourless oil; TLC (hexane:ether = 3:2) R
f
= 0.40; H NMR
(
CDCl
7.4 Hz, 2H, C5H
0.2, 4.3 Hz, 1H, SO
H, C=CHH), 7.52-7.58 (m, 2H), 7.64-7.72 (m, 1H), 7.77-
3
): δ 0.76-0.86 (m, 11H), 0.95-1.55 (m, 17H), 1.88 (t, J
), 2.47-2.62 (m, 2H, C3H ), 4.58 (dd, J =
CH), 4.62 (m, 1H, C=CHH), 4.76 (m,
(CDCl
3H, CCH
CHO); 13C NMR (CDCl
17.1/17.2 (CCH ),
31.7/33.6/33.7/37.4/37.5/39.4
32.9/33.0/33.1 (CH), 79.5/79.7 (CHOH); MS (CI-NH
3
3
): δ 0.26-0.35 (m, 4H), 0.82-0.88 (m, 12H), 1.01 (s,
=
2
2
3
), 1.02-1.58 (m, 20H, in which OH), 2.77 (m, 1H,
1
1
7
2
2
3
2
3
): δ 11.4/11.5/11.8/11.9 (CH
19.7/19.8 (CH
(CH ), 28.1
2
),
),
3
3
.83 (m, 2H); 13C NMR (CDCl
): δ 19.7 (CH
), 22.8 (CH
), 19.9 (CH
),
),
),
3
3
3
2
2
2
(C12H),
) m/z
0.1 (CH ), 20.2 (CH ), 22.7 (CH
2
2
3
3
), 24.9 (CH
), 36.2 (CH
), 37.4 (CH
), 128.9 (Carom), 130.0 (Carom),
34.3(Carom), 136.8 (C=CH ) 144.2 (Carom), 203.3 (C=O); MS
5.1 (CH
6.3 (CH
SO CH), 112.9 (C=CH
2
), 28.1 (CH), 32.7 (CH), 34.8 (CH
2
296 (M), 279, 268, 250, 239, 196, 165, 126, 111, 95, 85, 71,
2
), 36.7 (CH ), 37.3 (CH
2
2
2
), 67.9
57; HRMS found: m/z 296.3087; calcd for C20H40O:
1
(
2
2
296.3079. 50: TLC (hexane:ether = 3:2) R
f
= 0.50; H NMR
1
2
(CDCl
OH), 3.37 (m, 1H, CHO); 13C NMR (CDCl
(CH ), 13.2/13.3 (CH ), 19.7/19.8/20.0.22.8/22.9 (CH
24.5/24.6/24.7/24.9/25.0/26.2/26.3 (CH ), 28.1 [C(CH
(CH
3
): δ 0.84-0.95 (m, 18H), 1.01-1.65 (m, 23H, in which
+
(CI-NH
3
): m/z 433 (M + H ), 291 (M – SO
2
C
6
H
5
), 194, 151,
3
): δ 11.9/12.0
1
09, 95, 83, 55; Anal. Found: C, 72.54; H, 9.67%. Calcd for
S: C, 72.18; H 9.32%.
,8,12-Trimethyl-1-(1-methylcyclopropyl)tridecan-1-ol 2:
3
3
3
2
2
),
],
),
C
26
H
40
O
3
2
3
)
4
31.1/33.2/33.4/33.5/33.6/33.7/37.4/37.6/39.4
32.9/33.0/33.1/40.0/40.1/40.6/40.7 (CH),
In a flask equipped with a condenser connected to an argon
line, with stirring, β-ketosulfone 48 (600 mg, 1.38 mmol)
was heated to reflux in EtOH (12 mL) with activated Raney
3
75.4/75.5/76.2/76.4 (CHO); MS (CI-NH ) m/z 280 (M-18),
241, 197, 167, 139, 125, 111, 97, 83, 69, 57; HRMS found:

m/z 298.3243; calcd for C20
H
42O: 298.3236.
at ca. 100 °C (bath) for 10 h. After cooling, the reaction
mixture was diluted with water (10 mL) and extracted with
ether (3 x 10 mL). The pooled organic phases were washed
(E)-1-bromo-3,7,11,15-tetramethylhexadec-3-ene 11: The
protocol used is essentially that described by Johnson.1a In a
flask connected to an argon line, with stirring, a solution of
4
with brine (3 x 5 mL), dried (MgSO ), and evaporated.
PBr
3
(18 µL, 0.185 mmol) in ether (870 µL) was added
Chromatography of the residue on silica gel (hexane/ether)
dropwise with a syringe to a cooled (dry-ice/acetone bath)
mixture of alcohol 2 (47.2 mg, 0.16 mmol), collidine (82 µL)
and LiBr (16.1 mg, 0.185 mmol) diluted with ether (870 µL).
After 20 h stirring at rt, the flask was immersed in an ice bath
and collidine (50 µL) was added, followed by water (3 mL).
The aqueous layer was extracted with pentane (4 x 1 mL) and
afforded acetate 12a as a colourless oil (114.5 mg, 83%);
1
TLC (hexane:ether = 9.1) R
0.82-0.88 (m, 12H, 4 CH
f
= 0.43; H NMR (CDCl
3
): δ
),
3
), 1.02-1.58 (m, 17H, 3 CH, 7 CH
2
3 2 3
1.63 (s, 3H, C3CH ), 1.90-2.03 (m, 5H, C5H , C(O)CH ),
2.28 (t, J = 7.0 Hz, 2H, C2H
5.17 (tq, J = 6.8, 1.3 Hz, 1H, C4H); 13C NMR (CDCl
15.9 (C3CH ), 19.5/19.6/19.7 (C7CH /C11CH
2
), 4.12 (t, J = 7.0 Hz, 2H, C1H
2
),
3
): δ
the pooled organic phases were washed with 10% NaHCO
3
3
3
3
), 21.0
(
2 x 1 mL), brine (1 mL), and dried (MgSO ). The residue
4
3 3
[C(O)CH ], 22.6/22.7 (2 C15CH ), 24.4/24.8/25.6
left by evaporation of the solvents was diluted with ether
870 µL) and then added, with stirring, to a cooled (ice bath)
suspension of anhydrous ZnBr (37.0 mg, 0.164 mmol) in
(C5H
36.8/37.0/37.1/37.3/37.4/37.5/38.7/39.4
(C2H /C6H /C8H /C10H /C12H /C14H
2 2 2
/C9H /C13H ), 28.0 (C15H), 32.5/32.8 (C7H/C11H),
(
2
2
2
2
2
2
2
), 63.2 (C1H
2
),
ether (870 µL). After 3 h stirring at ca. 0 °C, the reaction
mixture was diluted with pentane (1 mL) and brine (1 mL).
The aqueous layer was extracted with pentane (4 x 1 mL) and
the pooled organic extracts were washed with brine (2 x 1
127.7 (C4H), 130.4 (C3), 171.1 (C=O); MS (CI-NH
3
): m/z
278 [M – OC(O)CH ], 179, 123, 109, 95, 82, 68, 57.
3
(E)-3,7,11,15-tetramethylhexadec-3-en-1-ol 12b: Acetate
12a (50.0 mg, 0.16 mmol) was stirred in methanol with
mL), and dried (K
2
CO
3
). The residue left by elimination of
added K
mixture was concentrated in a vacuum and the residue was
diluted with CH Cl . The solids were eliminated by filtration
2 3
CO (44.2 mg, 0.32 mmol) for 3 h at rt. The reaction
the solvents was purified by filtration on a column of neutral
alumina (washings with pentane) to give, after thorough
elimination of the solvents in a good vacuum, the bromide 11
2
2
2 2
on a sintered funnel (washings with CH Cl ) and the pooled
(48.6 mg, 84%) as a colourless oil; TLC (hexane:ether = 9:1)
filtrates were dried (MgSO ), and evaporated. The residue
4
1
R
f
= 0.70; H NMR (CDCl
3
): δ 0.83-0.89 (m, 12H, 4 CH
), 1.63 (s, 3H, C3CH ), 1.92-
), 2.53 (t, J = 7.6 Hz, 2H, C2H ), 3.43 (t, J
7.6 Hz, 2H, C1H
), 5.22 (tq, J = 7.1, 1.2 Hz, 1H, C4H); 13
3
),
was purified by column chromatography (hexane/ether) to
1
.01-1.58 (m, 17H, 3 CH, 7 CH
2
3
give alcohol 12b as a viscous oil (39.7 mg, 84%); TLC
1
2
.08 (m, 2H, C5H
2
2
(hexane:ether = 7:3) R
0.88 (m, 12H, 4 CH
f
= 0.16; H NMR (CDCl
3
): δ 0.83-
), 1.63
=
2
C
3
), 1.01-1.58 (m, 17H, 3 CH, 7 CH
2
NMR (CDCl
3
): δ 15.5 (C3CH
3
), 19.6/19.7 (C7CH
3
/C11CH
3
),
),
(s, 3H, C3CH
2H, C2H ), 3.64 (t, J = 6.2 Hz, 2H, C1H
1.2 Hz, 1H, C4H); 13C NMR (CDCl
): δ 15.6 (C3CH
19.6/19.7 (C7CH C11CH ), 22.6/22.7 (2 C15CH
3
), 1.91-2.10 (m, 2H, C5H
2
), 2.24 (t, J = 6.2 Hz,
2
2
3
2.6/22.7 (2 C15CH
3
), 24.4/24.8/26.5 (C5H
2
/C9H /C13H
2
2
2
2
), 5.23 (td, J = 7.1,
7.9 (C15H),
32.4/32.8
(C7H/C11H),
3
3
3
),
),
1.7/36.9/37.3/37.4/37.5/39.4/42.9
3
/
3
(
C1H
2
/C2H
2
/C6H
2
/C8H
2
/C10H
2
/C12H
2
/C14H
2
),
128.4
24.4/24.8/25.6 (C5H
2
/C9H
2
2
/C13H ), 28.0 (C15H), 32.5/32.8
+
(
C4H); 131.4 (C3); MS (CI-NH
3
): m/z 360 (M + H ), 245,
(C7H/C11H),
37.0/37.1/37.3/37.4/39.4/42.7
1
96, 153, 139, 126, 111, 97, 83, 69, 57.
(C2H
2
/C6H
2
/C8H
2
/C10H
2
/C12H
2
2 2
/C14H ), 60.1 (C1H ),
(E)-3,7,11,15-tetramethylhexadec-3-en-1-yl acetate 12a:
128.6 (C4H), 130.8 (C3); MS (CI-NH
3
): m/z 279 (M - OH),
With stirring, in a flask equipped with a condenser connected
to an argon line, bromide 11 (146.4 mg, 0.408 mmol) was
heated in DMF (1 mL) with NaOAc (36.8 mg, 0.449 mmol)
196, 138, 123, 111, 95, 81, 69, 57.
(E)-3,7,11,15-tetramethylhexadec-3-enal
13:
Swern
oxidation of alcohol 12b (35 mg, 0.118 mmol) with DMSO

(
51 µL, 0.567 mmol) and 1 M (in CH
2
Cl
2
) (COCl)
2
(260 µL,
(83 µL,
55.
0
0
2
.269 mmol) in CH
2
Cl
2
(0.6 mL), with added NEt
3
2-Ethyl-2-[(triethylsilyl)oxy]cyclobutan-1-one 52b:
A
.591 mmol) was realized using a protocol described in Ref.
a. Processing the reaction mixture as usual afforded, after
solution of 3,4-hexadione 51 (5.7 g, 50 mmol) in EtOAc (500
mL) was irradiated for 16 h under the conditions used with
21 to give, after thorough elimination of the solvents in a
vacuum, the hydroxyketone 52a as a pale-yellow oil (5.6 g,
purification by column chromatography (hexane/ether), a
colourless oil (29.1 mg, 84%) identified as aldehyde 13 by
98.2%); 13C NMR (CDCl
NMR and mass analyses; TLC (hexane:ether = 7:3) R
f
=
3
3 2 3
): δ 7.8 (CH ), 26.5 (CH CH ),
1
0
.52; H NMR (CDCl
3
): δ 0.83-0.88 (m, 12H, 4 CH
), 1.66 (s, 3H, C3CH ), 1.94-2.16
), 3.03 (t, J = 2.6 Hz, 2H, C2H ), 5.31 (tq, J =
.1, 1.4 Hz, 1H, C4H), 9.60 (t, J = 2.6 Hz, 1H, C1H); 13C
): δ 16.8 (C3CH ), 19.5/19.7 (C7CH / C11CH ),
/C9H /C13H ),
(C7H/C11H),
3
), 1.02-
28.6 (C3H ), 39.8 (C4H ), 91.8 (C2), 211.4 (C=O). At 0 °C
2
2
1
.58 (m, 17H, 3 CH, 7 CH
2
3
(ice bath), TES triflate (17.2 mL, 76 mmol) was added
dropwise to a stirred solution of 52a (5.1 g, 44.7 mmol) and
collidine (10.1 mL, 76 mmol) in DMF (25 mL). The bath was
removed and after a further 4 h stirring at rt the reaction
mixture was processed as usual to give, after purification by
column chromatography (hexane/ether), the TES ether 52b as
(
m, 2H, C5H
2
2
7
NMR (CDCl
3
3
3
3
2
2
3
2.6/22.7 (2 C15CH
3
), 24.4/24.8/25.6 (C5H
2
2
2
8.0 (C15H),
32.5/32.8
7.0/37.1/37.3/37.4/38.5/39.4
/C8H /C10H /C12H /C14H
a colourless oil (7.32 g; overall 72%); TLC (hexane:ether =
1
(C6H
2
2
2
2
2
), 54.3 (C2H
2
), 125.9
4:1) R
f
= 0.74; H NMR (CDCl
3
): δ 0.64 (m, 6H), 0.96 (m,
CH ), 2.05 (m, 2H, C3H ),
); 13C NMR (CDCl
): δ 5.9 (SiCH ), 6.8
), 7.9 (CH ), 27.2 (CH CH ), 30.3 (C3H ), 38.8
), 92.6 (C2), 211.2 (C=O); Anal. Found: C, 63.36; H,
Si: C, 63.10; H, 10.59%.
(
C4H); 131.4 (C3), 200.0 (C=O); MS (CI-NH
3
): m/z 295 (M
12H), 1,68 (q, J = 7.4 Hz, CH
2
3
2
+
+
H ), 277, 194, 163, 149, 123, 111, 97, 84, 69, 55.
2.72 (m, C4H
2
3
2
Phytal (1): A solution of aldehyde 13 (25 mg, 0.085 mmol)
in 0.5 M (in MeOH) NaOH (0.5 mL) was stirred 2 h at rt
before being diluted with ether (3 mL) and water (2 mL). The
aqueous layer was extracted with ether (4 x 1 mL) and the
pooled organic phases were washed with brine (3 x 2 mL),
SiCH
2
2
CH
3
3
2
3
2
(C4H
24 2
10.47%. Calcd for C12H O
2-Ethyl-1-[(phenylsulfonyl)methyl]-2-
[(triethylsilyl)oxy]cyclobutan-1-ol 53: General protocol for
cyclobutanone/sulfone condensation experiments. In THF (90
mL). From ketone 52b (2.92 g, 12.8 mmol) and sulfone 33
(2.0 g, 12.8 mmol). Isolated: hydroxysulfone 53 (65:35
mixture of the trans- and the cis-isomer, by GC and NMR) as
and dried (MgSO
evaporation of the solvents by column chromatography
hexane/ether) afforded a colourless oil (22.2 mg, 89%)
identified as a 7:3 mixture of E- and Z-phytal 1 respectively
GC-mass, NMR); TLC (hexane:ether = 7:3) R = 0.42, 0.40;
1H NMR (CDCl
): δ 0.81-0.89 (m, 12H, 4 CH ), 0.95-1.65
m, 19H, 3 CH, 8 CH ), 1.97 (s, 0.9H, C3CH ), 2.16 (s, 2.1H,
), 2.18 (t, J = 7.8 Hz, 1.4H, C4H ), 2.55 (t, J = 7.6 Hz,
4
). Purification of the residue left by
(
(
f
a pale-yellow oil (4.49 g, 91%); TLC (hexane:ether = 4:1) R
f
1
3
3
= 0.14; H NMR (CDCl
3
): δ 0.6-1.1 (m, 18H), 1.48-2.30 (m,
(
2
3
6H), 3.40 (brs, 0.7H), 3.41 (dd, J = 14.7, 1.3 Hz, 0.65H), 3.61
(d, J = 14.7 Hz, 0.65H), 7.59 (m, 3H), 7.94 (m, 2H) ; 13C
C3CH
3
2
0
0
.6H, C4H
2
), 5.86-5.91 (m, 1H, C2H), 9.96 (d, J = 8.2 Hz,
NMR (CDCl
3
): δ 6.7 (SiCH ), 8.38/8.46
2
), 7.11 (SiCH
2
CH
3
.3H, C1H), 9.99 (d, J = 8.0 Hz, 0.7H, C1H); 13C NMR
(CH ), 28.0/28.8 (CH
CH ), 29.2/29.5 (C3H ), 29.8/31.8
3
2
3
2
(
CDCl
3
): δ 17.6 (C3CH
2.7/22.8 (2 C15CH
8.0 (C15H),
3
), 19.6/19.7/19.8 (C7CH
3
/C11CH
3
),
),
(C4H
2 2 2
), 60.7/62.0 (SO CH ), 77.0/78.5 (C2), 81.0/82.6 (C1),
2
2
3
3
), 24.5/24.7/24.9 (C5H
2
/C9H /C13H
2
2
127.6/128.3/128.9/129.3/133.4/133.8/141.2/141.4 (Carom);
32.7/32.8
(C7H/C11H),
Anal. Found: C, 59.71; H, 8.73%. Calcd for C19
59.34; H, 8.39%.
32 4
H O SSi: C,
6.6/36.7/36.9/37.3/37.4/39.4/41.0
/C6H /C8H /C10H /C12H /C14H
(C4H
2
2
2
2
2
2
),
127.4/128.4
1-(1-Ethylcyclopropyl)-2-(phenylsulfonyl)ethan-1-one 54:
(
C2H); 164.4/165.0 (C3), 190.9/191.4 (C=O); MS (CI-NH
3
):
General protocol for TsF/DBU-mediated rearrangement
+
m/z 295 (M + H ), 277, 194, 163, 140, 121, 111, 97, 84, 69,
3
experiments. In CH CN (50 mL), with added TsF (7.6 g, 43.6

mmol) and DBU (6.53 mL, 43.6 mmol); 23 h at ca. 30-40 °C
bath). From sulfone 53 (4.64 g, 12 mmol). Obtained, after
re-crystallisation from ether/hexane: β-ketosulfone 54 (1.98
Anal. Found: C, 64.93; H, 7.78 %. Calcd for C16
C, 65.29; H, 7.53 %.
22 5
H O :
(
(E)-1-(1-Ethylcyclopropyl)-6-[(4-methoxybenzyl)oxy]-4-
methyl-2-[(phenylsulfonyl)methyl]hex-4-en-1-one 57:
f
g, 65%) as colourless crystals; TLC (hexane:ether = 3:7) R =
1
0
0
.41; mp 67 °C; H NMR (CDCl
3
): δ 0.87 (m, 2H, 2 CHH),
Ketosulfone 54 (400 mg, 1.58 mmol) and carbonate 55a (930
.90 (t, J = 7.3 Hz, 3H, CH
3
), 1.27 (m, 2H, 2 CHH), 1.64 (q,
mg, 3.16 mmol) were reacted in THF (7 mL) with added
J = 7.3 Hz, 2H, CH
2
CH
m, 3H), 7.90 (m, 2H); 13C NMR (CDCl
CH ), 26.3 (CH CH ), 34.3 (C), 61.2 (SO
28.6/129.1/134.1/139.0 (Carom), 198.5 (C=O); crystal data
3
), 4.06 (s, 2H, SO
2
CH
2
), 7.56-7.67
2 3 3 3
[Pd dba .CHCl ] (57 mg, 55 mmol) and PPh (41.5 mg,
(
(
3
): δ 11.6 (CH
3
), 16.1
CH ),
0.158 mmol) under the general Tsuji-allylation conditions
(see above). After 3 h stirring at rt, the reaction mixture was
filtered on Celite® (washings with ether) and the filtrates
2
2
3
2
2
1
C
13
H
16
O
3
S, MW= 252.32, 0.20
/n, T = 173 K, a = 15.1060(6), b
5.3930(3), c = 16.1750(9) Å, β = 108.160(3)°, V =
x
0.20 x 0.14 mm,
were concentrated in
a
vacuum. The residue was
Monoclinic, space group P 2
1
chromatographed on silica gel (hexane/ether) to give a
=
colourless oil (567 mg, 78%) identified as 57 by NMR
3
-1
= 0.22; 1H NMR
f
1
252.09(11) Å , λ (Mo-Kα) = 0.71073 Å, µ = 0.252 mm . A
analysis; TLC (hexane:ether = 1:1) R
(CDCl ): δ 0.86 (m, 1H, CHH), 0.89 (t, J = 7.4 Hz, 3H,
CH CH ), 1.08 (m, 1H, CHH), 1.51 (m, 3H, CHH, CH CH ),
1.57 (s, 3H, CH C=C), 1.76 (m, 1H, CHH), 2.54 (m, 2H,
SO CHCH ), 3.78 (s, 3H, OMe), 3.88 (d, J = 6.6 Hz, 2H,
CH OCH arom), 4.08 (dd, J = 10.7, 3.7 Hz, 1H, SO CH),
4.35 (s, 2H, OCH arom), 5.34 (brt, J = 6.6 Hz, 1H, C=CH),
6.64 (m, 2H, CaromH), 7.20 (m, 2H, CaromH), 7.54 (m, 2H,
aromH), 7.67 (m, 1H, CaromH), 7.77 (m, 2H, 2 CaromH; 13C
NMR (CDCl ): δ 11.4 (CH CH ), 15.7 (CH ), 16.1 (CH ),
16.7 (CH C=C), 26.3 (CH CH ), 34.9 (C), 38.7
total of 6345 reflections were measured and 3657 were
3
independent. Final = R1 = 0.0419, wR2 = 0.1069 (2696 refs; I
3
2
2
3
>
2σ(I)), and GOF =1.037 (for all data, R1 = 0.0662, wR2 =
3
0
.1180).
2
2
Ethyl {1-[(4-methoxybenzyl)oxy]-3-methylbut-3-en-2-yl}
2
2
C
2
carbonate 55a: Alcohol 55b was prepared from prenol 56 as
2
C
described;25 TLC (hexane:ether = 1:1) R = 0.32; 13C NMR
f
(
(
(
CDCl
3
): δ 18.8 (CH
3
), 55.25 (OCH
3
), 73.0 (2 CH
2
O), 73.9
C
CHOH), 112.0 (C=CH
2
), 113.9 (Carom), 129.4 (Carom), 130.0
3
2
3
2
2
C
arom), 143.8 (C=CH
2
), 159.4 (Carom). 55b (1.38 g, 6,21
3
2
3
mmol) was reacted with ethyl chloroformate (1.18 mL, 12.4
mmol) in ether (55 mL) with added pyridine (1.1 mL, 13.6
mmol) under the conditions used for carbonatation of the
exo-47b/endo-47b alcohol mixture (see above) to give, after
the usual processing, followed by purification by column
(SO
2
2
CHCH
2
), 55.3 (OCH
3
), 65.8 (C=CHCH
2
O), 66.7
),
(SO
CH), 71.7 (OCH
2
), 113.8 (Carom), 126.8 (C=CHCH
2
128.8 (Carom), 129.4 (Carom), 130.0 (Carom), 130.3 (Carom),
133.5 (C=CHCH
(Carom), 202.3 (C=O); Anal. Found: C, 68.61; H, 7.39%.
Calcd for C26 S: C, 68.39; H, 7.06%.
2
), 134.2 (Carom), 136.5 (Carom), 159.2
chromatography (hexane/ether), carbonate 55a as
a
=
),
32 5
H O
colourless oil (1.54 g, 84%); TLC (hexane:ether = 1:1) R
f
(E)-1-(1-Ethylcyclopropyl)-6-[(4-methoxybenzyl)oxy]]-4-
methylhex-4-en-1-one 58:
1
0
1
.58; H NMR (CDCl
3
): δ 1.30 (t, J = 7.1 Hz, 3H, CH
C=CH ), 3.51-3.62 (m, 2H, OCHCH
), 4.18 (q, J = 7.1 Hz, 2H, CH CH ), 4.49 (s,
2 3
CH
.74 (s, 3H, CH
3
2
2
), 3.79
In a flask connected to an argon line, freshly activated
aluminium (420 mg) was added to ketosulfone 57 (200 mg,
(
s, 3H, OCH
3
2
3
2
H, OCH
.19 (m, 1H, CHOH), 6.86 (m, 2H), 7.24 (m, 2H); 13C NMR
): δ 14.2 (CH CH ), 18.9 (CH C=CH ), 55.3 (OCH ),
4.0 (CH CH ), 70.2 (CHCH ), 72.9 (OCH ), 79.5
2
), 4.97 (brs, 1H, C=CHH), 5.06 (brs, 1H, C=CHH),
2
0.44 mmol) diluted with 9:1 THF/H O (12 mL). The resulting
5
mixture was stirred 4 h at rt, and then filtered on a sintered
funnel (washings with THF). The filtrates were concentrated
in a vacuum and the residue was diluted with ether (15 mL)
and water (10 mL). The aqueous phase was extracted with
ether (2 x 5 mL) and the pooled organic phases were washed
(CDCl
3
3
2
3
2
3
6
3
2
2
2
[CHO(CO)], 113.8 (Carom), 114.0 (CH
2
=C), 129.3 (Carom),
1
30.0 (Carom), 140.6 (C=CH ), 154.6 (C=O), 159.3 (Carom);
2

4
with brine (4 x 10 mL), and dried (MgSO ). The residue left
by evaporation of the solvents was purified by column
chromatography (hexane/ether) to give a colourless oil (103
References
# In memoriam, this paper is dedicated to Prof. Sir John
Cornforth, recipient of the 1975 Nobel Prize in Chemistry,
who passed away on 8th December 2013, as an
acknowledgement of his outstanding contributions to the
synthesis and biosynthesis of polyisoprene and steroid
derivatives.
mg, 75%) identified as 58 by NMR; TLC (hexane:ether =
1
1
:1) R
f
= 0.68; H NMR (CDCl
3
): δ 0.71 (m, 2 CHH), 0.93 (t,
J = 7.3 Hz, 3H, CH
CH
C(O)CH
2 3
CH ), 1.14 (m, 2H, 2 CHH), 1.62 (s, 3H,
3
C=C), 1.64 (q, J = 7.3 Hz, 2H, CH
2
CH
3
), 2.25 [m, 2H,
),
2
CH ], 2.41 [m, 2H, C(O)CH ], 3.75 (s, 3H, OCH
2
2
3
3
.97 (d, J = 6.7 Hz, 2H, CH
.34 (t, J = 6.7 Hz, 1H, C=CH), 6.86 (m, 2H), 7.25 (m, 2H);
): δ 11.9 (CH CH ), 15.6 (2 CH ), 16.7
C=C), 26.7 (CH CH ), 32.9 (C), 33.6 [C(O)CH CH ],
2 2
O), 4.41 (s, 2H, OCH Carom),
5
1.
a) S. F. Brady, M. A. Ilton, W. S. Johnson, J. Am. Chem.
Soc. 1968, 90, 2882; W. S. Johnson, T.-t. Li, D. J.
Faulkner, S. F. Campbell, J. Am. Chem. Soc. 1968, 90,
6225. b) M. Julia, S. Julia, R. Guegan, C. R. Acad. Sc.
1959, 248, 820.
13C NMR (CDCl
3
2
3
2
(CH
3
2
3
2
2
3
5.4 [C(O)CH CH ], 55.3 (OCH ), 66.3 (CH O), 71.9
2 2 3 2
(
OCH
2
C
arom), 113.8 (Carom), 121.1 (C=CHCH
2
), 129.4
(
C
arom), 130.6 (Carom), 139.2 (C=CHCH
2
), 159.2 (Carom),
2.
a) V. Gembus, N. Sala-Jung, D. Uguen, Bull. Chem.
Soc. Jpn. 2009, 82, 843. b) V. Gembus, N. Sala-Jung,
D. Uguen, Bull. Chem. Soc. Jpn. 2009, 82, 829.
V. Gembus, Master dissertation, the University of
Strasbourg (2002); since only reported in a University
document, the used procedures are described in the
supplementary material.
2
10.2 (C=O); Anal. Found: C, 76.22; H, 9.28 %. Calcd for
: C, 75.91; H, 8.92%.
20 28 3
C H O
3
.
Crystallographic data have been deposited with Cambridge
Crystallographic Data Centre: Deposition numbers CCDC-
1
568404 and CCDC-1568399 for compounds trans-34a and
5
4 respectively. Copies of the data can be obtained free of
4.
a) J. C Hubbs, D. C Attride, N. W Boaz, J. C. Ciula, J. T.
Maddox, T. Nabih, W. D Nottingham, D. C. Spencer,
World Patent WO 2002010116, 2002; J. C Hubbs, D. C
Attride, N. W Boaz, J. C. Ciula, J. T. Maddox, T. Nabih,
W. D Nottingham, D. C. Spencer, Chem. Abstr. 2002,
charge via http://www.ccdc.cam.ac.uk/conts/retrieving.html
or from the Cambridge Crystallographic Data Centre, 12,
Union Road, Cambridge, CB2 1EZ, UK; Fax: +44 1223
36033; e-mail: deposit@ccdc.cam.ac.uk).
(
3
1
36, 167107. b) W. Schwarze, A. Kleeman, H. Remmel,
Acknowledgments
W. Hohn, German Patent DE 2941211, 1981; W.
Schwarze, A. Kleeman, H. Remmel, W. Hohn, Chem.
Abstr. 1981, 95, 80273. c) L. V. Phillips, U. S. Patent
3299100, 1967; L. V. Phillips, Chem. Abstr. 1967, 66,
65122. d) From methacryclic acid esters: K. von
Auwers, F. Konig, Justus Liebigs Ann. Chem. 1932,
496, 252; S. Siegel, C. G. Bergstrom, J. Am. Chem. Soc.
1950, 72, 3815; D. E. McGreer, W. Wai, G. Carmichael,
Can. J. Chem. 1960, 38, 2410; E. J. Kox, M. C. Caserio,
M. S. Silver, J. D. Roberts, J. Am. Chem. Soc. 1961, 83,
2719; S. R Landor, N. Punja, J. Chem. Soc. C, 1967,
2495; P. G. Gassman, T. H. Johnson, J. Am. Chem. Soc.
1976, 98, 6058; M. P. Doyle, R. L. Dorow, W. H.
The results presented herein are taken in part from the thesis
dissertation of Vincent Gembus (ULP, Strasbourg; 2006).
This work was supported (grant to V. G) by the “Ministère de
la Recherche et de l’Education” (France). Thanks are due to
Dr. Tim Wallace (The University of Manchester, U.K.) for
helpful suggestions, and to Dr. Annie Jutand (Ecole Normale
Supérieure, Paris, France) for discussions.
Supporting Information
1H and 13C NMR spectra. Procedures for the synthesis of
alcohol 2 from ester 3 and dinitrile 5. This material is
available free of charge on J-STAGE.

Tamblyn, J. Org. Chem. 1982, 47, 4059; M. Mitani, Y.
Yamamoto, K. Koyama, J. Chem. Soc. Chem. Commun.
R. Brook, A. J. Duke, J. Chem. Soc. Perkin Trans. 1
1973, 1013.
1
983, 1446. Cyclopropanation of methyl methacrylate
11. a) W. H. Urry, D. J. Trecker, D. A. Winey, Tetrahedron
Lett. 1962, 609. b) J. C. Duggan, W. H. Hurry, J.
Schaefer, Tetrahedron Lett. 1971, 4197. c) W. H. Urry,
D. J. Trecker, J. Am. Chem. Soc. 1962, 84, 118. See,
also: N. J. Turro, T.-J. Lee, J. Am. Chem. Soc. 1969, 91,
5651.
with the CH /In reagent has been reported to give
2 2
I
ester 4 in good yield (Virender, S. L. Jain, B. Sain,
Tetrahedron Lett. 2005, 46, 37). However, possibly due
to discrepancy in the used conditions, we failed to
perfectly reproduce this result.
5
.
.
R. Prins, Catal. Today 1997, 37, 103; L. Bini, C. Müller,
D. Vogt, J. Chem. Soc., Chem Commun. 2010, 46, 8325.
a) J. M. Conia, J. L. Ripoll, C. R. Hebd. Seances Acad.
Sci. 1960, 251, 1071. b) J. M. Conia, J. L Ripoll, Bull.
Soc. Chim. Fr. 1963, 755. c) J. M. Conia, J. L Ripoll,
Bull. Soc. Chim. Fr. 1963, 773. d) J. Conia, J. Salaün,
Tetrahedron Lett. 1963, 1175. e) J. Conia, J. Salaün,
Bull. Soc. Chim. Fr. 1963, 1957. f) C. Rappe, L.
Knuttson, Acta. Chem. Scand. 1967, 21, 163. g) J.
Conia, J. Salaün, Bull. Chem. Soc. Fr. 1968, 3735. h) J.
Salaün, J. M. Conia, J. Chem. Soc. D 1970, 1358. i) J.
Salaün, B. Garnier, J. M. Conia, Tetrahedron
12. a) J. F. O’Connell, H. Rapoport, J. Org. Chem. 1992, 57,
4775. b) J. Hartung, S. Hünig, R. Kneuer, M. Schwarz,
H. Wenner, Synthesis 1997, 1433; S. Welgelt, N.
Sewald, Synlett, 2004, 726. c) K. Takeuchi, T. Ushino,
T. Okazaki, T. Kitagawa, T. Kinoshita, Y. Ohga, K.
Tanaka, F. Toda, Bull. Chem. Soc. Jpn 2001, 74, 363.
13. For reviews, see: H. Verbrügen, Synthesis, 2008, 1165;
R. Zimmer, M. Webel, H. U. Reissig, J. Prakt.
Chem./Chem.-Ztg 1998, 340, 274.
6
14. E. Hirsch, S. Huenig, H. U. Reissig, Chem. Berrichte
1982, 115, 3687; U. Hertenstein, S. Huenig, R. Reichelt,
R. Schaller, Chem. Berrichte 1986, 119, 699; M. Weibel,
H. U. Reissig, Synlett 1997, 1141; I. M. Lyapkalo, M.
Weibel, H. U. Reissig, Eur. J. Org. Chem. 2001, 4189;
E. V. Boltukhina, A. E. Sheshenev, I. M. Lyapkalo,
Synthesis 2011, 3507.
1
973, 29, 2895. j) J. P. Barnier, J. M. Denis, J. Salaün, J.
M. Conia, Tetrahedron 1974, 30, 1397. k) T. Kato, H.
Kondo, M. Nishino, M. Tanaka, G. Hata, A. Miyake,
Bull. Chem. Soc. Jpn 1980, 53, 2958.
7
.
a) J. Salaün, J. M. Conia, Tetrahedron Lett. 1968, 4545;
J. Salaün, J. M. Conia, Tetrahedron Lett. 1971, 4023; J.
P. Barnier, J. M. Denis, J. Salaün, J. M. Conia,
Tetrahedron 1974, 30, 1405. b) X. Creary, A. J. Rollin,
J. Org. Chem. 1977, 42, 423.
15. After this work was completed, one of us (V. G.) has
developed this result into
a practical tosylation
procedure: V. Gembus, F. Marsais, V. Levacher, Synlett,
2008, 1463. For application to azide preparation, see: A.
S. Barrow, J. E. Moses, Synlett, 2016, 27, 1840.
16. a) C. E. Griffin, R. B. Hager, R. B. J. Org. Chem. 1963,
28, 599; C. Pavlik, M. D. Morton, M. B. Smith, Synlett
2011, 2191. b) H. Maekawa, Y. Yamamoto, H. Shimada,
K. Yonemura, I. Nishiguchi, Tetrahedron Lett. 2004, 45,
3869.
8
9
.
.
For reviews, see: J. M. Conia, J. Salaün, Acc. Chem.
Res. 1972, 5, 33; J. M. Conia, M. J. Robson, Angew.
Chem., Int. Ed. Engl. 1975, 14, 473.
Quantum and molecular mechanical calculations also
favoured the quasi-Favorskii (i. e., semibenzylic)
reaction pathway over the Loftfield mechanism for the
rearrangement of 2-chloro-cyclobutanone in water (R.
Castillo, J. Andrés, V. Moliner, J. Phys. Chem. B 2001,
17. J. M. Conia, J. P. Barnier, Tetrahedron Lett. 1971, 4981;
J. P. Barnier, J. M. Conia, Bull. Soc. Chim. France 1976
(1-2 Part 2) 281; J. P. Barnier, J. M. Conia, Bull. Soc.
Chim. France 1976 (1-2 Part 2), 285. See also: J. P.
Barnier, J. Champion, J. M. Conia, Org. Synth. 1981,
60, 25.
1
05, 2453, and cited references).
1
0. P. R. Brook, Chem. Commun. (London) 1968, 565; P. R.
Brook, A. J. Duke, J. Chem. Soc. Chem. D 1970, 652; P.

®
1
8. Calculations using Spartan 08 . Such assistance has
Cryst. 1990, A46, 467. c) G. M. Sheldrick, Acta Cryst.
2008, A64, 112.
been evidenced in the cyclopentane-1,2-diol series: E.
Wistuba, C. Rüchardt Tetrahedron Lett. 1981, 22, 4069.
For general discussion on the mechanism of the pinacol
rearrangement, see (for instance): K. Nakamura, Y.
Osamura J. Am. Chem. Soc. 1993, 115, 9112.
34. C. Nishino, W. S. Bowers, M. E. Montgomery, L. R.
Nault, Appl. Entomol. Zool. 1976, 11, 340.
35. K. Takai, Y. Hotta, K. Hoshima, H. Nozaki, Bull. Chem.
Soc. Jpn 1980, 53, 1698.
1
2
2
9. M. Kirihara, T. Takuwa, T. Kambayashi, T. Momose, Y.
Takeuchi, J. Chem. Res., Synop. 1998, 652.
0. See figure A in: S. A. Monti, T. R. Dean, J. Org. Chem.
1
982, 47, 2679.
1. C. H. Heathcock, B. L. Finkelstein, E. T. Jarvi, P. A.
Radel, C. R. Hadley, J. Org. Chem. 1988, 53, 1922.
See, also: B. Jolivet, D. Uguen, Tetrahedron Lett. 2002,
4
3, 7907.
2
2. J. Tsuji, I. Shimizu, I. Minami, I. Ohashi, T. Sugiura, K.
Takahasi, J. Org. Chem. 1985, 50, 1523; J. Tsuji, I.
Shimizu, I. Minami, Y. Ohashi, Tetrahedron Lett. 1982,
2
3, 4809.
23. A. Jutand, Eur. J. Inorg. Chem. 2003, 2017.
24. W. A. Bonner, J. Am. Chem. Soc. 1952, 74, 1034.
25. M. Helliwell, S. Karim, E. R. Parmee, E. J. Thomas,
Org. Biomol. Chem. 2005, 3, 3636.
2
6. a) K. Kondo, D. Tunemoto, Tetrahedron Lett. 1975,
1
397; S. Cavicchioli, D. Savoia, C. Trombini, A.
Umani-Ronchi, J. Org. Chem. 1984, 49, 1246. b) K.
Sato, S. Mizuno, M. Hirayama, J. Org. Chem. 1967, 32,
1
77.
2
2
2
3
7. For a review, see: Y. Landais, J. M. Vincent, Science of
Synthesis, 2004, 26, 646.
8. N. Ishikawa, T. Kitazume, T. Yamazaki, Y. Moshida, T.
Tatsuno, Chem. Lett. 1981, 761.
9. T. Ukai, H. Kawazura, Y. Ishii, J. J. Bonnet, J. A. Ibers,
J. Organomet. Chem. 1974, 65, 253.
0. J. Tsuji, K. Sato, H. Okumoto, J. Org.Chem. 1984, 49,
1
341.
3
1. J. Suffert, J. Org. Chem. 1989, 54, 509.
3
2. L. Domon, F. Vogeleisen, D. Uguen, Tetrahedron Lett.
1
996, 37, 2773.
3
3. a) Kappa CCD Operation Manual, ed. by Nonius BV,
Delft, The Netherlands, 1997. b) G. M. Sheldrick, Acta