Remote functionalization of C60 with enantiomerically pure cyclo-[2]-malonate tethers bearing C12 and C14 spacers: Synthetic access to bisadducts of C60 with the inherently chiral trans-3 addition pattern

Article abstract of DOI:10.1021/jo4013173

In this Article, we describe the synthesis of two optically pure diols bearing a 1,2-diol moiety masked as an isopropylidene acetal group and long alkyl chains comprised of 12 and 14 carbon atoms, respectively. The synthetic methodology that was developed offers a general way for the synthesis of optically pure diols with long alkyl chains. Diols (-)-4 and (-)-9 were subjected to a condensation reaction with malonyl dichloride to afford two cyclo-[2]-malonate tethers that were separated by column chromatography in optically pure form. The bismalonates (-)-4b and (-)-9b proved to be excellent tethers for the regioselective Bingel functionalization of C₆₀, furnishing in a regioselective manner the corresponding ^f,sC and ^f,sA trans-3 bisadducts with low diastereoselectivity but in very good to excellent total yields. In both cases, the formed trans-3 bisadducts were isolated in pure form by simple column chromatography and were fully characterized. The successful acetal deprotection of the synthesized trans-3 bisadducts afforded quantitatively the corresponding polyalcohols, which represent novel chiral fullerene compounds equipped with glycol moieties.

Full text of DOI:10.1021/jo4013173

Article
pubs.acs.org/joc
Remote Functionalization of C60 with Enantiomerically Pure cyclo-[2]-
Malonate Tethers Bearing C12 and C14 Spacers: Synthetic Access to
Bisadducts of C60 with the Inherently Chiral trans‑3 Addition Pattern
Maria Riala and Nikos Chronakis*
Department of Chemistry, University of Cyprus, University Str 1, Building no. 13, Aglantzia, 2109 Nicosia, Cyprus
S
* Supporting Information
ABSTRACT: In this Article, we describe the synthesis of two optically pure diols bearing a 1,2-diol moiety masked as an
isopropylidene acetal group and long alkyl chains comprised of 12 and 14 carbon atoms, respectively. The synthetic methodology
that was developed offers a general way for the synthesis of optically pure diols with long alkyl chains. Diols (−)-4 and (−)-9
were subjected to a condensation reaction with malonyl dichloride to afford two cyclo-[2]-malonate tethers that were separated
by column chromatography in optically pure form. The bismalonates (−)-4b and (−)-9b proved to be excellent tethers for the
regioselective Bingel functionalization of C60, furnishing in a regioselective manner the corresponding f,sC and f,sA trans-3
bisadducts with low diastereoselectivity but in very good to excellent total yields. In both cases, the formed trans-3 bisadducts
were isolated in pure form by simple column chromatography and were fully characterized. The successful acetal deprotection of
the synthesized trans-3 bisadducts afforded quantitatively the corresponding polyalcohols, which represent novel chiral fullerene
compounds equipped with glycol moieties.
attracted great attention because of their possible applications
in enantioselective synthesis, in chiral recognition, and in the
construction of chiral macromolecular architectures. Inves-
tigations and synthetic efforts focused on this exciting area over
the last 15 years have been reviewed in detail by Thilgen and
Diederich.4 The above-mentioned target was approached by the
following ways: (1) The stepwise addition of achiral addends
on C60 followed by the subsequent separation of the f,sC and f,sA
enantiomers5 of the inherently chiral bisadducts by means of
preparative HPLC on chiral stationary phases, (2) the stepwise
addition of enantiomerically pure addends followed by the
separation of the corresponding diastereomers on achiral
stationary phases, and (3) the tether-directed remote
functionalization of C60 utilizing chiral, racemic, or enantiomeri-
cally pure tethers equipped with the reactive groups responsible
for the addition reactions on the double bonds of the fullerene
sphere. The inherently chiral trans-2 and trans-3 addition
patterns of C60 have attracted particular attention because of
INTRODUCTION
■
Enantiomerically pure organic compounds are essential in life,
and the development of synthetic methodologies aiming to
access them still remains a great challenge for organic chemists.
Although [60]fullerene is an achiral molecule, it can be easily
equipped with the property of chirality by functionalizing its
double bonds with chiral addends. By taking advantage of the
30 reactive double bonds of C60 that are localized at the
junctions of two hexagons,1 different regioisomeric multi-
adducts can be constructed. If the addends are located at
specific positions on the fullerene sphere, then adducts
endowed with the property of inherent chirality can be
formed.2 After the first monoaddition on the fullerene cage,
eight regioisomeric bisadducts (for identical addends) are
possible because of the nonequivalent double bonds located in
both hemispheres.3 The C2-symmetrical addition patterns cis-3,
trans-2, and trans-3 are inherently chiral, which is a property
exclusively attributed to the functionalization pattern and is
characterized by the chirality of the π system of the fullerene
chromophore.2 Thus, the synthesis of enantiomerically pure
bisadducts of C60 with an inherently chiral addition pattern has
Received: June 19, 2013
© XXXX American Chemical Society
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the fact that the chiral tethers required for the synthesis of the
Now, we wish to present a complete study on the synthesis
of enantiomerically pure bisadducts of C60 with the inherently
chiral trans-3 addition pattern with the aid of two enantiopure
cyclo-bismalonate tethers bearing spacers comprised of 12 and
14 carbon atoms, respectively. The experimental results have
also allowed us to draw conclusions regarding the advantages
and disadvantages of each tether on the basis of the number of
synthetic steps required in each case, the ease of the separation
and purification procedures, the regioselectivities of the Bingel
twofold cyclopropanation of C60, and the yield of the fullerene
products formed. The key synthetic intermediates to access the
enantiopure cyclo-bismalonates employed in this study are
optically pure diols bearing a 1,2-diol moiety masked as an
isopropylidene acetal group and long alkyl chains with 12 and
14 carbon atoms. Thus, we developed and present here an
efficient and general methodology for the synthesis of these
synthetically valuable chiral compounds in enantiopure form.
f,s
f,sC and A enantiomers should have large and rigid structures.
In a pioneering work, Diederich and co-workers7 employed
bismalonate tethers bearing the Troger base motif as a spacer.
̈
Bingel addition of an optically pure Troger tether to C , after
̈
60
separation of the racemic mixture by preparative HPLC on a
chiral stationary phase, afforded the enantiomerically pure
trans-2 bisadducts with complete regioselectivity and excellent
diastereoselectivity.6 By using the pure enantiomers of a more
extended Troger tether (with enantiomeric separation on chiral
̈
HPLC column), the isolation of the pure enantiomers of the
trans-3 bisadducts was achieved after their separation by
preparative HPLC on a Bucky Clutcher column (Scheme 1).
Scheme 1. f,sClockwise and f,sAnticlockwise Enantiomers of
the trans-3 Bisadduct of C60 and the Troger’s Base Tether
̈
Employed by Diederich7 for Their Synthesis
RESULTS AND DISCUSSION
■
Following our previous work on the regio- and diastereose-
lective tris-functionalization of C60 with an enantiopure cyclo-
trismalonate tether derived from 3,4-O-isopropylidene-D-
mannitol11 and the report of Hirsch9a where achiral cyclo-[2]-
dodecylmalonate was allowed to react with C60 under Bingel
conditions and afforded completely regioselectivly a trans-3
bisadduct of C60 in 56% yield, we designed two optically pure
cyclo-[2]-malonate esters with C12 and C14 spacers connecting
the reactive malonate groups, respectively. If these tethers are
selective for the trans-3 addition pattern of C60, then it is
expected to convert the two enantiomeric forms of the
inherently chiral trans-3 addition pattern into diastereomeric;
thus, their successful separation and isolation should in
principle be feasible by simple column chromatography. The
synthesis of cyclo-[2]-malonate esters can be realized by the
condensation reaction of the appropriate enantiopure diol with
malonyl dichloride under the optimized conditions reported
earlier12 (Scheme 2).
The remote Bingel bis-functionalization of C60 was completely
regioselective for the trans-3 addition pattern and afforded only
bisadducts with an in−out configuration.7 This work provided a
major contribution to the synthesis of enantiopure bisadducts
of C60 with the trans-3 addition pattern via the tether-directed
remote functionalization concept. However, preparative HPLC
was required for the successful separation of the two
enantiomeric forms of the tether and/or the formed fullerene
adducts. Moreover, apart from transesterification the fullerene
products cannot be further derivatized because the tethers
located on the fullerene core are not equipped with additional
reactive groups.
Scheme 2. Retrosynthesis of the Optically Pure cyclo-[2]-
Malonate Tethers Bearing C12 and C14 Spacers
Stimulated by the challenge of establishing a procedure for
the synthesis and isolation of the pure enantiomers of C60
bisadducts with the inherently chiral trans-3 addition pattern
but without the need of preparative HPLC for the enantiomeric
separation of the chiral tether or the formed fullerene adducts,
we communicated recently8 the synthesis of enantiomerically
pure bisadducts of C60 with the inherently chiral trans-3
addition pattern using an optically pure cyclo-bismalonate tether
derived from (−)-dimethyl-2,3-O-isopropylidene-L-tartrate.
The concept of cyclo-[n]-malonate tethers, introduced by
Hirsch,9 has been successfully employed for the regioselective
remote functionalization of C60. We also reported on the
further derivatization of the isolated enantiomerically pure
bisadducts resulting from the promising properties of the trans-
3 addition pattern.8 For example, Nishimura et al.10 reported
the construction of helical arrays of C60 molecules along a
polymer backbone using an optically active trans-3 bisadduct of
C60.
Synthesis of Enantiomerically Pure Diols Bearing C12
and C14 Alkyl Spacers. Our initial investigation was focused
on the synthesis of optically pure diols bearing a 1,2-diol moiety
masked as an isopropylidene acetal group and long alkyl chains
composed of 12 and 14 carbon atoms, respectively. In our first
approach, we investigated the nucleophilic substitution reaction
of the ditosylate13 and diiodide14 derived from (−)-2,3-O-
isopropylidene-D-threitol (Scheme 3) with Grignard and
acetylide nucleophiles bearing C4 and C5 alkyl chains
terminated by alcohol groups protected as THP or TBDMS
ethers. In all cases, the reactions afforded complicated mixtures
where the desired product could barely be detected by mass
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with LAH in THF solvent furnished optically pure diol (−)-4
in 92% yield.
Scheme 3. Approaches to the Synthesis of Optically Pure
Diols Bearing Long Alkyl Spacers
For the synthesis of optically pure diol (−)-9 bearing a C14
alkyl spacer (Scheme 5), we started from unsaturated diester
(−)-2 that bears an eight-carbon chain and requires the
elongation of each side chain by three carbon atoms. First,
(−)-2 was treated with LAH in THF to furnish diol (−)-5 in
98% yield. Swern oxidation of diol (−)-5 under inert
conditions18 afforded the optically pure dialdehyde (−)-6 that
proved to be stable during chromatography on SiO2 and was
isolated as a yellowish oil in 77% yield (Scheme 5). According
to the literature,19 dialdehydes that do not contain stabilizing α
substituents are usually unstable. For this reason, they are
further manipulated directly after their isolation or their in situ
formation without further purification. However, dialdehyde
(−)-6 seemed to be quite stable and could be stored for several
weeks at 0 °C without showing signs of decomposition.
The next step of our synthetic approach involves the twofold
Wittig reaction of dialdehyde (−)-6 with a three-carbon ylide
bearing a terminal functional group that can be transformed to
an alcohol. For this purpose, we synthesized a series of
phosphonium salts starting from the corresponding organic
precursor reagents (Scheme 6) and tested them in the Wittig
reaction with dialdehyde (−)-6. Phosphonium salt 10a was
synthesized following a general experimental procedure20 by
the reaction of methyl-3-bromopropionate with PPh3 in 94%
yield. Treatment of 10a with n-BuLi or KHMDS at −78 °C
failed to generate the corresponding ylide because the
phosphonium salt remained glued and completely unreacted
at the bottom of the flask, which most probably resulted from
the insolubility of this waxy material in THF. An extensive
search of the literature revealed only limited reports where the
employment of phosphonium salt 10a in Wittig reactions is
mentioned.21 In general, it seems that salt 10a is not preferred
as a three-carbon synthon for the elongation of a carbon chain
under Wittig olefination conditions. Therefore, three-carbon
phosphonium salt 11a was employed that possesses a terminal
hydroxyl group (Scheme 6).
spectrometry. Thus, we changed our strategy and focused our
efforts on the Wittig olefination reaction. The versatile chiral
synthon (−)-3,4-O-isopropylidene-D-mannitol was first sub-
jected to oxidative cleavage (with NaIO4 or Pb(OAc)4)14,15 to
afford the corresponding dialdehyde (Scheme 3) that cannot be
isolated15b,16 but should be used in situ in the Wittig step. To
achieve the introduction of the alkyl chains, we employed
nonstabilized ylides bearing four and five carbon atoms
terminated by an ester moiety that can be easily transformed
to an alcohol. The resulting reaction mixtures were again
complicated, and only traces of the product could be detected
with the aid of mass spectrometry.
The synthesis of the optically pure diol (−)-4 bearing a C12
spacer was finally performed via a five-step synthetic route8 and
is illustrated in Scheme 4. In a one-pot two-step transformation,
(−)-dimethyl-2,3-O-isopropylidene-L-tartrate was reduced with
DIBAL-H followed by the in situ Wittig−Horner reaction with
triethyl phosphonoacetate to afford unsaturated diester (−)-1
in 83% overall yield. This sequential transformation has been
reported before17 and served in our case as a general
methodology for the elongation of alkyl chains terminated by
an ester moiety by two carbon atoms. Each side chain of (−)-2,
derived from hydrogenation of the double bonds of diester
(−)-1, was subsequently elongated by two more carbon atoms
via the same sequence (DIBAL-H reduction/Wittig−Horner/
hydrogenation), and saturated diester (−)-3 was obtained in
very good overall yield. Finally, reduction of the ester moieties
According to the literature,22 onefold Wittig reactions were
carried out successfully using the specific phosphonium salt,
and the corresponding products were obtained in good-to-high
yields. Phosphonium salt 11a was synthesized in 94% yield by
the reaction of 3-bromopropanol with PPh322a and treated with
the optically pure dialdehyde (−)-6 under Wittig conditions.
The reaction led to the formation of a complicated mixture
consisting of unidentified products from which the desired diol
could not be detected. Literature reports22a,23 mention that a
Scheme 4. Synthesis of Optically Pure Diol (−)-4 Bearing a C12 Alkyl Spacer
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Scheme 5. Synthesis of Optically Pure Diol (−)-9 Bearing a C14 Alkyl Spacer
Scheme 6. Three-Carbon Phosphonium Salts Employed in the Wittig Reaction with Aldehyde (−)-6
Scheme 7. Wittig Reaction of Dialdehyde (−)-6 with the Ylide Derived from Phosphonium Salt 12a
temporary masking of the hydroxyl group present in 11a favors
the formation of the Z isomer of the Wittig product with high
isomeric purity and overall yield. With this in mind, we decided
to follow the same strategy in an attempt to achieve a less
complicated reaction mixture and therefore manage to isolate
and elucidate the structure of the main products. As such,
phosphonium salt 11a was treated with n-BuLi at 0 °C followed
by the addition of TMSCl in the reaction mixture. The mixture
was cooled at −78 °C, and a solution of dialdehyde (−)-6 in
THF was added dropwise. The reaction progress was
monitored by TLC, but again the formation of a complicated
mixture seemed to be inevitable. However, it could not be
confirmed whether the in situ TMS protection of the hydroxyl
group in phosphonium salt 11a had occurred effectively. Thus,
a conclusion concerning the influence of the protected
phosphonium salt in the Wittig reaction progress could not
be safely made. To test this approach further, we decided to
ensure the protection of the hydroxyl group of salt 11a prior to
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Table 1. Optimization of the Wittig Reaction of Dialdehyde (−)-6 with the Ylide Derived from Phosphonium Salt 13a
Regarding the Equivalents of the Salt
a
entry
(−)-6 (equiv)
13a (equiv)
yield of (−)-7 (%)
yield of 16 (%)
1
2
3
1
1
1
3
5
6
44
52
69
14
15
13
a
Relative to 13a.
Table 2. Optimization of the Twofold THP Deprotection of (−)-8
entry
catalyst
PTSA
solvent
conditions
time
24 h
yield of (−)-9 (%)
a
1
2
3
4
5
6
7
8
9
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
Et2O
rt
a
a
a
PTSA
50 °C
24 h
24 h
24 h
48 h
48 h
10 min
2.5 h
4 d
Amberlyst 15
Amberlyst 15
PPTS
rt
50 °C
rt
44
55
58
88
90
PPTS
50 °C
60 °C/microwave
I2
TBATB
MgBr2·Et2O
rt
rt
a
Complicated mixture.
the Wittig reaction. For this purpose, the protection of 3-
bromopropanol was performed first followed by the reaction
with PPh3 to produce the corresponding protected phospho-
nium salt 12a (Scheme 6). As the chosen protecting group will
have to be deprotected selectively leaving the isopropylidene
acetal moiety intact, we first synthesized the TBDMS-protected
3-bromopropanol24a that was reacted with PPh3 to produce
phosphonium salt 12a in 75% yield.24b The twofold Wittig
reaction of optically pure dialdehyde (−)-6 with the
phosphonium ylide of salt 12a was then carried out (Scheme
7). Surprisingly, the reaction afforded olefin 14 as the main
product that was separated and isolated in 16% yield, whereas
mass spectrometric measurement of the crude reaction mixture
revealed only traces of desired Wittig product 15.
It is known that nonstabilized ylides can autoxidatively self-
condense to afford symmetrical olefins when exposed to an
oxidative reagent. Efficient oxidants for this purpose are
molecular oxygen,25a,b NaIO4,25c (PhO)3PO3,25d N-camphor-
sulfonyloxaziridine,25e and VO(acac)2.25f The oxidative cou-
pling reaction proceeds through the in situ formation of the
corresponding aldehyde upon treatment of the ylide with the
oxidant. The aldehyde further reacts with a second ylide
molecule via a standard Wittig reaction to afford the
symmetrical olefin. To exclude the presence of oxygen, the
Wittig transformation was repeated under strict inert conditions
by repeatedly degassing the solvent prior to the reaction and by
using high-purity inert gases. In all cases, the formation of olefin
14 as the main product was unavoidable, whereas desired
product 15 was only detectable with the aid of mass
spectrometry. Such byproducts have been reported in the
literature,26 but the mechanism of their formation has not been
clarified.
Our efforts then turned to the alteration of the protecting
group of the phosphonium salt from TBDMS ether to THP
ether. The reaction of 3-bromopropanol with DHP in the
presence of PTSA yielded quantitatively THP ether 13, which
was allowed to react with PPh3 in CH3CN to furnish the
corresponding phosphonium salt 13a in 67% yield (Scheme
6).27 The twofold Wittig reaction of the ylide derived from
phosphonium salt 13a with optically pure dialdehyde (−)-6 was
carried out using 3 equiv of the salt, affording two main
products that were isolated as one fraction by column
chromatography on SiO2 (Table 1). Because the Rf values of
the two compounds were almost identical regardless of the
solvent system used, their separation by column chromatog-
raphy on SiO2 or Al2O3 was not possible. This problem was
efficiently confronted by employing the silver ion chromatog-
raphy technique,28 which is based on the ability of an
unsaturated organic compound to reversibly form charge-
transfer complexes with silver. Even though such complexes are
unstable, this method can be efficiently utilized in chromato-
graphic techniques for the separation of olefins possessing
uneven double bonds. The order of elution depends on the
number of the double bonds present in the molecules. The
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Scheme 8. Cyclization Reaction of the Enantiopure Diols (−)-4 and (−)-9 with Malonyl Dichloride
more double bonds the substrate has the longer the retention
time is by the Ag−SiO2 stationary phase. This separation
approach is widely used in lipid chemistry, and several silver ion
chromatographic techniques have been successfully developed
so far.28 The successful separation of products (−)-7 and 16
(Table 1) was achieved by column chromatography (SiO2
impregnated with silver nitrate)29 using a mixture of DCM/
EtOAc (11:5) as the eluent. Olefin 16 was eluted first followed
by desired Wittig product (−)-7. However, the yield of product
(−)-7 (44%, Table 1, entry 1) was moderate; thus, the Wittig
reaction was repeated using 5 and 6 equiv of the phosphonium
salt.
As shown in Table 1, the optimum yield of product (−)-7
(69%) was achieved when 6 equiv of salt 13a were employed,
whereas the yield of byproduct 16 did not change significantly.
Further optimization of the reaction conditions was not
necessary at this point because the yield of product (−)-7
(69%) was satisfactory for a twofold Wittig reaction;
furthermore, a larger wasteful stoichiometry of 13a was not
desired.
The final step for the synthesis of optically pure diol (−)-9
bearing a 14-carbon chain was the double THP deprotection of
(−)-8 (Scheme 5). Although the specific THP deprotection
was presumed to be a straightforward process, several acidic
catalysts had to be explored to find the optimum conditions.
The results are summarized in Table 2. To our surprise, double
THP deprotection of (−)-8 was always accompanied by the
formation of fully deprotected product (−)-17 regardless of the
catalyst used. The complete deprotection of (−)-8 was
observed even in the presence of catalysts such as TBATB
and MgBr2·Et2O that do not affect the isopropylidene acetal
groups according to the literature.30 As a result, the yield of
desired diol (−)-9 dropped significantly. This problem was
efficiently circumvented by adding an excess of acetone to the
mixture after the reaction was completed. By this approach,
fully deprotected product (−)-17 was transformed in situ back
to optically pure diol (−)- 9 (Table 2). As illustrated in Table 2,
the employment of PTSA and Amberlyst 15 as catalysts either
at rt or at 50 °C led to complicated mixtures (Table 2, entries
1−4). Among the other catalysts screened, TBATB and
MgBr2·Et2O afforded the best yields for diol (−)-9 (Table 2,
entries 8 and 9). However, TBATB was the catalyst of choice
because of its associated ease of handling and workup.30a In
addition, a significantly shorter reaction time was required. The
specific reaction was performed in MeOH solvent by stirring
the reaction mixture at rt for 2.5 h followed by the addition of
an excess of acetone and additional stirring for 5 min. By this
approach, diol (−)-9 was isolated in 88% yield.
Synthesis of the Enantiopure cyclo-[2]-Malonate
Tethers. With diols (−)-4 and (−)-9 available on a large
scale, the next step toward the synthesis of the corresponding
optically pure cyclo-[n]-malonate esters was a one-pot
condensation reaction with malonyl dichloride. Following the
optimized general experimental procedure,9a the condensation
reactions of diols (−)-4 and (−)-9 with malonyl dichloride
were performed in separate experiments under high dilution
conditions in DCM solvent and in the presence of pyridine as a
base. After stirring at rt overnight, the macrocyclic products
were separated from polymeric material and pyridine salts by
filtration over a short pad of SiO2 using a 1:1 mixture of DCM/
EtOAc as the eluent. The oligo-malonates were isolated as one
fraction, and they were subsequently separated and purified by
column chromatography with the elution sequence being
proportional to the increasing size of the macrocyclic rings. As
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Scheme 9. Synthesis of the Enantiomerically Pure trans-3 Bisadducts of C60 Utilizing C12-Bismalonate Tether (−)-4b.8
we have already reported,8 the condensation reaction of
optically pure C12-diol (−)-4 with malonyl dichloride (Scheme
8) afforded corresponding monomalonate (−)-4a as a
yellowish oil in 23% yield, bismalonate (−)-4b as a waxy
white solid in 6% yield, and trismalonate (−)-4c as a yellowish
oil in 2.1% yield. The separation and isolation of the
macrocyclic compounds was accomplished by column
chromatography using a mixture of DCM/EtOAc/Hexane in
a 8:2:4 ratio. The cyclization reaction of C14-diol (−)-9 with
malonyl dichloride led to the formation of mono- (−)-9a, bis-
(−)-9b, and trismalonate (−)-9c in 30, 4.5, and 2% yields,
respectively. Their separation was accomplished by column
chromatography on SiO2 (DCM/EtOAc/hexane = 8:2:3).
Mono- and trismalonate esters (−)-9a and (−)-9c were
obtained as yellowish oils, whereas bismalonate (−)-9b was
isolated as a waxy white solid. It should be mentioned that the
purification procedure for the macrocyclic oligo-malonates
bearing C14 spacers turned out to be very difficult, and tedious
chromatographic separations were required in comparison to
those used for the corresponding C12 analogues shown in
Scheme 8. This indicates that the length of the alkyl spacer of
diol (−)-9, composed of 14 carbon atoms, might represent the
limit for the successful separation and isolation of such optically
pure macrocyclic oligo-malonates esters resulting from the
condensation reaction of malonyl dichloride with diols bearing
a chiral 1,2-acetonide core. The cyclization reactions illustrated
in Scheme 8 favored the formation of the monomeric rings,
whereas the corresponding dimeric and trimeric products were
obtained in significantly lower yields. Furthermore, when C14
diol (−)-9 was employed the yield of corresponding
monomalonate (−)-9a was higher compared with that of
(−)-4a, whereas the yield of bismalonate ester (−)-9b was
lower compared with that of (−)-4b. Both families of the
enantiomerically pure cyclo-[n]-malonate esters were isolated in
pure form and were fully characterized. According to the
literature,9a,12 an interesting feature of macrocyclic bismalonate
esters resulting from condensation reactions of α,ω-diols with
malonyl dichloride is their pronounced ability to crystallize,
forming columnar structures with molecular channels in the
solid state. However, all attempts to obtain X-ray-quality
crystals of optically pure bismalonate esters (−)-4b and (−)-9b,
either by slow evaporation of the solvent or by slow diffusion of
pentane into their DCM solutions, failed.
Synthesis of Enantiomerically Pure Bisadducts of C60
with the Inherently Chiral trans-3 Addition Pattern. To
reach our initial target, which is the synthesis of enantiomeri-
cally pure bisadducts of C60 with the inherently chiral trans-3
addition pattern utilizing the cyclo-[2]-malonate tethers (−)-4b
and (−)-9b, we carried out the remote bis-functionalization of
C60 under the experimental conditions of the modified Bingel
cyclopropanation reaction. According to our recent report,8
cyclo-[2]-malonate tether (−)-4b reacted in a regioselective
manner with C60 to afford bisadducts (+)-18a and (−)-18b,
which were separated by column chromatography (Scheme 9).
After an extensive screening of eluent systems, the fullerene
adducts were successfully separated using a mixture of PhCl/
DCM/MeCN (65:30:5), which resulted in an Rf value of 0.27
for (+)-18a and 0.31 for (−)-18b. Precipitation from DCM/
pentane afforded (+)-18a and (−)-18b as dark-red/brown
solids in a 31 and 20% yield, respectively. The Bingel
functionalization of C60 with tether (−)-4b showed low
diastereoselectivity with a de value of 20%, favoring the
formation of (+)-18a. Bisadducts (+)-18a and (−)-18b were
1
characterized by H and 13C NMR, UV−vis spectroscopy, and
MALDI−TOF mass spectrometry. Their enantiomeric relation-
ship resulting from the inherent chirality of the trans-3 addition
pattern and their absolute configuration were confirmed by CD
spectroscopy. Finally, the specific optical rotation values, [α]2D5,
were measured in CHCl3 and were found to be +1295 for
clockwise isomer (+)-18a and −1314 for anticlockwise
(−)-18b. In our recent work,8 we also reported the successful
acetal deprotection of synthesized bisadducts (+)-18a and
(−)-18b, which afforded quantitatively the corresponding
polyalcohols that represent novel chiral fullerene compounds
equipped with glycol moieties. This offers the potential for
further derivatization of the specific compounds targeting the
construction of enantiopure functional fullerene materials
equipped with fascinating chiroptical properties resulting from
the inherently chiral trans-3 addition pattern of the fullerene
chromophore.
Our primary goal, which was the synthesis and isolation of
the pure enantiomers of the inherently chiral trans-3
bisaddition pattern of C60 without the need for preparative
HPLC, was successfully accomplished. The enantiopure f,sC and
f,sA trans-3 bisadducts were formed regioselectively by employ-
ing C12-bismalonate ester (−)-4b as a tether and were isolated
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Scheme 10. Synthesis of the Enantiomerically Pure trans-3 Bisadducts of C60 Utilizing C14-Bismalonate Tether (−)-9b
Scheme 11. Synthesis of the Enantiomerically Pure trans-3 Derivatives of C60 (+)-20a and (−)-20b
by column chromatography in a remarkable 51% total yield.
These results prompted us to investigate whether larger C14-
bismalonate ester (−)-9b is a more advantageous tether than
(−)-4b and to complete our study that is focused on the
investigation of this family of tethers in the regioselective
synthesis of enantiomerically pure trans-3 bisadducts of C60.
C14-bismalonate ester (−)-9b and C60 were allowed to react
under modified Bingel conditions, and monitoring the reaction
progress by TLC revealed the formation of two major products
(Scheme 10). To achieve a satisfactory difference in their Rf
values, a variety of solvent mixtures were screened, and the
successful separation of the two products was accomplished by
employing a mixture of toluene/EtOAc in a 10:0.5 ratio. It has
to be mentioned that the separation procedure of the formed
products was much easier compared to that of trans-3
bisadducts (+)-18a and (−)-18b derived from the remote
functionalization of C60 with bismalonate tether (−)-4b.
Precipitation from DCM/hexane afforded bisadducts (+)-19a
and (−)-19b as dark-red/brown solids in a 35 and 33% yield,
respectively. The total yield of (+)-19a and (−)-19b was 68%,
which is an excellent value for a twofold Bingel cyclo-
propanation of C60. To the best or our knowledge, this is the
highest yield obtained so far for a one-pot bis-cyclopropanation
of fullerene C60 via the tether-directed remote-functionalization
concept. This demonstrates undoubtedly that C14-bismalonate
ester (−)-9b is in fact a superior tether compared to C12-
analogue (−)-4b with regard to the yield and the ease of
separation of the formed enantiomerically pure trans-3
bisadducts. By HPLC analysis of the crude reaction mixture,
the relative yields of (+)-19a and (−)-19b were found to be 60
and 40%, respectively, whereas the de value of the reaction was
calculated to be 20%, favoring the formation of (+)-19a. The
MALDI−TOF spectra of (+)- 19a and (−)-19b were measured
in negative mode using DCTB as a matrix, and in both cases
the M− molecular ion at 1457 m/z was clearly observed
(Supporting Information).
The C2-symmetrical structure of bisadducts (+)-19a and
1
(−)-19b is clearly reflected in their H and 13C NMR spectra
(Supporting Information). In particular, the 13C NMR spectra
of both adducts displayed the expected 28 signals for the sp2
fullerene carbons in the region between 137 and 148 ppm,
whereas the carbonyl carbons showed 2 signals at around 164
ppm. Two absorptions corresponding to the stereogenic
methine carbon atoms were observed at around 80 ppm,
whereas the sp3 carbon atoms of the fullerene core appeared as
two distinct peaks at 71 to 72 ppm. The peak at 53 ppm is also
H
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characteristic and corresponds to the bridgehead sp3 carbon
atoms.
transformations. The condensation reactions of optically pure
diols (−)-4 and (−)-9 with malonyl dichloride gave access to
two novel families of enantiopure cyclo-[n]-malonate esters
bearing long alkyl spacers connecting the malonate moieties.
The only major drawback of this method is the low total yields
of the macrocyclic products resulting from the statistical nature
of the specific reactions. These yields could be improved by
templated synthesis or by designing alternative synthetic
pathways involving multistep protection/deprotection chem-
istry. However, our primary goal was to gain quick access to the
specific optically pure macrocyclic oligo-malonate ester families
to test their ability to serve as efficient tethers for the
regioselective synthesis of the inherently chiral trans-3
bisadducts of C60 via Bingel cyclopropanation. Enantiopure
bismalonates (−)-4b and (−)-9b were excellent tethers for the
regioselective Bingel functionalization of C60 and led to the
regioselective formation of the corresponding f,sC and f,sA trans-
3 bisadducts with low diastereoselectivity but with very good to
excellent total yields. Noteworthy is the combined yield of the
trans-3 bisadducts resulting from the cyclopropanation of C60
with C14-tether (−)-9b, which reached a remarkable value of
68%. This clearly demonstrates the superior efficiency of the
specific tether compared to C12-analogue (−)-4b. In both cases,
the formed trans-3 bisadducts were isolated in pure form by
column chromatography and were fully characterized. The
separation of bisadducts (−)-19a and (−)-19b, derived from
the remote functionalization of C60 with C14-tether (−)-9b, was
easier compared to those formed when C12-tether (−)-4b was
used, crediting this cyclo-malonate tether with an additional
advantage. Finally, the successful acetal deprotection of the
synthesized bisadducts afforded quantitatively the correspond-
ing polyalcohols that represent novel chiral fullerene com-
pounds equipped with glycol moieties. This offers the potential
for further derivatization of the specific compounds targeting
the construction of enantiopure functional fullerene materials
equipped with fascinating chiroptical properties resulting from
the inherently chiral trans-3 addition pattern of the fullerene
chromophore.
The trans-3 addition pattern of bisadducts (+)-19a and
(−)-19b was unambiguously confirmed by their UV−vis
spectra (Supporting Information), which were found to be
identical to those of trans-3 bisadducts (+)-18a and (−)-18b
that were synthesized utilizing C12-bismalonate (−)-4b. The
absolute configuration of bisadducts (+)-19a and (−)-19b was
determined by a direct comparison of their recorded CD
spectra (Supporting Information) with the data reported in the
literature6b,31 and were assigned as f,sC and f,sA, respectively.
The spectra showed mirror image behavior and strong Cotton
effects due to the chirality of the fullerene chromophore.
To this end, trans-3 bisadducts (+)-19a and (−)-19b were
subjected in separate experiments to a twofold acetal
deprotection using p-toluenesulfonic acid (PTSA) as a catalyst.
The reactions proceeded cleanly to quantitatively afford the
fully deprotected products (+)-20a and (−)-20b (Scheme 11),
which were easily isolated by flash column chromatography on
SiO2 using a 10:1 mixture of toluene/MeOH as the eluent. The
enantiomerically pure trans-3 fullerene polyalcohols were fully
characterized by NMR, UV−vis, CD spectroscopy, and
MALDI−TOF mass spectrometry (Supporting Information).
Acetal deprotection of trans-3 bisadducts (+)-19a and
(−)-19b does not affect the addition pattern of the fullerene
core; therefore, the UV−vis and CD spectra (Supporting
Information) of corresponding polyalcohols (+)-20a and
(−)-20b were identical to those of protected adducts (+)-19a
and (−)-19b. In the 13C NMR spectra of bisadducts (+)-20a
and (−)-20b (Supporting Information), the cleavage of the
isopropylidene acetal groups was clearly demonstrated by the
absence of the two signals corresponding to the bridgehead sp3
carbon atoms and the methyl carbons of the 1,2-acetonide five-
membered rings that should absorb at approximately 110 and
27 ppm, respectively. In addition, the stereogenic methine
carbon atoms were shifted at higher field and observed at
around 74 ppm, whereas the sp3 carbon atoms of the fullerene
core appeared as two distinct peaks at 71 to 72 ppm.
Furthermore, the 13C NMR spectra of both adducts displayed
the expected (for a C2-symmetrical structure) 28 signals for the
sp2 fullerene carbons in the region between 137 and 148 ppm,
whereas the carbonyl carbons showed two signals at around
164 ppm.
EXPERIMENTAL SECTION
■
General Remarks. All starting materials were purchased from
commercial sources and used without further purification. The
solvents were dried using appropriate standard procedures. Column
chromatography was carried out using silica gel 60H (40−60 nm,
230−300 mesh). Thin-layer chromatography (TLC) was carried out
on aluminum plates coated with HF254/366 silica gel. Visualization was
accomplished with a 254 nm ultraviolet (UV) light source and/or by
immersion in potassium permanganate (KMnO4) or phosphomolyb-
dic acid (PMA) solutions followed by heating. 1H and 13C NMR
spectra were recorded on 300 and 500 MHz spectrometers. Residual
Finally, a facile and less time-consuming procedure to obtain
pure (+)-20a, (−)-20b, or the trans-3 fullerene polyalcohols
derived from the acetal deprotection of (+)-18a and (−)-18b8
was achieved when the mixtures of the enantiomerically pure
trans-3 derivatives were not separated after the Bingel
functionalization of C60 with tethers (−)-4b and (−)-9b but
were purified only from an excess of reagents and polymeric
material on a short plug (SiO2, PhMe/EtOAc). Then, the
mixtures were subjected to acetal deprotection, and the final
separation of the inherently chiral trans-3 polyalcohols was
easily carried out by column chromatography on SiO2 using the
appropriate solvent mixtures as eluents.
1
nondeuterated solvent was used as the internal standard for H NMR
spectra, and a carbon signal of the solvent was used as the internal
standard for 13C NMR spectra. Chemical shifts (δ) are given in parts
per million (ppm) downfield from tetramethylsilane (TMS). The
resonance multiplicity patterns are described as singlet (s), broad
singlet (br s), doublet (d), triplet (t), quartet (q), quintet (quin),
multiplet (m), or a combination of these. Coupling constants (J) are
quoted in hertz (Hz). Peak assignments were aided by 1H−1H COSY,
1H−13C HMQC, DEPT-135, and/or DEPT-90 when necessary. Low-
resolution (EI) mass spectra were recorded on a GCMS instrument
with a direct inlet probe. High-resolution mass spectra were recorded
on a MALDI−TOF instrument using DCTB as a matrix or on an ESI
mass spectrometer. UV−vis and IR spectrometers were used for the
measurements of the corresponding spectra. IR spectra were measured
as a film on NaCl plates, and bands are given in cm−1. Analytical
CONCLUSIONS
■
We have described the synthesis of two optically pure diols
bearing a 1,2-diol moiety masked as an isopropylidene acetal
group and long alkyl chains composed of 12 and 14 carbon
atoms, respectively. The synthetic methodology that was
developed offers a general way for the synthesis of optically
pure diols with long alkyl chains utilizing classical organic
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HPLC measurements were performed using a SiO2 column (250 × 4
mm, silica gel 100−5, 5 μm) at a flow rate of 1 mL/min and UV
detection at 340 nm. A CEM Discover Microwave Reactor was used
for microwave experiments, and reaction temperatures were controlled
using standard IR thermometry. Optical rotations were measured on a
polarimeter, and circular dichroism (CD) spectra were recorded on a
CD spectrometer. Melting points (mp) were uncorrected.
magnetic stirrer, a 0.5 M solution of KHMDS in toluene (60 mL, 0.03
mol) was added dropwise to a suspension of phosphonium salt 13a
(15.00 g, 0.03 mol) in dry THF (200 mL) at −78 °C. The solution of
the formed ylide was left stirring for 20 min at the same temperature
followed by the dropwise addition of a solution of dialdehyde (−)-6
(1.07 g, 5 mmol) in dry THF (20 mL). The resulting reaction mixture
was warmed to rt and stirred at the same temperature overnight.
Filtration and evaporation of the solvent afforded a crude mixture that
was chromatographed on SiO2 (EtOAc/hexane = 1:5) to give a
fraction consisting of compound (−)-7 and olefin 16. The two
products were separated and isolated in pure form by silver ion
chromatography (Ag−SiO2, DCM/EtOAc = 11:5).
2,2′-{[(4S,5S)-2,2-Dimethyl-1,3-dioxolane-4,5-diyl]bis[hex-3-ene-
6,1-diyloxy]}bis(tetrahydro-2H-pyran) (−)-7. Colorless oil (1.61 g,
69%). Rf = 0.36 (SiO2, hexane/EtOAc = 5:1, stain = PMA) and 0.07
(Ag−SiO2, DCM/EtOAc = 11:5, stain = PMA). IR (NaCl, evap. film)
cm−1 νmax 3013, 2943, 2868, 1755, 1720, 1692, 1445, 1389, 1352,
1271, 1202, 1128, 1074, 982, 906, 870, 814, 737. 1H NMR (300 MHz,
CDCl3) δ 5.50−5.39 (m, 4H, 2 × CHCH), 4.59 (apparent t, J = 3.4
Hz, 2H, 2 × OCHO), 3.90−3.82 (m, 2H, OCH2), 3.78−3.68 (m, 2H,
OCH2), 3.64−3.57 (m, 2H, 2 × OCHCH2), 3.53−3.46 (m, 2H,
OCH2), 3.44−3.36 (m, 2H, OCH2), 2.40−2.33 (m, 4H, 2 × CH2),
2.25−2.13 (m, 4H, 2 × CH2), 1.86−1.49 (m, 16H, 8 × CH2), 1.37 (s,
6H, (CH3)2C). 13C NMR (75 MHz, CDCl3) δ 130.7 (CHCH),
126.5 (CHCH), 107.9 ((CH3)2C), 98.7 (OCHO), 80.2
(OCHCH2), 67.0 (OCH2), 62.3 (OCH2), 32.8 (CH2), 30.7 (CH2),
27.9 (CH2), 27.3 ((CH3)2C), 25.5 (CH2), 24.0 (CH2), 19.6 (CH2).
HRMS (ESI+): [M + Na]+ calcd for C27H46O6Na, 489.3187; found,
489.3181.
Compounds (−)-1,8 (−)-2,8 (−)-3,8 (−)-4,8 (−)-4a,8 (−)-4b,8
(−)-4c,8 12,24a 13,27 10a,20 11a,22a 12a,24b and 13a27 were prepared
according to literature procedures.
(4S,5S)-4,5-Bis(3-hydroxypropyl)-2,2-dimethyl-1,3-dioxolan
(−)-5. In a dry 50 mL three-necked round-bottomed flask equipped
with a gas inlet, dropping funnel, and magnetic stirrer, LiAlH4 (0.38 g,
0.01 mol) was added in dry THF (30 mL). The mixture was cooled to
0 °C and stirred vigorously for 15 min. A solution of diester (−)-2
(1.52 g, 5.03 mmol) in dry THF (10 mL) was added dropwise, and the
mixture was left stirring overnight at rt. Subsequently, the mixture was
cooled to 0 °C and 0.40 mL of H2O was very carefully added
dropwise. The reaction mixture was then held at 66 °C for 15 min
followed by cooling to 0 °C, and 0.40 mL of a 15% aqueous solution of
NaOH were added dropwise. The mixture was again held at 66 °C for
15 min followed by cooling to 0 °C, and 1.20 mL of H2O was added
dropwise. Subsequently, the mixture was held at 66 °C until the
formation of a characteristic white precipitate was observed, which was
then removed by filtration. The filtrate was dried over MgSO4.
Filtration and evaporation of the solvent afforded the crude mixture,
which was chromatographed on a SiO2 column (100% EtOAc) to give
diol (−)-5 (1.06 g, 97%) as a colorless oil. Rf = 0.24 (SiO2, 100%
EtOAc, stain = KMnO4). [α]D25 (c = 0.33 g/100 mL, CHCl3) −28.2. IR
(NaCl, evap. film) cm−1 vmax 3335, 2984, 2936, 2868, 1447, 1435,
1420, 1369, 1337, 1317, 1240, 1219, 1180, 1163, 1094, 1018, 968, 949,
1,6-Di(tetrahydropyran)hex-3-ene 16. Colorless oil (0.91 g, 13%
relative to phosphonium salt 13a). Rf = 0.36 (SiO2, hexane/EtOAc =
5:1, stain = PMA) and 0.22 (Ag−SiO2, DCM/EtOAc = 11:5, stain =
PMA). 1H NMR (300 MHz, CDCl3) δ 5.56−5.46 (m, 2H, CHCH),
4.59 (apparent t, J = 3.6 Hz, 2H, 2 × OCHO), 3.91−3.83 (m, 2H,
OCH2), 3.78−3.70 (m, 2H, OCH2), 3.53−3.37 (m, 4H, 2 × OCH2),
2.41−2.35 (m, 4H, 2 × CH2), 1.87−1.49 (m, 12H, 6 × CH2). 13C
NMR (75 MHz, CDCl3) δ 127.7 (CHCH), 98.7 (OCHO), 67.0
(OCH2), 62.3 (OCH2), 30.7 (CH2), 28.1 (CH2), 25.5 (CH2), 19.6
(CH2). HRMS (ESI+): [M + Na]+ calcd for C16H28O4Na, 307.1880;
found, 307.1869.
1
887, 856, 835, 804, 779, 756, 735. H NMR (500 MHz, CDCl3, 25
°C) δ 3.68 (br s, 4H, 2 × CH2CH2OH), 3.65−3.63 (m, 2H, 2 ×
OCHCH2), 2.13 (br s, 2H, 2 × CH2OH), 1.77−1.70 (m, 6H, 3 ×
CH2), 1.56−1.51 (m, 2H, CH2), 1.40 (s, 6H, (CH3)2C). 13C NMR
(125 MHz, CDCl3, 25 °C) δ 108.3 ((CH3)2C), 80.9 (OCHCH2), 62.6
(CH2CH2OH), 29.5 (CH2), 29.4 (CH2), 27.2 ((CH3)2C). HRMS
(ESI+): [M + H]+ calcd for C11H23O4, 219.1591; found, 219.1581.
3,3′-[(4S,5S)-2,2-Dimethyl-1,3-dioxolane-4,5-diyl]dipropanal
(−)-6. In a dry 500 mL three-necked round-bottomed flask equipped
with a gas inlet, dropping funnel, and magnetic stirrer, (COCl)2 (2.22
mL, 0.027 mol) was added in 140 mL of dry DCM under an Ar
atmosphere. The mixture was cooled to −78 °C, and a solution of dry
DMSO (3.50 mL, 0.049 mol) in dry DCM (25 mL) was added
dropwise. The resulting reaction mixture was stirred for 0.5 h at −78
°C followed by the dropwise addition of a solution of diol (−)-5 (1.95
g, 8.95 mmol) in dry DCM (20 mL) at the same temperature. The
mixture was again left stirring for 0.5 h at −78 °C. Subsequently, dry
Et3N (12.5 mL, 0.089 mol) was added dropwise at the same
temperature. The resulting mixture was stirred for 1 h with the
temperature at −78 °C, and then it was warmed slowly to 0 °C over a
period of 1 h. The mixture was stirred at the same temperature for 0.5
h and subsequently diluted with 250 mL of dry toluene. Filtration and
evaporation of the solvent under vacuum at a temperature not
exceeding 35 °C afforded a crude mixture that was then mixed with
250 mL of dry hexane. The resulting mixture was filtered, and the
solvent was carefully evaporated under vacuum with the temperature
at 35 °C. Chromatography (SiO2, hexane/EtOAc = 6:4) of the
resulting crude mixture afforded dialdehyde (−)-6 (1.48 g, 77%) as a
2,2′-{[(4S,5S)-2,2-Dimethyl-1,3-dioxolane-4,5-diyl]bis(hexane-
6,1-diyloxy)}bis(tetrahydro-2H-pyran) (−)-8. Unsaturated diol (−)-7
(1.52 g, 3.26 mmol) was dissolved in EtOH (30 mL) and
hydrogenated under an H2 atmosphere (hydrogen pressure 2.5 bar)
using 10% Pd/C (70 mg) as a catalyst for 0.5 h at rt. The reaction
mixture was filtered through a Celite pad, and the filtrate was
evaporated to dryness to afford saturated diester (−)-8 (1.52 g, 99%)
as a colorless oil. Rf = 0.7 (SiO2, hexane/EtOAc = 1:1, stain = PMA).
[α]2D0 (c = 0.46g/100 mL, CHCl3) −13.4. IR (NaCl, evap. film) cm−1
νmax 2936, 2860, 1454, 1441, 1377, 1367, 1352, 1323, 1283, 1259,
1240, 1200, 1184, 1161, 1136, 1121, 1078, 1064, 1024, 986, 905, 868,
845, 814, 785, 729. 1H NMR (500 MHz, CDCl3) δ 4.57 (br s, 2H, 2 ×
OCHO), 3.87 (apparent t, J = 9.5 Hz, 2H, OCH2), 3.75−3.70 (m, 2H,
OCH2), 3.58 (br s, 2H, 2 × OCHCH2), 3.51−3.50 (m, 2H, OCH2),
3.49−3.36 (m, 2H, OCH2), 1.85−1.80 (m, 2H, CH2CHO), 1.73−1.69
(m, 2H, CH2CHO), 1.60−1.50 (m, 22H, 11 × CH2), 1.37 (br s, 16H,
(CH3)2C and 5 × CH2). 13C NMR (125 MHz, CDCl3) δ 107.7
((CH3)2C), 98.8 (OCHO), 81.0 (OCHCH2), 67.6 (OCH2), 62.3
(OCH2), 32.9 (CH2), 30.8 (CH2), 29.7 (CH2), 29.7 (CH2), 29.6
(CH2), 27.3 ((CH3)2C), 26.1 (CH2), 25.5 (CH2), 19.7 (CH2). HRMS
(ESI+): [M + Na]+ calcd for C27H50O6Na, 493.3500; found, 493.3493.
6,6′-[(4S,5S)-2,2-Dimethyl-1,3-dioxolane-4,5-diyl]dihexan-1-ol
(−)-9. In a 100 mL single-necked round-bottomed flask equipped with
a magnetic stirrer, saturated THP-protected diol (−)-8 (4.11 g, 8.73
mmol) and TBATB (0.85 g, 1.75 mmol) were dissolved in 35 mL of
MeOH. After stirring at rt for 2.5 h, an excess of acetone was added,
and the reaction mixture was stirred for 5 min. The mixture was
subsequently diluted with EtOAc and washed with a 5% aqueous
solution of sodium bisulfite. The organic phase was washed with brine,
dried over MgSO4, filtered, and evaporated to dryness. Column
1
colorless oil. Rf = 0.22 (SiO2, hexane/EtOAc = 6:4, stain = PMA). H
NMR (300 MHz, CDCl3) δ 9.80 (br s, 2H, 2 × CH2CHO), 3.67−3.59
(m, 2H, 2 × OCHCH2), 2.73−2.55 (m, 4H, 2 × CH2CHO), 2.04−
1.93 (m, 2H, CH2), 1.82−1.70 (m, 2H, CH2), 1.35 (s, 6H, (CH3)2C).
13C NMR (75 MHz, CDCl3) δ 201.6 (CH2CHO), 108.5 ((CH3)2CO),
79.5 (OCHCH2), 40.2 (CH2CHO), 27.1 ((CH3)2C), 24.7 (CH2). MS
(EI) m/z: [M − CH3]+ 199.
2,2′-{[(4S,5S)-2,2-Dimethyl-1,3-dioxolane-4,5-diyl]bis[hex-3-ene-
6,1-diyloxy]}bis(tetrahydro-2H-pyran) (−)-7 and 1,6-Di-
(tetrahydropyran)hex-3-ene 16. In a dry 500 mL three-necked
round-bottomed flask equipped with a gas inlet, dropping funnel, and
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chromatography (SiO2, EtOAc/DCM = 9:1) of the crude residue
afforded diol (−)-9 (2.32 g, 88%) as a colorless oil. Rf = 0.35 (SiO2,
EtOAc/DCM = 9:1, stain = PMA); [α]2D0 (c = 0.296g/100 mL,
CHCl3) −29.3. IR (NaCl, evap. film) cm−1 νmax 3339, 2984, 2932,
2858, 1456, 1435, 1377, 1369, 1339, 1286, 1240, 1219, 1173, 1097,
1074, 1055, 941, 878, 854, 802, 723, 705. 1H NMR (300 MHz,
CDCl3) δ 3.64 (t, J = 6.6 Hz, 4H, 2 × CH2OH), 3.58 (apparent t, J =
3.0 Hz, 2H, 2 × OCHCH2), 1.60−1.48 (m, 12H, 5 × CH2 and 2 ×
CH2OH), 1.37 (br s, 16H, (CH3)2C and 5 × CH2). 13C NMR (75
MHz, CDCl3) δ 107.8 ((CH3)2C), 80.9 (OCHCH2), 62.9 (CH2OH),
32.8 (CH2), 32.6 (CH2), 29.4 (CH2), 27.3 ((CH3)2C), 26.1 (CH2),
25.5 (CH2). HRMS (ESI+): [M + H]+ calcd for C17H35O4, 303.2530;
found, 303.2526.
COCH2CO), 1.68−1.63 (m, 12H, 6 × CH2), 1.51 (br s, 18H, 9 ×
CH2), 1.37 (br s, 48H, 3(CH3)2C and 15 × CH2). 13C NMR (125
MHz, CDCl3) δ 166.7 (CO), 107.8 ((CH3)2C), 80.9 (OCHCH2),
65.5 (CH2O), 41.7 (COCH2CO), 32.9 (CH2), 29.3 (CH2), 28.4
(CH2), 27.3 ((CH3)2C), 26.0 (CH2), 25.7 (CH2). HRMS (MALDI−
TOF): [M + Na]+ calcd for C60H102O18Na, 1133.6958; found,
1133.6975.
Synthesis of Bisadducts (+)-19a and (−)-19b. In a dry 100 mL
three-necked round-bottomed flask equipped with a gas inlet,
dropping funnel, and magnetic stirrer, C60 (31 mg, 0.04 mmol) was
dissolved in dry toluene (31 mL) under an argon atmosphere.
Subsequently, macrocycle (−)-9b (29 mg, 0.039 mmol) and iodine
(20 mg, 0.08 mmol) were added followed by the dropwise addition of
a solution of DBU (0.02 mL, 0.16 mmol) in dry toluene (12 mL) over
a period of 1 h. The solution was stirred at rt for 1 day, and the crude
reaction mixture was subjected to flash column chromatography on
SiO2. Unreacted C60 and other impurities were eluted with toluene and
the eluent was changed to toluene/EtOAc = 8:2. Diastereomers
(+)-19a and (−)-19b were obtained as a mixture and were separated
by column chromatography on SiO2 using a 10:0.5 mixture of toluene/
EtOAc as the eluent. Precipitation from DCM/hexane afforded
(+)-19a and (−)-19b in pure form.
(7S,8S)-Tetradecane-1,7,8,14-tetraol (−)-17. White solid. Rf = 0.11
(SiO2, EtOAc/DCM = 10:1, stain = PMA); [α]2D5 (c = 0.102g/100 mL,
CH3OH) −34.2. IR (NaCl, evap. film) cm−1 νmax 3381, 2914, 2846,
2361, 2336, 1728, 1601, 1456, 1387, 1111, 1067, 717, 687, 665, 432,
1
413. H NMR (300 MHz, CD3OD) δ 3.50 (t, J = 6.6 Hz, 4H, 2 ×
CH2OH), 3.34−3.30 (m, 2H, 2 × OCHCH2), 1.49−1.24 (m, 20H, 10
× CH2). 13C NMR (75 MHz, CD3OD): δ 75.3 (OCHCH2), 63.0
(CH2OH), 33.9 (CH2), 33.6 (CH2), 30.7 (CH2), 27.1 (CH2), 26.9
(CH2). HRMS (ESI+): [M + Na]+ calcd for C14H30O4Na, 285.2036;
found, 285.2039.
(S,S,S,S-f,sC-trans-3) (+)-19a. Dark-red solid (22 mg, 35%). Rf =
0.45 (SiO2, toluene/EtOAc = 10:0.5). HPLC: retention time = 9.93
min (toluene/EtOAc = 95:5). [α]2D0 (c = 0.0081g/100 mL, CHCl3)
+1062. 1H NMR (500 MHz, CDCl3) δ 4.80−4.76 (m, 2H,
OCH2CH2), 4.53−4.43 (m, 4H, 2 × OCH2CH2), 4.40−4.36 (m,
2H, OCH2CH2), 3.45−3.42 (m, 2H, 2 × OCHCH2), 3.39−3.36 (m,
2H, 2 × OCHCH2), 1.83−1.16 (m, 52H, 2(CH3)2C and 20 × CH2).
13C NMR (125 MHz, CDCl3) δ 164.18 (CO), 164.06 (CO),
147.29, 147.15, 147.08, 146.84, 146.73, 146.63, 146.49, 146.32, 146.17,
146.04, 145.59, 145.45, 144.70, 144.42, 144.32, 143.97, 143.69, 143.68,
143.58, 142.85, 142.64, 142.08, 141.99, 141.88, 141.59, 140.19, 138.57,
137.65 (sp2 C of C60), 107.61 ((CH3)2C), 80.78 (OCHCH2), 80.74
(OCHCH2), 71.92 (sp3 C of C60), 71.62 (sp3 C of C60), 67.64
(CH2CH2O), 67.22 (CH2CH2O), 53.33 (COCCO), 33.22 (CH2),
32.65 (CH2), 29.66 (CH2), 29.01 (CH2), 28.96 (CH2), 28.40 (CH2),
27.27 ((CH3)2C), 27.18 ((CH3)2C), 26.62 (CH2), 26.54 (CH2), 25.97
(CH2), 25.87 (CH2). UV−vis (CHCl3) λmax nm (ε/dm3 mol−1 cm−1)
317 (45 094), 380 (11 803), 400 (6510), 411.5 (5446), 423 (4541),
482.5 (3554), 573 (1498), 633 (536), 688 (174). CD (CHCl3) 286
nm (Δε = −87.2), 347.6 (−44.2), 391.0 (30.4), 403.8 (22.9), 417.4
(10.8), 447.6 (47.8), 521.0 (−27.0), 580.4 (11.8), 614.6 (−3.4), 664.4
(−7.3). HRMS (MALDI−TOF, negative mode, DCTB): [M]− calcd
for C100H64O12, 1457.4426; found, 1457.4368.
Synthesis of cyclo-Malonates (−)-9a, (−)-9b, and (−)-9c. In a dry
500 mL three-necked round-bottomed flask equipped with a gas inlet,
dropping funnel, and magnetic stirrer, diol (−)-9 (1.10 g, 3.64 mmol)
was dissolved under an argon atmosphere in dry DCM (240 mL)
followed by the addition of pyridine (0.59 mL, 7.28 mmol).
Subsequently, a solution of malonyl dichloride (0.71 mL, 7.28
mmol) in dry DCM (120 mL) was added dropwise over a period of
2 h. After stirring for 1 day at rt, the mixture was concentrated,
absorbed on SiO2, and chromatographed on a short column (SiO2,
DCM/EtOAc = 1:1) to remove polymeric material and pyridine salts.
The isolated mixture was then evaporated and separated by column
chromatography (SiO2, DCM/EtOAc/hexane = 8:2:3) to give cyclo-
[1]-malonate (−)-9a, cyclo-[2]-malonate (−)-9b, and cyclo-[3]-
malonate (−)-9c. The order of elution was (−)-9a, (−)-9b, and
(−)-9c.
cyclo-[1]-Malonate (−)-9a. Yellowish oil (0.40 g, 30%). Rf = 0.58
(SiO2, DCM/EtOAc/hexane = 8:2:3, stain = KMnO4); [α]2D5 (c =
0.11g/100 mL, CHCl3) −10.2. IR (NaCl, evap. film) cm−1 νmax 2982,
2934, 2858, 1751, 1736, 1460, 1412, 1373, 1323, 1254, 1221, 1153,
1092, 1051, 1003, 914, 881. 1H NMR (300 MHz, CDCl3) δ 4.22−4.09
(m, 4H, 2 × OCH2CH2), 3.69−3.62 (m, 2H, 2 × OCHCH2), 3.37 (s,
2H, COCH2CO), 1.68−1.62 (m, 8H, 4 × CH2), 1.42−1.38 (m, 18H,
(CH3)2C and 6 × CH2). 13C NMR (75 MHz, CDCl3) δ 166.6 (C
O), 107.5 ((CH3)2C), 80.4 (OCHCH2), 65.6 (CH2O), 42.0
(COCH2CO), 32.3 (CH2), 28.2 (CH2), 28.1 (CH2), 27.2
((CH3)2C), 25.1 (CH2), 24.8 (CH2). HRMS (ESI+): [M + Na]+
calcd for C20H34O6Na, 393.2248; found, 393.2261.
cyclo-[2]-Malonate (−)-9b. Waxy white solid (60.7 mg, 4.5%). Rf =
0.41 (SiO2, DCM/EtOAc/hexane = 8:2:3, stain = PMA). mp 85 °C;
[α]2D5 (c = 0.15g/100 mL, CHCl3) −20.6. IR (NaCl, evap. film) cm−1
νmax 2982, 2930, 2857, 1730, 1468, 1435, 1406, 1389, 1377, 1367,
1342, 1290, 1248, 1211, 1194, 1175, 1115, 1103, 1067, 1026, 1016,
987, 951, 897, 879, 854, 820, 723. 1H NMR (300 MHz, CDCl3) δ 4.10
(t, J = 6.7 Hz, 8H, 4 × OCH2CH2), 3.57 (br s, 4H, 4 × OCHCH2),
3.36 (s, 4H, 2 × COCH2CO), 1.70−1.61 (m, 8H, 4 × CH2), 1.51 (br
s, 12H, 6 × CH2), 1.37 (br s, 32H, 2(CH3)2C and 10 × CH2). 13C
NMR (75 MHz, CDCl3) δ 166.6 (CO), 107.8 ((CH3)2C), 80.8
(OCHCH2), 65.5 (CH2O), 41.8 (COCH2CO), 32.9 (CH2), 29.3
(CH2), 28.4 (CH2), 27.3 ((CH3)2C), 26.0 (CH2), 25.7 (CH2). HRMS
(MALDI−TOF): [M + Na]+ calcd for C40H68O12Na, 763.4603; found,
763.4589.
cyclo-[3]-Malonate (−)-9c. Colorless oil (26.6 mg, 2%). Rf = 0.28
(SiO2, DCM/EtOAc/hexane = 8:2:3, stain = PMA); [α]2D0 (c =
0.205g/100 mL, CHCl3) −22.6. IR (NaCl, evap. film) cm−1 νmax 2984,
2932, 2858, 1751, 1734, 1464, 1377, 1329, 1248, 1151, 1103, 1047,
889, 667. 1H NMR (500 MHz, CDCl3) δ 4.14 (t, J = 6.5 Hz, 12H, 6 ×
OCH2CH2), 3.57 (br s, 6H, 6 × OCHCH2), 3.36 (s, 6H, 3 ×
(S,S,S,S-f,sA-trans-3) (−)-19b. Dark-red solid (20.7 mg, 33%). Rf =
0.52 (SiO2, toluene/EtOAc = 10:0.5). HPLC: retention time = 11.92
min (toluene/EtOAc = 95:5). [α]2D0 (c = 0.0074g/100 mL, CHCl3)
−1094. 1H NMR (500 MHz, CDCl3) δ 4.86−4.81 (m, 2H,
OCH2CH2), 4.61−4.56 (m, 2H, OCH2CH2), 4.39−4.34 (m, 4H, 2
× OCH2CH2), 3.45 (br s, 4H, 4 × OCHCH2), 1.85−1.10 (m, 52H,
2(CH3)2C and 20 × CH2). 13C NMR (125 MHz, CDCl3) δ 164.08
(CO), 163.87 (CO), 147.29, 147.15, 147.11, 146.69, 146.64,
146.48, 146.38, 146.29, 146.26, 145.89, 145.51, 145.47, 144.69, 144.41,
144.32, 143.92, 143.70, 143.56, 143.54, 142.88, 142.63, 142.41, 142.13,
142.01, 141.65, 140.18, 138.52, 137.71 (sp2 C of C60), 107.72
((CH3)2C), 80.65 (OCHCH2), 80.46 (OCHCH2), 71.82 (sp3 C of
C60), 71.53 (sp3 C of C60), 67.30 (CH2CH2O), 67.21 (CH2CH2O),
52.90 (COCCO), 32.93 (CH2), 32.59 (CH2), 29.39 (CH2), 29.12
(CH2), 28.75 (CH2), 28.61 (CH2), 27.30 ((CH3)2C), 27.25
((CH3)2C), 26.25 (CH2), 26.08 (CH2), 25.98 (CH2), 25.91 (CH2).
UV−vis (CHCl3) λmax nm (ε/dm3 mol−1 cm−1) 315 (32 737), 378
(8803), 401 (4153), 411 (3497), 423 (3005), 482 (2587), 575 (1058),
629 (453), 688 (167). CD (CHCl3) 285.8 nm (Δε = 90.8), 347.4
(45.2), 390.8 (−27.2), 404.2 (−19.3), 417.2 (−6.9), 446.4 (−42.3),
521.6 (25.6), 580.2 (−8.4), 610.0 (2.3), 668.0 (10.7); HRMS
(MALDI−TOF, negative mode, DCTB): [M]− calcd for
C100H64O12, 1457.4426; found, 1457.4495.
Synthesis of Bisadduct (S,S,S,S-f,sC-trans-3) (+)-20a. In a 15 mL
two-necked round-bottomed flask equipped with a condenser, gas
K
dx.doi.org/10.1021/jo4013173 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
inlet, and magnetic stirrer, (+)-19a (20 mg, 1.37 × 10−5 mmol) was
dissolved in CHCl3 (3 mL) followed by the addition of MeOH (1
mL). Subsequently, PTSA was added to the reaction mixture (5.1 mg,
0.027 mmol) followed by the addition of a few drops of H2O. The
mixture was held overnight at 70 °C. The solution was then extracted
with H2O, dried over Na2SO4, and filtered. The filtrate was evaporated
and chromatographed on a SiO2 column (toluene/MeOH = 10:1) to
afford (+)-20a. Precipitation from CHCl3/pentane afforded (+)-20a
(18.9 mg, 100%) as a red solid in pure form. Rf = 0.28 (SiO2, toluene/
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR data of compounds (−)-5, (−)-6, (−)-7, 16,
(−)-8, (−)-9, (−)-9a, (−)-9b, (−)-9c, (−)-17, (+)-19a,
(−)-19b, (+)-20a, and (−)-20b. UV−vis spectra of compounds
(+)-19a, (−)-19b, (+)-20a, and (−)-20b. CD spectra of
compounds (+)-19a, (−)-19b, (+)-20a and (−)-20b. High-
resolution MALDI−TOF spectra of compounds (+)-19a,
(−)-19b, (+)-20a, and (−)-20b. This material is available
free of charge via the Internet at http://pubs.acs.org.
1
MeOH = 10:1). H NMR (500 MHz, CDCl3) δ 4.79−4.75 (m, 2H,
OCH2CH2), 4.54−4.49 (m, 2H, OCH2CH2), 4.48−4.43 (m, 2H,
OCH2CH2), 4.41−4.37 (m, 2H, OCH2CH2), 3.29−3.25 (m, 2H, 2 ×
OCHCH2), 3.21−3.20 (m, 2H, 2 × OCHCH2), 2.11 (apparent d, J =
5.5 Hz, 2H, 2 × CH2OH), 1.89−1.66 (m, 10H, 4 × CH2 and 2 ×
OH), 1.47−1.18 (m, 32H, 16 × CH2). 13C NMR (125 MHz, CDCl3)
δ 164.17 (CO), 163.82 (CO), 147.26, 147.15, 147.03, 146.70,
146.50, 146.48, 146.39, 146.28, 146.20, 146.00, 145.58, 145.46, 144.64,
144.40, 144.29, 143.93, 143.67, 143.64, 143.53, 142.91, 142.60, 142.41,
142.19, 141.98, 141.66, 140.24, 138.33, 137.53 (sp2 C of C60), 73.91
(HOCHCH2), 73.78 (HOCHCH2), 71.89 (sp3 C of C60), 71.64 (sp3 C
of C60), 67.56 (CH2CH2O), 67.47 (CH2CH2O), 53.04 (COCCO),
33.75 (CH2), 33.31 (CH2), 29.01 (CH2), 28.91 (CH2), 28.64 (CH2),
28.41 (CH2), 26.35 (CH2), 26.14 (CH2), 25.81 (CH2), 25.52 (CH2).
UV−vis (CHCl3) λmax nm (ε/dm3 mol−1 cm−1) 315 (46 229), 380
(11 803), 400 (6510), 411.5 (5462), 423 (4541), 483 (3553), 574
(1483), 629 (579), 687 (177). CD (CHCl3) 285.8 nm (Δε = −66.9),
347.0 (−33.6), 391.2 (25.6), 403.8 (19.7), 417.6 (9.9), 446.4 (38.6),
521.8 (−18.5), 577.0 (10.7), 614.4 (−6.5), 680.6 (−10.11). HRMS
(MALDI−TOF, negative mode, DCTB): [M]− calcd for C94H56O12,
1376.3766; found, 1376.3794.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: nchronak@ucy.ac.cy.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by the Cyprus Research
Promotion Foundation (grant nos. PENEK/ENISX/0506/07
and NEKYP/0308/02).
DEDICATION
■
Dedicated to Professor Michael Orfanopoulos on the occasion
of his 65th birthday.
Synthesis of Bisadduct (S,S,S,S-f,sA-trans-3) (−)-20b. (−)-19b (18
mg, 1.23 × 10−5 mol) was subjected to the acetal deprotection reaction
following the procedure described for the synthesis of (+)-19a to give
(−)-20b (17 mg, 100%) as a red solid after column chromatography
(SiO2, toluene/MeOH = 10:1). Rf = 0.27 (SiO2, toluene/MeOH =
10:1). 1H NMR (500 MHz, CDCl3) δ 4.80−4.76 (m, 2H, OCH2CH2),
4.66−4.61 (m, 2H, OCH2CH2), 4.40−4.32 (m, 4H, 2 × OCH2CH2),
3.25 (br s, 2H, 2 × OCHCH2), 3.18 (br s, 2H, 2 × OCHCH2), 2.39
(br s, 2H, 2 × CH2OH), 1.97 (br s, 2H, 2 × CH2OH), 1.82−1.07 (m,
40H, 20 × CH2). 13C NMR (125 MHz, CDCl3) δ 163.90 (CO),
163.75 (CO), 147.25, 147.12, 147.04, 146.68, 146.48, 146.43,
146.34, 146.33, 146.03, 145.65, 145.46, 145.37, 144.68, 144.40, 144.32,
143.92, 143.70, 143.54, 143.41, 142.92, 142.61, 142.53, 142.27, 142.01,
141.67, 140.27, 138.61, 137.76 (sp2 C of C60), 73.88 (HOCHCH2),
73.85 (HOCHCH2), 71.82 (sp3 C of C60), 71.60 (sp3 C of C60), 67.41
(CH2CH2O), 66.95 (CH2CH2O), 52.61 (COCCO), 33.73 (CH2),
33.27 (CH2), 28.76 (CH2), 28.71 (CH2), 28.50 (CH2), 28.12 (CH2),
26.11 (CH2), 25.96 (CH2), 25.82 (CH2), 25.20 (CH2); UV−vis
(CHCl3) λmax nm (ε/dm3 mol−1 cm−1) 315 (27 761), 378 (7702), 398
(4689), 412 (3750), 422 (3322), 488 (2496), 573 (941), 627 (430),
690 (187). CD (CHCl3) 286.2 nm (Δε = 73.3), 346 (39.2), 390.8
(−22.1), 403.6 (−16.2), 416.2 (−8.5), 447.0 (−35.8), 520.4 (19.3),
582.0 (−8.5), 618.8 (4.1), 671.0 (5.1). HRMS (MALDI−TOF,
negative mode, DCTB): [M + 1]− calcd for C94H56O12, 1377.3800;
found, 1377.3743.
Synthesis of Bisadducts (+)-20a and (−)-20b from (+)-19a/
(−)-19b. In a 25 mL two-necked round-bottomed flask equipped with
a condenser, gas inlet, and magnetic stirrer, a mixture of (+)-19a/
(−)-19b (45 mg, 3.08 × 10−5 mol) as obtained from the Bingel
reaction of C60 with (−)-9b was dissolved in CHCl3 (6 mL) followed
by the addition of MeOH (2 mL). Subsequently, PTSA (14 mg, 0.072
mmol) and a few drops of H2O were added, and the reaction mixture
was held overnight at 70 °C. The solution was then extracted with
H2O, dried over Na2SO4, and filtered. The filtrate was evaporated and
flash chromatographed on a SiO2 column (toluene/EtOAc/MeOH =
4:4:1) to afford (+)-20a (25.5 mg, 100%) and (−)-20b (17.0 mg,
100%) as red solids.
REFERENCES
(1) Hirsch, A. Top. Curr. Chem. 1999, 199, 1.
■
(2) Thilgen, C.; Gosse, I.; Diederich, F. Top. Stereochem. 2003, 23, 1.
(3) Hirsch, A.; Lamparth, I.; Karfunkel, H. R. Angew. Chem., Int. Ed.
Engl. 1994, 33, 437.
(4) Thilgen, C.; Diederich, F. Chem. Rev. 2006, 106, 5049.
(5) (a) Hirsch, A.; Lamparth, I.; Schick, G. Liebigs Ann. 1996, 1725.
(b) Thilgen, C.; Herrmann, A.; Diederich, F. Helv. Chim. Acta 1997,
80, 183.
(6) (a) Sergeyev, S.; Diederich, F. Angew. Chem., Int. Ed. 2004, 43,
1738. (b) Sergeyev, S.; Schar, M.; Seiler, P.; Lukoyanova, O.;
̈
Echegoyen, L.; Diederich, F. Chem.Eur. J. 2005, 11, 2284.
(7) (a) Nierengarten, J.-F.; Habicher, T.; Kessinger, R.; Cardullo, F.;
Diederich, F.; Gramlich, V.; Gisselbrecht, J.-P.; Boudon, C.; Gross, M.
Helv. Chim. Acta 1997, 80, 2238. (b) Bourgeois, J.-P.; Seiler, P.;
Fibbioli, M.; Pretsch, E.; Diederich, F.; Echegoyen, L. Helv. Chim. Acta
1999, 82, 1572.
(8) Riala, M.; Chronakis, N. Org. Lett. 2011, 13, 2844.
(9) (a) Reuther, U.; Brandmuller, T.; Donaubauer, W.; Hampel, F.;
̈
Hirsch, A. Chem.Eur. J. 2002, 8, 2261. (b) Chronakis, N.; Hirsch, A.
C. R. Chim. 2006, 9, 862.
(10) Nishimura, T.; Tsuchiya, K.; Ohsawa, S.; Maeda, K.; Yashima,
E.; Nakamura, Y.; Nishimura, J. J. Am. Chem. Soc. 2004, 126, 11711.
(11) Chronakis, N.; Hirsch, A. Chem. Commun. 2005, 3709.
(12) Chronakis, N.; Brandmuller, T.; Kovacs, C.; Reuther, U.;
Donaubauer, W.; Hampel, F.; Fischer, F.; Diederich, F.; Hirsch, A. Eur.
J. Org. Chem. 2006, 2296.
(13) Rubin, L. J.; Lardy, H. A.; Fischer, H. O. L. J. Am. Chem. Soc.
1952, 74, 425.
(14) Khanapure, S. P.; Najafi, N.; Manna, S.; Yang, J.-J.; Rokach, J. J.
Org. Chem. 1995, 60, 7548.
(15) (a) Krief, A.; Dumont, W.; Pasau, P.; Lecomte, Ph. Tetrahedron
1989, 45, 3039. (b) Helms, M.; Schade, W.; Pulz, R.; Watanabe, T.; Al-
̈
Harassi, A.; Fise
Chem. 2005, 1003.
̂ ́
ra, L.; Hlobilova, I.; Zahn, G.; Reißig, H.-U. Eur. J. Org.
(16) (a) Lee, W.-W.; Chang, S. Tetrahedron: Asymmetry 1999, 10,
4473. (b) Kang, S. H.; Ryu, D. H. Chem. Commun. 1996, 3, 355.
L
dx.doi.org/10.1021/jo4013173 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(17) (a) Krief, A.; Dumont, W.; Pasau, P. Tetrahedron Lett. 1988, 29,
1079. (b) Naito, H.; Kawahara, E.; Maruta, K.; Maeda, M.; Sasaki, S. J.
Org. Chem. 1995, 60, 4419.
(18) Tullis, J. S.; Vares, L.; Kann, N.; Norrby, P.-O.; Rein, T. J. Org.
Chem. 1998, 63, 8284.
(19) For some examples, see (a) Saniere, M.; Merrer, Y. L.;
Koscielniak, T.; Depezay, J. C. Tetrahedron 1989, 45, 7317.
(b) Moeller, K. D.; Tinao, L. V. J. Am. Chem. Soc. 1992, 114, 1033.
(c) Karatholuvhu, M. S.; Sinclair, A.; Newton, A. F.; Alcaraz, M. -L.;
Stockman, R. A.; Fuchs, P. L. J. Am. Chem. Soc. 2006, 128, 12656.
(d) Taferner, B.; Schuehly, W.; Huefner, A.; Baburin, I.; Wiesner, K.;
Ecker, G. F.; Hering, S. J. Med. Chem. 2011, 54, 5349.
(20) Le Bigot, Y.; Delmas, M.; Gaset, A. J. Agric. Food Chem. 1983,
31, 1096.
(21) (a) Davies, H. M. L.; Jin, Q. Tetrahedron: Asymmetry 2003, 14,
941. (b) Sarabia, F.; Martín-Ortiz, L.; Lop
2003, 5, 3927.
́
ez-Herrera, F. J. Org. Lett.
(22) For some examples, see (a) Couturier, M.; Dory, Y. L.;
Rouillard, F.; Deslongchamps, P. Tetrahedron 1998, 54, 1529. (b) Sibi,
M. P.; Christensen, J. W. J. Org. Chem. 1999, 64, 6434. (c) Ozawa, T.;
Aoyagi, S.; Kibayashi, C. J. Org. Chem. 2001, 66, 3338. (d) Wu, P.-L.;
Chung, T.-H.; Chou, Y. J. Org. Chem. 2001, 66, 6585. (e) Cryle, M. J.;
Ortiz de Montellano, P. R.; De Voss, J. J. J. Org. Chem. 2005, 70, 2455.
(f) Hanessian, S.; Tremblay, M.; Petersen, J. F. W. J. Am. Chem. Soc.
2004, 126, 6064.
(23) (a) Pearson, W. H.; Bergmeier, S. C. J. Org. Chem. 1991, 56,
1976. (b) Pearson, W. H.; Hines, J. V. Tetrahedron Lett. 1991, 32,
5513.
(24) (a) Boutellier, M.; Wallach, D.; Tamm, C. Helv. Chim. Acta
1993, 76, 2515. (b) Cushman, M.; Golebiewski, W. M.; McMahon, J.
B.; Buckheit, R. W., Jr.; Clanton, D. J.; Weislow, O.; Haugwitz, R. D.;
Bader, J. P.; Graham, L.; Rice, W. G. J. Med. Chem. 1994, 37, 3040.
(25) (a) Bestmann, H. J.; Kratzer, O. Chem. Ber. 1963, 96, 1899.
(b) Poulain, S.; Noiret, N.; Patin, H. Tetrahedron Lett. 1996, 37, 7703.
(c) Bestmann, H. J.; Armsen, R.; Wagner, H. Chem. Ber. 1969, 102,
2259. (d) Bestmann, H. J.; Kisielowski, L.; Distler, W. Angew. Chem.,
Int. Ed. Engl. 1976, 15, 298. (e) Davis, F. A.; Chen, B. C. J. Org. Chem.
1990, 55, 360. (f) Shi, M.; Xu, B. J. Org. Chem. 2002, 67, 294.
(26) Paterson, I.; Coster, M. J. In Strategies and Tactics in Organic
Synthesis; Harmata, M., Ed.; Elsevier Ltd.: Amsterdam, Netherlands,
2004; Vol. 4, pp 236−239.
(27) Schow, S. R.; McMorris, T. C. J. Org. Chem. 1979, 44, 3760.
(28) Momchilova, S.; Nicolova-Damyanova, B. J. Sep. Sci. 2003, 26,
261.
(29) Li, T.-S.; Li, J.-T.; Li, H.-Z. J. Chromatogr., A 1995, 715, 372.
(30) (a) Naik, S.; Gopinath, R.; Patel, B. K. Tetrahedron Lett. 2001,
42, 7679. (b) Klein, M.; Zabel, M.; Bernhardt, G.; Konig, B. J. Org.
̈
Chem. 2003, 68, 9379.
(31) (a) Hawkins, J. M.; Meyer, A.; Nambu, M. J. Am. Chem. Soc.
1993, 115, 9844. (b) Djojo, F.; Hirsch, A. Chem.Eur. J. 1998, 4, 344.
(c) Djojo, F.; Hirsch, A.; Grimme, S. Eur. J. Org. Chem. 1999, 3027.
(d) Nakamura, Y.; O-kawa, K.; Nishimura, T.; Yashima, E.; Nishimura,
J. J. Org. Chem. 2003, 68, 3251.
M
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