Unprecedented double benzylic rearrangement: Regio- and stereospecific tandem 1,4-shift and Curtin rearrangement

Article abstract of DOI:10.1016/j.tet.2012.07.053

An α-benzyloxyketone forming part of a strained cyclopentane carbon framework when treated with 10 equiv of anhydrous NaOH in absolute ethanol, for 2 h, affords in a 65% yield a new 2-benzyl-2-hydroxyketone, resulting from an unprecedented double benzylic rearrangement. This new rearrangement could be interpreted as an initial benzylic 1,4-shift between the O-enolate alkoxide of the ketone group and the oxygen atom of the benzyloxy ether, followed by a Curtin type benzylic 1,2-shift. Apart from the novelty and the synthetic application of this transformation it is worth noting the complete regio- and stereoselectivity observed. The structures of both substrate and product have been confirmed by X-ray diffraction studies. A tentative mechanism is herein proposed.

Full text of DOI:10.1016/j.tet.2012.07.053

Tetrahedron 68 (2012) 8276e8285
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Unprecedented double benzylic rearrangement: regio- and stereospecific tandem
1,4-shift and Curtin rearrangement
a,
a,
y
a
b,c
ꢀ
*
~
ꢁ
Angel M. Montana , Stefano Ponzano , Consuelo Batalla , Merce Font-Bardia
a
b
c
ꢁ
Industrial and Applied Organic Chemistry Research Unit, Department of Organic Chemistry, University of Barcelona, c/Martí i Franques 1-11, 08028 Barcelona, Spain
ꢁ
Department of Crystallography, Mineralogy and Mineral Deposits, University of Barcelona, c/Martí i Franques s/n, 08028 Barcelona, Spain
ꢀ
ꢁ
ꢀ
Unitat de Difraccio RX, Centre Cientific i Tecnologic (CCiTUB), Universitat de Barcelona, c/Sole Sabarís 1-3, 08028 Barcelona, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 11 June 2012
Received in revised form 13 July 2012
Accepted 16 July 2012
Available online 24 July 2012
An a-benzyloxyketone forming part of a strained cyclopentane carbon framework when treated with
10 equiv of anhydrous NaOH in absolute ethanol, for 2 h, affords in a 65% yield a new 2-benzyl-2-
hydroxyketone, resulting from an unprecedented double benzylic rearrangement. This new rearrange-
ment could be interpreted as an initial benzylic 1,4-shift between the O-enolate alkoxide of the ketone
group and the oxygen atom of the benzyloxy ether, followed by a Curtin type benzylic 1,2-shift. Apart
from the novelty and the synthetic application of this transformation it is worth noting the complete
regio- and stereoselectivity observed. The structures of both substrate and product have been confirmed
by X-ray diffraction studies. A tentative mechanism is herein proposed.
Keywords:
Benzyl ethers
Benzylic rearrangement
Enolates
Ó 2012 Elsevier Ltd. All rights reserved.
1,2-Shift
1,4-Shift
Curtin rearrangement
Wittig rearrangement
1. Introduction
products. For this reason this rearrangement, discovered by Curtin
more than 60 years ago, did not have synthetic applications until
Benzylic rearrangements are important in organic chemistry
and have been described in a wide variety of chemical trans-
formations and mechanisms. Thus, benzyl ethers undergo [1,2] and
[2,3] Wittig rearrangements1,2 when treated with butyl lithium
recently when L.A. Paquette et al.7 found an interesting rear-
rangement of an
a-benzyloxyketone when synthesizing C10-
alkylated toxoids, to afford an unexpected product with high
yield (94%) and regio- and stereoselectivity (Fig. 6).
(Fig. 1).
a
-Alkoxy-stannanes and
a
-alkoxy-silanes undergo [1,2]
We came across with a similar reaction when synthesizing the
precursor 2 of antitumor oxabicyclo[6.2.1]undecanes 4 via an aldol
cyclization of methylketones 1, under strong basic conditions.8
However, in our case we observed an unexpected and un-
precedented double benzylic rearrangement: a 1,4-shift followed
by a 1,2-benzylic shift in a regio- and stereoselective manner.
WittigeStill rearrangements3 under similar conditions (Fig. 2). Also
benzyl shifts are observed in benzyl ammonium salts in the pres-
ence of sodium amalgam (Stevens rearrangement)4 (Fig. 3). On the
other hand, b-benzyl silanes in a,b-unsaturated ketones undergo
a 1,2-migration of benzyl group from silicon to carbon atom upon
treatment with TBFA in anhydrous polar solvents.5 This silicon-
based 1,2-benzylic shift is highly stereoselective (Fig. 4). Finally it
is worth noting the Curtin rearrangement6 (Fig. 5) that takes place
2. Results and discussion
in a-benzyloxyketones to afford a-benzyl substituted a-hydroxy-
In the synthesis of oxatricyclo[6.2.1.02,6]undecan-4-one de-
rivatives 2, by an intramolecular aldol cyclization process (Fig. 7),
cyclization of methyl ketone 1 was carried out at room temperature
by using 10 equiv of NaOH in absolute ethanol for 8e24 h. The
conversion fell within the range of 80e100% and the yield was
normally high, 80e95%, depending on the size and bulkiness of
group R.
ketones, by heating the substrates with 1 M potassium hydroxide in
ethanol. These strong reaction conditions induced further reactions
of the initially-formed products to generate several fragmentation
ꢀ
* Corresponding author. E-mail addresses: angel.montana@ub.edu (A.M. Mon-
~
tana), sponzano@hotmail.com (S. Ponzano), mercef@sct.ub.es (M. Font-Bardia).
y
In the particular case of R¼benzyloxy, (1d), the yield of cyclic
Present address: Department of Drug Discovery and Development, Istituto
Italiano di Tecnologia, Via Morego 30, 16163 Genova, Italy.
aldol 2d was 95% in 15 h at room temperature. The remaining 5%
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.07.053

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A.M. Montana et al. / Tetrahedron 68 (2012) 8276e8285
8277
Fig. 1. [1,2] Wittig rearrangement.
Fig. 2. [1,2] WittigeStill rearrangement.
Fig. 3. Ammonium-based 1,2-benzylic shift: Stevens rearrangement.
Fig. 4. Silicon-based 1,2-benzylic shift.
was unchanged starting material 1d that was recovered and reused.
The usual work-up procedure comported careful neutralization of
the crude reaction mixture with HCl 1 M, removal of EtOH, addition
of water, and extraction with ether.
As some times it happens in science our finding was a conse-
quence of serendipity, when we accidentally heated, while con-
centrating the reaction crude to dryness, and before neutralizing
the reaction mixture. In that occasion the work-up protocol was
thus inverted and consequently a high concentration of NaOH in
EtOH was reached while heating. We observed the formation of
a new product 3 in 44% yield, together with our usual aldol product
2 in 30% yield (Fig. 8).
We tried to emulate the new reaction conditions that afforded
the new product 3 and also tried to optimize the yield by using the

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A.M. Montana et al. / Tetrahedron 68 (2012) 8276e8285
8278
takes place only for high concentrations of base (entries 1e3), no
R = H, Ph
R
matter of the reaction time. These findings moved us to think that
the parameters evaluated do not condition the reaction outcome,
due to 3 is generated from 2, not from 1, and because the formation
of 3 takes place during work-up and not during aldol cyclization.
This was confirmed by performing the reaction several times and at
different scales, using the right standard protocol, which afforded
compound 2 as the only product and with isolated yields (by col-
umn chromatography) of 86e95%.
Ph
HO
R
KOH (1M)
Ph
Ph
Ph
Ph
O
EtOH,Δ
O
Ph
O
Fig. 5. Curtin rearrangement.
Fig. 6. Synthetic applications of Curtin rearrangement: examples from Paquette’s work.
Fig. 7. Synthesis of oxabicyclo[6.2.1]undecanes 4 from precursors 1 and 2.
Δ
Fig. 8. Unexpected formation of 3 from 2, during work-up of the aldol cyclization of 1d.
‘inverted protocol’. We evaluated different parameters like: scale of
1 (from 40 to 300 mg), concentration, reaction time (from 10 min to
15 h), molar ratio substrate/NaOH (from 1:1 to 1:10), nature of used
base (NaOH or LieHMDS), and reaction temperature (ꢀ78 ꢁC to
40 ꢁC). The results are quoted in Table 1 for comparative purposes.
Observing the results from Table 1 it is possible to conclude that
the scale of reaction is not relevant and that the formation of 3
To convert directly 2 into 3, we reacted pure compound 2 with
NaOH in absolute ethanol (3/NaOH¼1:10) at 2 M concentration,
obtaining compound 3 in a 65% yield (Fig. 9). The remaining mass
was unchanged product 2.
Both compounds were separated by flash column chromatog-
raphy and physically and spectroscopically characterized, and the
1H and 13C NMR data assigned and correlated by COSY and HSQC

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A.M. Montana et al. / Tetrahedron 68 (2012) 8276e8285
8279
Table 1
Trials of the intramolecular aldol reaction of 1 under the new reaction conditions
Entry
Scale of 1 (mg)
Scale of 1
(mmol)
Solvent (mL)
Time
NaOH (equiv)
Li-HMDS
(equiv)
Concn of base
(mol/L)
T (ꢁC)
2 (%)
3 (%)
1 (%)
Conv. (%)
1
2
3
4
5
6
7
8
100
300
40
40
40
40
40
40
40
40
40
0.316
0.948
0.126
0.126
0.126
0.126
0.126
0.126
0.126
0.126
0.126
EtOH (12)
EtOH (40)
EtOH (5)
EtOH (5)
EtOH (20)
EtOH (20)
EtOH (5)
EtOH (5)
THF (3)
15 h
2.3 h
45 min
45 min
22 h
10
10
10
1.05
1.05
1.05
1.05
0.5
d
d
d
d
d
d
d
d
d
1.05
1.1
2
0.260
0.240
0.250
0.026
0.006
0.006
0.026
0.013
0.044
0.046
0.080
rt
rt
rt
rt
rt
rt
rt
rt
46
30
43
27
39
37
23
9
14
44
35
0
0
0
0
0
0
0
40
26
22
73
61
63
77
91
60
74
78
27
39
37
23
9
10 h
90 min
45 min
10 min
24 h
9
10
11
rt
rt
0
0
0
100
100
100
0
0
0
THF (3)
THF (3)
d
72 h
d
ꢀ78 to rt
0
other from 13 years ago by L.A. Paquette,7 both of them related with
a 1,2-benzylic shift, as mentioned in the Introduction section, but
none of them could explain the whole observed transformation of 2
into 3. Other striking result was the complete regio- and stereo-
selectivity observed: a possible regioisomer 30 (Fig. 12) has not been
detected at all and, on the other hand, the configuration at C4 of 3 is
S . No epimer in this position has been detected, after a meticulous
*
and careful screening of reaction crudes by NMR, GC, and GCeMS
techniques.
A possible mechanism, which could justify the formation of
product 3 is represented in Fig. 12. Once the cyclic aldol 2 is formed,
the base abstracts the most acidic hydrogen, situated in the a-po-
sition to the carbonyl group (C-4) and geminal to the benzyloxy
group on C-3, to generate the corresponding delocalized enolate
anion A. It is envisioned an initial abstraction of H-3, a to the ketone
group on C-4, by NaOH due to its pKa in EtOH medium is 18.46
(calculated by the SPARC computer program)9 instead of an alter-
native abstraction of a benzylic hydrogen H-10 because of its much
higher pKa¼32.77 (see Table 2).9,10 This great difference of acidity
(by a factor of 1014) prompted us to propose the mechanism illus-
trated in Fig. 12.
At this point, to justify the migration of the benzylic group, two
consecutives benzylic shift reactions should take place: (a) one 1,4-
benzyl shift11 originated from the oxyanion of enolate A on the
spatially nearby and partially positively charged carbon (C-10) of
the benzylic group, to generate a second enolate anion B; the sec-
ond one coming from the carbanion of the newly formed enolate B
on the benzylic carbon (C-10) via a transitory oxirane ring C with the
resulting cleavage of the carboneoxygen bond and the formation of
a new carbonecarbon bond (intermediate D). The new oxyanion
generated would then abstract a proton from water during the
work-up process to generate 3.
Fig. 9. Direct obtention of 3 by rearrangement of 2 in the presence of NaOH (10:1) in
absolute EtOH.
spectra. In the NMR spectra of 3, it was not observed any signal
corresponding to a hydrogen geminal to the benzyloxy group (like
H3 in 2), which usually appears at a chemical shift between 4 and
5 ppm. Another peculiarity of this, then unknown, product 3 was
the position in the 1H NMR spectra of the benzylic CH2 hydrogen
atoms. The typical two doublets appeared around 3 ppm, while this
kind of hydrogens usually appear in 1H NMR of 2 in the zone of
4e5 ppm.
Thus, the information obtained from NMR studies confirmed
that product 3 bore a benzyl group at a different position with re-
spect to the substrate 2. From the HSQC experiment, a CeH carbon
was missing, which inferred its possible transformation into a new
quaternary carbon atom. This was confirmed by the totally
decoupled 13C NMR spectra. Two new singlets appeared in the 1H
NMR spectrum registered in deuterated benzene, without any CeH
correlation in the HSQC two-dimensional spectra. These two sin-
glets showed no CeH correlation due to the absence of protons on
the carbons that carry the hydroxyl groups (C4 and C6 in 3).
To unveil the structure of 3 and to compare it with that of 2,
single crystals of both compounds were obtained and analyzed by
X-ray diffraction analysis, that showed us a surprising and un-
expected structure for 3, which then could be envisioned as the
result of an unusual rearrangement process (Figs. 10 and 11).
It is worth noting that analogues of methylketones 1 (with R¼H,
OMe, OEt, MOM) have been reacted under these conditions and no
rearrangement products analogue of 3 have never been observed.
Thus, it is immediate to conclude that this type of rearrangement,
under strong basic conditions, is related to the presence of the
benzyloxy group. Is for this reason that we looked for similar
transformations in the literature and we found only two references
regarding this process: one from 60 years ago by D.Y. Curtin6 and
One important aspect that remains to be unveiled in our process
and also in the reaction described by Paquette et al.7 is the expla-
nation of the regio- and stereospecificity observed in the formation
of the rearranged product.
The 1,4-benzylic shift could be envisioned as a stepwise or as
a sigmatropic rearrangement. The approach of 1e4 termini could
€
be rationalized on the basis of the electron density (Huckel charge
of benzylic carbon is þ0.1317e and that of O-enolate oxygen
is ꢀ0.5790e) and the distance through space between both atoms
ꢀ
ꢂ
(PheCH2/O ¼2.812 A). The second step would be the 1,2-
benzylic shift (Curtin rearrangement) that would afford (through
transition state C) intermediate alkoxide D, which after aqueous
work-up will yield product 3 in a stereoselective manner. In our
case and also in Paquette’s work, in a first look, it is not clear how
starting from a planar enolate B (due to resonance stabilization
between C- and O-enolate) it is possible to generate a chiral
quaternary center on C4 in a stereoselective way. One may appeal
to the different energy of the transition states (type C) leading to
both theoretically possible epimers at the new stereogenic center

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A.M. Montana et al. / Tetrahedron 68 (2012) 8276e8285
Fig. 10. ORTEP representation of the oxatricyclic precursor 2.
Fig. 11. X-ray structure of the rearrangement product 3.
(C4), resulting from the attack of the HOMO orbital of the enolate
B to the LUMO orbital of the CeO bond at the benzylic carbon
(Fig. 13). In Table 3, it is possible to observe how the most energy-
favorable transition state is TS-2, with lower activation energy and
bridging oxygen of the TS, which minimizes steric constraints and
propitiates the right orientation of orbitals and the HOMOeLUMO
interaction (Fig. 13).14
s
*
An alternative mechanism to explain the formation of 3 from 2
could be a two-step process consisting in a Curtin rearrangement to
higher
DHf (in absolute value), which affords the formation of
compound 3. 12Also the energy of the four TS has been calculated
by the DFT (B3LYP, 6-311þþG) method.13 TS-3 and TS-4 leading to
the non-formed isomer 300 are less energetically favored. On the
other hand, in both types of TS it is worth to mention that TS-2 is
preferred to TS-1 and thus is TS-3 over TS-4. This could be due to
the exo disposition of the phenyl group with respect to the
generate 30, in first place, followed by an -ketol rearrangement15 to
a
afford 3. The stereochemistry of the first Curtin process could be
determined on the basis of the energy of the TS, as mentioned
before, which also conditions the stereochemical outcome of the
acyloin rearrangement due to the right disposition of the benzylic
methylene, oriented toward the Si face of the carbonyl group.

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A.M. Montana et al. / Tetrahedron 68 (2012) 8276e8285
8281
Δ
Δ
Fig. 12. Mechanism proposal for the formation of product 3.
However, we have discarded this alternative mechanism as we
have never detected the formation of 30. Moreover, the driving force
of the a-ketol rearrangement usually is the release of the strain of
Table 2
pKa values of acidic hydrogens in 3
cyclic systems (or very sterically crowded structures) having the a-
hydroxyketone functionality13 but in our case the cyclopentanone
substructure remains intact. One question remains without
answer: why none of the substrates illustrated in Fig. 6 that un-
derwent a Curtin rearrangement afforded a further 1,4-sigmatropic
shift11 or an
a-ketol rearrangement?
On the other hand, a mechanism based on a radical pair dis-
sociationerecombination as proposed for [1,2]-Wittig rear-
rangements,1cee in our opinion could not be applied in the present
case, because the nature of substrates and the reaction conditions
make more feasible a heterolytic bond breaking with generation
of ionic intermediates. For this reason a stereospecificity involving
retention at the migrating center and inversion of the free
radical-alkoxide-bearing terminus, proposed for the [1,2]-Wittig
rearrangement, cannot be appealed.16 Finally, it could be addressed
the possibility that the reaction proceeds via a heterolytic cleavage
pathwaysimilar tothatof theanionic oxy-Claisen’s rearrangement.17
Hydrogen
pKa (in water)9,10
pKa (in EtOH)9
pKa (in THF)9
Ha
Hb
Hc
Hd
17.14
19.96
15.78
34.10
24.14
20.71
18.46
32.77
36.54
31.46
29.21
43.12

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A.M. Montana et al. / Tetrahedron 68 (2012) 8276e8285
8282
used as internal standard. 13C NMR spectra were referenced to the
77.0 ppm resonance of chloroform. Mass spectra were measured on
a HEWLETT-PACKARD 5890 mass spectrometer using chemical ioni-
zation. GC analyses were performed on HP-8790 gas chromatograph
equipped with a HEWLETT-PACKARD-crosslinked 5% MePhe-Silicone
capillary column (L¼25 m, D¼0.2 mm, thickness¼2.5
mm) using he-
lium as a carrier gas and an FID detector (T¼250 ꢁC, PH ¼ 4:2 psi,
2
Pair¼2.1 psi). The elemental analyses were obtained in a FISONS ele-
mental analyzer, Model Na-1500. The samples were previously py-
rolized at 1000 ꢁC under oxygen atmosphere and the content of
carbon and hydrogen was determined by evaluation of the combus-
tion gases by gas chromatography using an FID detector.
4.2. X-ray diffraction analyses
Suitable crystals (0.2ꢂ0.1ꢂ0.1 mm) from compounds 2 and 3
were selected and mounted on
a CAD4-Enraf-Nonius and
a MAR345 apparatus, respectively, with image plate detector. Unit
cell parameters were determined from automatic centering of re-
flections and refined by least-squares method. Intensities were
collected with graphite monochromatized Mo
Ka radiation.
Lorentz-polarization and absorption corrections were made.
The structure was solved by direct methods and refined by full-
matrix least-squares method using SHELXS-97 computer pro-
gram,18 on the basis of the non-equivalent reflections by symmetry
(very negative intensities were not assumed). The function mini-
Fig. 13. HOMOeLUMO approach in the TS of the Curtin rearrangement.
mized was: Sw[(Fo)2ꢀ(Fc)2]2, where w¼[
s
2(I)þ(0.0591P)2]ꢀ1 for 2
2(I)þ(0.0555P)2þ0.1371P)ꢀ1 for 3. P¼[(Fo)2þ2(Fc)2]/3; f, f0
3. Conclusions
and w¼[
s
and f00 were taken from the International Tables of X-ray Crystal-
lography.19 All the H atoms were computed and refined, using
a riding model, with isotropic temperature factor equal to 1.2 times
the equivalent temperature factor of the atom, which are linked. The
final R (on F) factors and goodness-of-fit are shown in Table 4. The
number of refined parameters was 210 for 2 and 416 for 3. Max. shift/
esd¼0.00. Mean shift/esd¼0.00. Refinement of F2 was done against
all reflections. The weighted R-factor wR and goodness-of-fit S are
based on F2, conventional R-factors R are based on F, with F set to
An unexpected and unprecedented double rearrangement of an
-benzyloxyketone has been observed when reacted with 10 equiv
a
of anhydrous NaOH in absolute ethanol, for 2 h, affording in a 65%
yield a new 2-benzyl-2-hydroxyketone. This new rearrangement
could be interpreted as an initial benzylic 1,4-shift between the
O-enolate alkoxide of the ketone group and the oxygen atom of the
benzyloxy ether, followed by a Curtin type benzylic 1,2-shift. Apart
from the novelty and the synthetic application of this transformation
it is worth noting the complete regio- and stereoselectivity observed.
The structures of both substrate and product have been confirmed by
X-ray diffraction studies. A tentative mechanism is herein proposed.
We consider that the results presented here have sound ex-
perimental support for the usefulness of Curtin type base promoted
zero for negative F2. The threshold expression of F2>2 (F2) is used
s
only for calculating R-factors(gt), etc. and is not relevant to the
choice of reflections for refinement. R-factors based on F2 are sta-
tisticallyabout twice as largeas those based on F, and R-factors based
on all data will be even larger. All esds (except the esd in the dihedral
angle between two l.s. planes) are estimated using the full co-
variance matrix. The cell esds are taken into account individually in
the estimation of esds in distances, angles, and torsion angles; cor-
relations between esds in cell parameters are only used when they
are defined by crystal symmetry. An approximate (isotropic) treat-
ment of cell esds is used for estimating esds involving l.s. planes.
The main X-ray data are quoted in Table 4. For additional in-
formation regarding bond lengths and bond angles for compounds
2 and 3, as well as the hydrogen coordinates and the anisotropic
thermal parameters see the CIF files deposited as supplementary
material with the Cambridge Crystallographic Data Centre. Crys-
tallographic data (excluding structure factors) for the structures in
this paper have been deposited with the Cambridge Crystallo-
graphic Data Centre as supplementary publication nos. CCDC-
873346 and CCDC-873347 for compounds 2 and 3, respectively.
Copies of these data can be obtained, free of charge, on application
to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK, (fax: þ44 (0)1223
336033 or e-mail: deposit@ccdc.cam.ac.uk).
a
-benzyloxyketone rearrangements in organic synthesis. Even
though reactivity patterns should be screened and theoretical
studies should be accomplished in order to understand the com-
plete regio- and stereoselectivity, sufficient understanding and
empirical data are available to encourage synthetic chemists to use
the Curtin rearrangements, in general, and the herein described
methodology in their synthetic planning. Further efforts to expand
the scope of this rearrangement to other substrates, and to unveil
the reaction mechanism are under way in our laboratory.
4. Experimental section
4.1. General methods
Unless otherwise noted, all reactions were conducted under an
atmosphere of dry nitrogen or argon in oven-dried glassware. All
solvents were purified using standard techniques before use: ether,
tetrahydrofuran, hexane, and pentane were distilled under nitrogen
fromsodium/benzophenone. Acetonitrilewasdistilledundernitrogen
from CaH2. Infrared spectra were recorded on an FT-IR NICOLET 510
spectrophotometerasthin films over NaCl. NMR spectrawere taken in
CDCl3 on VARIAN spectrometers at 200 MHz (GEMINI-200), 400 MHz
(MERCURY-400), and/or 500 MHz (UNITY-500) for 1H NMR, and at
50 MHz and 100 MHz for 13C NMR. For 1H NMR tetramethylsilane was
4.3. Synthesis of (1S,2R,4S,5R,10S)-2-(1-benzyloxy-2-oxoprop-
1-yl)-2,4-dimethyl-8-oxabicyclo[3.2.1]octan-3-one, (1d)
Compound 1d was synthesized according to a procedure pre-
viously developed in our research group.8

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A.M. Montana et al. / Tetrahedron 68 (2012) 8276e8285
8283
Table 3
Possible transition states (TS) leading to final product 3 or to its epimer 300
Transition State C (TS-i)
TE,
DHf, E (kcal/mol)
Delta;Delta;Es
Product
(TS-i)ꢀ(TS-2) (kcal/mol)
TE¼160.13 (MM2)
Hf¼ꢀ67.53 (PM6)
E¼ꢀ651,895.9764 (DFT)
10.71
20.17
ꢀ0.05
TS-1
D
TE¼149.42 (MM2)
Hf¼ꢀ87.71 (PM6)
E¼ꢀ651,895.9277 (DFT)
0
0
0
TS-2
D
3
TE¼148.60 (MM2)
Hf¼ꢀ85.88 (PM6)
ꢀ0.82
1.82
1.56
TS-3
D
E¼ꢀ651,894.3678 (DFT)
TE¼158.53 (MM2)
9.11
19.91
19.19
D
Hf¼ꢀ67.80 (PM6)
E¼ꢀ651,876.7375
TS-4
3”
IR (film
deform), 1379, 1352, 1225, 1194, 1095, 1030 (CeO, st). 1H NMR
(400 MHz, CDCl3,
n
, cmꢀ1): 2975 (Csp3eH, st), 1703 (C]O, st), 1476 (CeC
5"
4"
d
, ppm): 0.93 (3H, s, H9), 0.96 (3H, d, J¼6.8 Hz,
H10), 1.62e1.84 (4H, m, H6 and H7), 2.14 (3H, s, H30), 3.22 (1H, dq,
J1¼6.4 Hz, J2¼6.4 Hz, H4), 4.52 (1H, dd, J1¼J2¼5.6 Hz, H5), 4.56 (1H,
d, J¼7.6 Hz, H1), 4.71 (1H, d, J¼11.2 Hz, H100), 4.75 (1H, s, H10), 4.77
(1H, d, J¼11.2 Hz, H100), 7.30e7.43 (5H, m, H300 and H400 and H500 and
6"
3"
7"
2"
H600 and H700). 13C NMR (400 MHz, CDCl3,
d, ppm): 10.10 (C10), 11.93
(C9), 24.75, 25.11 (C6 and C7), 28.08 (C30), 48.34 (C4), 60.44 (C2),
74.95 (C100), 80.87 (C1), 82.65 (C5), 86.78 (C10), 128.05 (C300 and
C700), 128.33 (C400 and C600), 128.79 (C500), 137.55 (C200), 208.37 (C3),
212.72 (C20). MS (DIP-CI-NH3, 70 eV, 150C, m/z (%)): 334.5 (100,
MþNHþ4 ), 317.5 (86.5, Mþ1), 209 (4, MꢀC7H7O). EA calcd for
C19H24O4: C, 72.13; H, 7.65; O, 20.23%. Found: C, 72.19; H, 7.64; O,
20.17%. TLC (SiO2; hexane/ether, 3:7): Rf¼0.49. GC (ti¼1 min;
Ti¼150 ꢁC; Tf¼250 ꢁC; rate¼5 ꢁC/min; tf¼20 min): tR¼13.3 min.
1"
O
O
10
9
2'
3
3'
1'
2
4
O
O
1
5
8
6
7

ꢀ
~
8284
A.M. Montana et al. / Tetrahedron 68 (2012) 8276e8285
Table 4
Crystal data refinement for 2 and 3
Parameters
Compound 2
Compound 3
Temperature
Wavelength
293(2) K
0.71073 A
293(2) K
0.71073 A
ꢂ
ꢂ
Crystal system
Space group
Unit cell dimensions
Monoclinic
Cc
Monoclinic
P21/c
¼90ꢁ
a¼12.465(7) A;
a
b
¼90ꢁ
ꢂ
ꢂ
a¼20.125(9)A;
a
b¼6.419(2) A;
b
¼121.76(4)ꢁ
b¼10.761(4) A;
¼109.29(3)ꢁ
ꢂ
ꢂ
¼90ꢁ
c¼26.134(12) A;
g
¼90ꢁ
ꢂ
3
ꢂ
ꢂ
c¼15.359(9) A;
g
3
ꢂ
Volume
Z
Calculated density
Absorption coefficient
F(000)
1687.0(14) A
4
3309(3)A
8
1.246 Mg/m3
0.086 mmꢀ1
680
1.270 Mg/m3
0.088 mmꢀ1
1360
Crystal size
Theta range for data collection
Limiting indices
Reflections collected
Independent reflections
Completeness to theta
Refinement method
Data/restraints/parameters
Goodness-of-fit on F2
0.2ꢂ0.1ꢂ0.1 mm
0.2ꢂ0.1ꢂ0.1 mm
2.38e30.01ꢁ
2.57e32.38ꢁ
ꢀ27ꢃhꢃ28; ꢀ9ꢃkꢃ8; ꢀ14ꢃlꢃ21
4689
ꢀ18ꢃhꢃ17; ꢀ15ꢃkꢃ13; ꢀ39ꢃlꢃ39
27,098
2450 [R(int)¼0.0658]
9527 [R(int)¼0.0421]
(30.01ꢁ) 99.8%
(25.0ꢁ) 91.6%
Full-matrix least-squares on F2
2450/2/210
Full-matrix least-squares on F2
9527/8/416
1.005
1.130
Final R indices [I>2
R indices (all data)
Largest diff. peak and hole
s
(I)]
R1¼0.0508; wR2¼0.1043
R1¼0.0678, wR2¼0.1396
R1¼0.1440; wR2¼0.1304
R1¼0.1299, wR2¼0.1608
ꢂꢀ3
ꢂꢀ3
0.131 and ꢀ0.178 e A
0.223 and ꢀ0.259 e A
4.4. Synthesis of (1S,2R,3R,6S,7S,8R)-6-hydroxy-3-benzyloxy-
d, J¼19.2 Hz, H5b), 2.11e2.22 (2H, m, H9 and H10), 2.51 (1H, dd,
J1¼19.2 Hz, J2¼1.6 Hz, H5b), 4.05 (1H, d, J¼7.6 Hz, H1), 4.11 (1H, dd,
J1¼7.6 Hz, J2¼4.0 Hz, H8), 4.62 (1H, d, J¼1.2 Hz, H3), 4.69 (1H, d,
J¼11.6 Hz, H10), 5.06 (1H, d, J¼11.6 Hz, H10), 7.26e7.40 (5H, m, H30
2,7-dimethyl-11-oxatricyclo[6.2.1.02,6]undecan-4-one, (2)
In a 25 mL round-bottomed flask previously heated under vac-
uum, compound 1 (1 g, 3.16 mmol) was placed. The system was
purged under argon and the product was dissolved in absolute
ethanol (6 mL). In a second rounded bottom flask also previously
heated under vacuum, NaOH (1.27 g, 31.8 mmol) was placed, which
was subsequently dissolved in absolute ethanol (5 mL). The solu-
tion was heated at 30e40 ꢁC in order to favor the solubility of the
base. This solution was then transferred via cannula under an argon
flow to the reaction flask containing the methyl ketone 1 and the
operation was repeated with absolute ethanol (2 mL) in order to
wash the cannula and the flask to recover the NaOH solution. The
reaction mixture was stirred at room temperature for 15 h and then
neutralized by adding dropwise a solution of HCl (2 M) to reach
a slightly acidic pH (6e7). The crude was concentrated to dryness to
remove ethanol and then redissolved in water. The resulting solu-
tion was then extracted three times with CH2Cl2 and the organic
extract was dried over anhydrous MgSO4. The organic phase was
filtered and concentrated to dryness affording 0.98 g of crude
mixture. The product was purified by flash column chromatogra-
phy on silica gel, eluting with mixtures of hexane and diethyl ether
of increasing polarity, obtaining (with H/E 30:70) 0.94 g of 2 (95%).
and H40 and H50 and H60 and H70). 13C NMR (100 MHz, CDCl3,
d,
ppm): 10.23 (C13), 11.83 (C12), 24.00 and 24.97 (C9 and C10), 41.46
(C7), 49.18 (C5), 49.94 (C2), 73.06 (C6), 74.20 (C10), 77.43 (C1) 79.19
(C8), 85.32 (C3), 127.87 (C300 and C700), 127.90 (C400 and C600), 128.53
(C500), 138.42 (C200), 213.78 (C4). MS (DIP-CI-NH3, 70 eV, 150ꢁC, m/z
(%)): 334.5 (100, MþNHþ4 ), 317.5 (13.8, Mþ1), 209 (2, MꢀC7H7O). EA
calcd for C19H24O4: C, 72.13; H, 7.65; O, 20.23%. Found: C, 72.11; H,
7.68; O, 20.21%. TLC (SiO2; hexane/ether, 2:8, two elutions): Rf¼0.47.
GC (ti¼1 min; Ti¼150 ꢁC; Tf¼250 ꢁC; rate¼5 ꢁC/min; tf¼20 min):
tR¼16.56 min.
4.5. Synthesis of (1S,2S,4S,6S,7S,8R)-4-benzyloxy-
4,6-dihydroxy-2,7-dimethyl-11-oxatricyclo[6.2.1.02,6
undecan-3-one, (3)
]
In a 100 mL round-bottomed flask previously heated under
vacuum, compound 2 (0.300 g, 0.954 mmol) was placed. The
Mp: 122e124 ꢁC (ether). IR (film
(Csp3eH, st), 1748 (C]O, st), 1466 (CeC deform), 1256, 1146, 1101
(CeO, st). 1H NMR (400 MHz, CDCl3,
n
, cmꢀ1): 3448 (OeH, st), 2959
d
, ppm): 0.92 (3H, d, J¼7.2 Hz,
H13), 0.97 (3H, s, H12), 1.7e1.95 (3H, m, H7, H9 and H10), 2.08 (1H,
O
Hb
Ha
3'
4'
2'
7'
4
HO
5
1'
3
1
O
5'
13
6
6'
2
7
12
O
11
8
9
10

ꢀ
~
A.M. Montana et al. / Tetrahedron 68 (2012) 8276e8285
8285
system was purged under argon and the product was dissolved in
absolute ethanol (10 mL). In a second round-bottomed flask also
previously heated under vacuum, NaOH (0.381 g, 9.54 mmol) was
placed and subsequently dissolved in absolute ethanol (15 mL).
The solution was heated at 30e40 ꢁC in order to facilitate the
solubility of the base. This dissolution was then transferred via
cannula under an argon flow to the reaction flask containing the
ketone 2. The reaction mixture was stirred at room temperature for
2.5 h and then concentrated to dryness using a rotary evaporator.
The obtained crude solid was dissolved in water and then neu-
tralized by adding dropwise a solution of HCl (1 M). The resulting
solution was then extracted three times with CHCl2 and the or-
ganic extracts were dried over anhydrous MgSO4. The organic
phase was filtered and concentrated to dryness affording 0.287 g of
crude mixture. The product was purified by flash column chro-
matography on silica gel, eluting with mixtures of hexane and
diethyl ether of increasing polarity, obtaining (with H/E 1:9)
0.195 g of 3 (65%) and 0.105 g of unchanged starting material 2
(35%).
2012/AR000126) for financial assistance. Also, a fellowship to S.P.
from the Generalitat de Catalunya is gratefully acknowledged.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2012.07.053.
These data include MOL files and InChiKeys of the most important
compounds described in this article.
References and notes
€
1. (a) Wittig, G.; Lohmann, L. Liebigs Ann. Chem. 1942, 550, 260e268; (b) Tomooka,
K.; Yamamoto, H.; Nakai, T. Liebigs Ann. Chem. 1997, 1275e1281; (c) Tomooka,
K.; Yamamoto, H.; Nakai, T. J. Am. Chem. Soc. 1996, 118, 3317e3318; (d) Azzena,
U.; Denurra, T.; Melloni, G.; Piroddi, A. M. J. Org. Chem. 1990, 55, 5532e5535; (e)
Evans, D. A.; Baillargeon, D. J. Tetrahedron Lett. 1978, 3315e3318; (f) Schafer, H.;
€
€
Schollkoft, U.; Walter, D. Tetrahedron Lett. 1968, 2809e2814; (g) Schollkopf, U.
Angew. Chem., Int. Ed. Engl. 1970, 9, 763e773.
2. (a) Nakai, T.; Mikami, K. Org. React. 1994, 46, 105e209; (b) Nakai, T.; Mikami, K.
Chem. Rev. 1986, 86, 885e895; (c) McNally, A.; Evans, B.; Gaunt, M. J. Angew. Chem.,
Int. Ed. 2006, 45, 2116e2119; (d) Maleczka, R. E.; Geng, F. Org. Lett.1999,1, 1111e1113.
3. Still, C.; Mitra, A. J. Am. Chem. Soc. 1978, 100, 1927e1928.
4. (a) Dunn, J. L.; Stevens, T. S. J. Chem. Soc. 1934, 279e282; (b) Haslam, E.; Morris,
D. G. Biogr. Mems Fell. R. Soc. 2003, 49, 521e535.
5. (a) Trost, B. M.; Ball, Z. T. J. Am. Chem. Soc. 2004, 126, 13942e13944; (b) Trost, B.
M.; Bertogg, A. Org. Lett. 2009, 11, 511e513.
6. (a) Curtin, D.; Leskowitz, S. J. Am. Chem. Soc. 1951, 73, 2630e2633; (b) Curtin, D.;
Mp: 171e173 ꢁC (ether/hexane 2:8). IR (film
st), 2959 (Csp3eH, st), 1748 (C]O, st), 1466 (CeC deform), 1256, 1146,
1101 (CeO, st). 1H NMR (400 MHz, CDCl3,
, ppm): 0.92 (3H, d,
n
, cmꢀ1): 3448 (OeH,
d
J¼7.2 Hz, H13), 0.97 (3H, s, H12), 1.7e1.95 (3H, m, H7, H9 and H10),
2.08 (1H, d, J¼19.2 Hz, H5b), 2.11e2.22 (2H, m, H9 and H10), 2.51 (1H,
dd, J1¼19.2 Hz, J2¼1.6 Hz, H5b), 4.05 (1H, d, J¼7.6 Hz, H1), 4.11 (1H, dd,
J1¼7.6 Hz, J2¼4.0 Hz, H8), 4.62 (1H, d, J¼1.2 Hz, H3), 4.69 (1H, d,
J¼11.6 Hz, H10), 5.06 (1H, d, J¼11.6 Hz, H10), 7.26e7.40 (5H, m, H300 and
Leskowitz, S. J. Am. Chem. Soc. 1951, 73, 2633e2635.
7. (a) Paquette, L.; Zeng, Q. Tetrahedron Lett. 1999, 40, 3823e3826; (b) Paquette, L.
A.; Pegg, N. A.; Toops, D.; Maynard, G. D.; Rogers, R. D. J. Am. Chem. Soc. 1990,
112, 277e283.
H400 and H500 and H600 and H700). 13C NMR (100 MHz, CDCl3,
d, ppm):
~
€
8. (a) Montana, A. M.; Ponzano, S.; Kociok-Kohn, G.; Font-Bardia, M.; Solans, X.
~
Eur. J. Org. Chem. 2007, 4383e4401; (b) Montana, A. M.; Fernandez, D. Tetra-
hedron Lett. 1999, 40, 6499e6502; (c) Montana, A. M.; Fernandez, D.; Pages, R.;
Filippou, A. C.; Kociok-Kohn, G. Tetrahedron 2000, 56, 425e439.
10.23 (C13), 11.83 (C12), 24.00 & 24.97 (C9 & C10), 41.46 (C7), 49.18
(C5), 49.94 (C2), 73.06 (C6), 74.20 (C10), 77.43 (C1) 79.19 (C8), 85.32
(C3), 127.87 (C300 and C700), 127.90 (C400 and C600), 128.53 (C500), 138.42
(C200), 213.78 (C4). MS (DIP-CI-NH3, 70 eV,150 ꢁC, m/z (%)): 334.5 (100,
MþNHþ4 ), 317.5 (13.8, Mþ1), 209 (2, MꢀC7H7O). EA calcd for C19H24O4:
C, 72.13; H, 7.65; O, 20.23%. Found: C, 72.15; H, 7.63; O, 20.22%. TLC
(SiO2; hexane/ether, 2:8, two elutions): Rf¼0.47. GC (ti¼1 min; Ti¼150
ꢁC; Tf¼250 ꢁC; rate¼5 ꢁC/min; tf¼20 min): tR¼17.14 min.
~
ꢁ
€
9. Calculated by the SPARC algorithm: (a) Hilal, S. H.; Karickhoff, S. W.; Carreira, L. A.
Quant. Struct.-Act. Relat.1995,14, 348e355; (b) http://ibmlc2.chem.uga.edu/sparc.
10. Calculated according to the algorithm of Marvin (ChemAxon) http://www.
chemaxon.com/.
11. (a) Bailey, W. F.; Zarcone, L. M. Tetrahedron Lett. 1991, 32, 4425e4426; (b) To-
mooka, K.; Yamamoto, H.; Nakai, T. Angew. Chem., Int. Ed. 2000, 39, 4500e4502;
(c) Onyeozili, E. N.; Maleczka, R. E., Jr. Chem. Commun. 2006, 2466e2468.
12. Calculated by using a semiempirical quantum mechanical PM6 algorithm,
implemented in the MOPAC software, and optimizing to TS: (a) Dobes, P.; Rezac,
J.; Fanfrlík, J.; Otyepka, M.; Hobza, P. J. Phys. Chem. B. 2011, 115, 8581e8589; (b)
Stewart, J. J. P. J. Comput.-Aided Mol. Des. 1990, 4, 1e105; (c) Stewart, J. J. P. J. Mol.
Model. 2007, 13, 1173e1213.
4.6. Computational calculations
13. Calculations have been performed using a DFT (B3LYP) method using a 6-
Calculations reported here were carried out using Gaussian 03W
Revision E.01 (version 6.1) software.20 All molecular ground state
and transition state structures were energy preoptimized by mo-
lecular mechanics MM2 followed by semiempirical quantum me-
chanical PM6 algorithm,12 implemented in the MOPAC software,
and optimizing to TS. Density functional theory (DFT) based
methods at the B3LYP/6e311þþG(d) level21 were used for sub-
sequent full refinements. All calculations were performed on the
isolated molecules (gas phase), as consideration of solvation by the
311þþG(d) base, implemented in the Gaussian-03 software.
14. King, J. F.; Tsang, G. T. Y.; Abdel-Malik, M. M.; Payne, N. C. J. Am. Chem. Soc. 1985,
107, 3224e3232.
15. Paquette, L. A.; Hofferberth, J. E. Org. React. 2003, 62, 477e567.
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Verner, E. J.; Cohen, T. J. Am. Chem. Soc. 1992, 114, 375e377; (c) Hoffmann, R.;
€
Bruckner, R. Chem. Ber. 1992, 125, 1957e1963; (d) Schreiber, S. L.; Goulet, M. T.
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1993, 43, 93e250 and especially pp 144e145; (c) Koreeda, M.; Luengo, J. I. J. Am.
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molecules of the solvent (ethanol,
3
¼24.5) by a polarizable con-
18. Sheldrick, G. M. SHELXS-97, A Computer Program for Determination of Crystal
tinuum model (PCM)22 produced a loss in computational perfor-
mance (increase of CPU calculation time and change of convergence
behavior), but did not result in significant changes of the calculated
energies. As the transition states were clearly little affected by the
solvent, its effect was not considered. Energies reported here are
given relative to the most stable conformers of the reactants. En-
€
€
Structure, University Gottingen, Gottingen, Germany Acta Crystallogr. 2008,
A64, 112e122.
19. International Tables of X-ray Crystallography; Kynoch: Birmingham, UK, 1974;
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S.; Millam, J. M.; Daniels, A. D.; Kudin, K. N.; Strain, M. C.; Farkas, O.; Tomasi, J.;
Barone, V.; Cossi, M.; Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo, C.; Clifford, S.;
Ochterski, J.; Petersson, G. A.; Ayala, P. Y.; Cui, Q.; Morokuma, K.; Malick, A. D.;
Rabuck, K. D.; Raghavachari, K.; Foresman, J. B.; Cioslowski, J.; Ortiz, J. V.; Baboul,
A. G.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Gomperts, R.;
Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.;
Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Andres, J. L.;
Gonzalez, C.; Head-Gordon, M.; Replogle, E. S.; Pople, J. A. Gaussian 03, Revision E.
01-SMP; Gaussian: Wallingford, CT, 2004.
thalpies (DH) including zero point correction, temperature correc-
tion, and vibrational energy were computed for standard
conditions (T¼298.15 K, P¼1.0 atm). Analysis of all data and plot-
ting of molecular structures were performed using Gaussian View
4.1 program.
21. (a) Becke, A. D. Phys. Rev. A. 1988, 38, 3098e3100; (b) Becke, A. D. J. Chem. Phys.
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Acknowledgements
We thank the Spanish Ministry of Education and Science
(CTQ2007-64843/BQU) and the University of Barcelona (UB-VRR-