Stereoselective cross aldol condensation of bicyclo[3.2.0]alkanones

Article abstract of DOI:10.1039/c3ob40431e

A cross aldol reaction between [(S)-(-)] or [(R)-(+)]-benzyloxypropanal and silyl enol ethers derived from bicyclo[3.2.0]alkanones was carried out in the presence of TiCl₄, leading with total stereoselectivity to a 1:1 mixture of enantiomerically pure diastereomers isolated in 81% overall yield. Thus, 5 stereogenic centers could be created starting from one. Furthermore, an efficient access to an enantiomerically pure tricyclo[5.3.0.0 ^2,6]decane scaffold was possible via a 4 step reaction sequence. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3ob40431e

Organic &
Biomolecular Chemistry
View Article Online
View Journal | View Issue
PAPER
Stereoselective cross aldol condensation of
bicyclo[3.2.0]alkanones†
Cite this: Org. Biomol. Chem., 2013, 11,
4025
Laurence Miesch,* Tania Welsch and Michel Miesch*
A cross aldol reaction between [(S)-(−)] or [(R)-(+)]-benzyloxypropanal and silyl enol ethers derived from
bicyclo[3.2.0]alkanones was carried out in the presence of TiCl4, leading with total stereoselectivity to a
1 : 1 mixture of enantiomerically pure diastereomers isolated in 81% overall yield. Thus, 5 stereogenic
centers could be created starting from one. Furthermore, an efficient access to an enantiomerically pure
tricyclo[5.3.0.02,6]decane scaffold was possible via a 4 step reaction sequence.
Received 1st March 2013,
Accepted 18th April 2013
DOI: 10.1039/c3ob40431e
www.rsc.org/obc
Introduction
Results and discussion
The aldol reaction is one of the most powerful methods for
forming carbon–carbon bonds and for generating stereo-
chemistry in a controlled fashion.1 In this context, the conden-
sation involving bicyclo[3.2.0]alkanone derivatives and
aldehydes is poorly documented in the literature. Indeed, to
the best of our knowledge, a unique report by Clark et al.
showed that the addition of racemic aldehydes to the lithio
enolate derived from bicyclo[3.2.0]heptanone afforded the
corresponding aldol products.2 On the other hand, it has also
been mentioned that the boron enolate or the silyl enol
ether derived from bicyclo[3.2.0]heptan-6-one led to the corres-
ponding aldol product as a mixture of syn–anti products when
benzaldehyde was added to the latter: however, no experi-
mental details and no spectroscopic data are available to
support these results.3
To the best of our knowledge, no cross-aldol reactions invol-
ving enantiomerically pure aldehydes and bicyclo[3.2.0]alka-
nones have been described in the literature. Being already
involved in the reactivity of bicyclo[3.2.0]alkanone derivatives,4
we became interested in the stereochemical outcome of the
TiCl4-mediated aldol reaction of enantiomerically pure benzyl-
oxypropanal with silyl enol ethers derived from ( )-bicyclo-
[3.2.0]alkanones.
The bicyclo[3.2.0]heptane skeleton represents not only a sub-
structure of numerous natural products5 but also a very useful
building block for different purposes such as ring expansion
and skeletal isomerization.6 Therefore, the functionalization of
such a scaffold is of importance.
In particular, cross aldol reactions between bicylo[3.2.0]-
alkanones and an aldehyde could represent a powerful tool
to access polyfunctionalized bicyclo[3.2.0]heptane skeletons.
To this end, we examined the cross aldol reaction between
[(S)-(−)]-benzyloxy propanal (−)-2 and the silyl enol ether
derived from racemic bicyclo[3.2.0]heptan-6-one 1. When
this reaction was carried out in the presence of TiCl4, a
1 : 1 mixture of diastereomers (+)-3 and (−)-4 was isolated in
81% overall yield. A similar reaction was repeated with (R)-(+)
benzyloxypropanal (+)-2, providing the corresponding enantio-
mers (−)-3 and (+)-4 as confirmed by the opposite optical
rotation (Scheme 1). Cross aldol products were easily separable
by silica gel chromatography.
The formation of two diastereomers (+)-3 and (−)-4 could
be explained according to the following mechanism: first, the
approach of aldehyde 2 takes place exclusively on the concave
face of the trimethylsilyl enol ether derived from bicyclo[3.2.0]-
heptanone 1.
Herein, we report on a completely stereoselective cross-
aldol condensation that takes place between the silyl enol
ether derived from bicyclo[3.2.0]alkanone derivatives and
[(S)-(−)] or [(R)-(+)]-benzyloxypropanal.
Université de Strasbourg, Institut de Chimie, UMR UdS/CNRS 7177, Laboratoire de
Chimie Organique Synthétique, 1 rue Blaise Pascal, BP 296/R8, 67008 Strasbourg-
Cedex, France. E-mail: lmiesch@unistra.fr, m.miesch@unistra.fr;
Fax: +33 3 68 85 17 54; Tel: +33 3 68 17 51
†CCDC 767591. For crystallographic data in CIF or other electronic format see
DOI: 10.1039/c3ob40431e
Scheme 1 Cross aldol condensation between bicyclo[3.2.0]heptan-6-one
and [(S)-(−)]-benzyloxy propanal (−)-2.
1
This journal is © The Royal Society of Chemistry 2013
Org. Biomol. Chem., 2013, 11, 4025–4029 | 4025

View Article Online
Paper
Organic & Biomolecular Chemistry
Scheme 3 Cross aldol condensation between 7-methylbicyclo[3.2.0]heptan-6-
one 6 and (−)-2.
Fig. 1 The Cram chelate model.
of the aldehyde and, in this way, 5 stereogenic centers could
be created starting from one. These results are in accordance
with cross aldol reactions previously reported by our group.9
Having compound (+)-7 in hand, the latter could be con-
sidered as a precursor of a 1,4-diketone that could undergo an
intramolecular condensation to afford a tricyclo[5.3.0.02,6]-
decane ring system. Indeed, this scaffold is prevalent
in numerous natural products and could be considered as a
formal precursor of hydroazulene ring systems via ring
opening reactions.11
On the other hand, the exclusive formation of two diastereo-
isomers can be explained by the Cram chelate model:7 indeed,
titanium chelates not only the two oxygens of the benzyloxy-
propanal, but also the oxygen of the trimethylsilyl enol ether
derived from bicyclo[3.2.0]heptanone 1. Therefore, only two
pathways are possible, leading to only two of eight possible
enantiomerically pure diastereomers with complete stereo-
selectivity (Fig. 1).
For that purpose, the hydroxyl group of compound 7
was protected as a MEM ether to afford 9 using standard
This reaction also constitutes a resolution of the racemic
bicyclo[3.2.0]heptan-6-one.
conditions. After hydrogenolysis of the benzyl ether,
a
The absolute configuration of compound (+)-3 was un-
ambiguously confirmed by X-ray crystallographic analysis of
the acetate 5, which was readily obtained by treatment of (+)-3
with acetic anhydride in the presence of NEt3 and DMAP
(Scheme 2, Fig. 2).8
This reaction was extended to the silyl enol ether derived
from 7-methylbicyclo[3.2.0]heptan-6-one 6, giving readily the
two ketols (+)-7 and (−)-8. Equally, the reaction took place with
complete stereoselectivity (Scheme 3).
2 : 1 mixture of two inseparable compounds was obtained: the
hydroxy derivative 10 and the lactol derivative 11 resulting
from an intramolecular nucleophilic addition of the hydroxyl
group to the cyclobutanone (Scheme 4).
Finally, a Dess–Martin oxidation10 of this mixture provided
the desired 1,4-diketone 12 which, after treatment with
sodium methoxide, led to the desired tricyclo[5.3.0.02,6]decane
scaffold 13 (Scheme 5).
Thus, the aldol reaction promoted by TiCl4 induced a
double induction process where the two enantiomers of the
racemic ketone react with total stereoselectivity with the chiral
aldehyde. It turned out that the configuration of the newly
formed stereogenic center was controlled by the configuration
Scheme 4 Synthesis of compounds 10 and 11.
Scheme 2 Synthesis of acetate (+)-5.
Fig. 2 X-ray structure of compound 5.
Scheme 5 Synthesis of tricyclo[5.3.0.02,6]decane 13.
4026 | Org. Biomol. Chem., 2013, 11, 4025–4029
This journal is © The Royal Society of Chemistry 2013

View Article Online
Organic & Biomolecular Chemistry
Paper
In summary, a cross aldol reaction between [(S)-(−)] or for 1.5 h and hydrolyzed with a saturated aqueous solution of
[(R)-(+)]-benzyloxypropanal and silyl enol ethers derived from NaHCO3 (10 mL/1 mmol).. The aqueous layer was extracted
bicylo[3.2.0]alkanones allowed the resolution of the bicyclic with CH2Cl2 (10 mL/1 mmol) and Et2O (10 mL/1 mmol). The
system and constitutes a good way to introduce concomitantly combined organic extracts were washed with brine (10 mL/
3 stereogenic centers and allow access to a key intermediate 1 mmol), dried over Na2SO4 and concentrated. Purification
for the synthesis of tricyclic skeletons. The aldol compounds of the resulting residue by chromatography on a silica gel
provided an enantiomerically enriched tricyclo[5.3.0.02,6]- column with petroleum ether–AcOEt (80 : 20) as an eluent pro-
decane substructure in a four step sequence, providing possi- vided the desired compounds.
ble entry to natural compounds possessing the same structural
Bicyclo[3.2.0]heptanones (+)-(3) and (−)-(4)
platform.11
Bicyclo[3.2.0]heptan-6-one 1: 1.583 g (14.37 mmol); NEt3:
5.01 mL (35.93 mmol); Me3SiOTf: 3.38 mL (18.68 mmol); (S)-2-
(benzyloxy)propanal (−)-2: 2.831 g (17.24 mmol); TiCl4 1 M in
CH2Cl2: 17.30 mL (17.24 mmol). Purification by column
chromatography afforded compounds (+)-3 and (−)-4.
Experimental section
General information
Reactions were carried out under a positive pressure of argon
with magnetic stirring and using degassed solvents in oven-
dried glassware. Et2O and THF were distilled from Na/benzo-
phenone. Thin-layer chromatography (TLC) was carried out on
silica gel plates Merck 60F254 and the spots were visualized
under a UV lamp (254 or 365 nm) and/or sprayed with a solu-
tion of vanillin (25 g) in EtOH–H2SO4 (98 : 2; 1 L) or with phos-
phomolybdic acid followed by heating on a hot plate. For
column chromatography, silica gel (Merck, Si60, 40–60 μm)
was used. Melting points (m.p.) were measured on a hot plate
Stuart Scientific SMP 3 apparatus. 1H NMR spectra were
recorded at 200 or 300 MHz and 13C NMR spectra at 75 or
125 MHz on a Bruker AC-300 or ARX-500 using the signal of
the residual nondeuterated solvent as the internal reference.
Significant 1H NMR spectroscopic data are tabulated in the fol-
lowing order: chemical shift (δ) expressed in ppm, multiplicity
(s, singlet; d, doublet; t, triplet; q, quadruplet; m, multiplet),
coupling constants J in hertz, the number of protons. The
ratios of compounds indicated below were calculated from the
NMR integrations. IR spectra were recorded as CCl4 solutions
(1R,5S,7R)-7-((1S,2S)-2-(benzyloxy)-1-hydroxypropyl)bicyclo-
[3.2.0]heptan-6-one (+)-(3). Colorless oil, yield: 1.633 g (41%);
[α]2D0 +70 (c 1.0, CHCl3); IR (CCl4): νmax 1775, 3573 cm−1; 1NMR
(300 MHz, CDCl3) δ 7.27–7.38 (m, 5 H), δA = 4.44, δB = 4.66 (AB,
JAB = 11.4 Hz, Δν = 62.9 Hz, 2 H), 3.74 (t, J = 6.3 Hz, 1 H), 3.70
(q, J = 5.7 Hz, 1 H), 3.47 (td, J = 8.0, 2.8 Hz, 1 H), 2.90 (q large,
J = 6.0 Hz, 1 H), 2.84 (sl, 1 H), 2.77 (td, J = 4.7, 3.3 Hz, 1 H),
1.49–2.10 (m, 6 H), 1.21 (d, J = 6.0 Hz, 3 H); 13C NMR (75 MHz,
CDCl3) δ 216.1, 138.3, 128.6, 128.0, 127.9, 76.5, 74.5, 71.3, 65.4,
62.9, 33.5, 32.6, 29.6, 25.5, 15.6; HRMS (ESI): m/z [M + Na]+
calcd for C17H22NaO3 [M + Na]+: 297.3445; found: 297.3451.
(1S,5R,7S)-7-((1S,2S)-2-(benzyloxy)-1-hydroxypropyl)bicyclo-
[3.2.0]heptan-6-one (−)-(4). Colorless oil, yield: 1.595 g (40%);
[α]2D0 −50 (c 1.0, CHCl3); IR (CCl4): νmax 1768, 3573 cm−1; 1NMR
(300 MHz, CDCl3) δ 7.26–7.40 (m, 5 H), δA = 4.47, δB = 4.66 (AB,
JAB = 11.4 Hz, Δν = 58.3 Hz, 2 H), 3.76 (q, J = 5.4 Hz, 1 H), 3.63
(q, J = 6.1 Hz, 1 H), 3.47 (d, J = 5.0 Hz, 1 H), 2.97 (td, J = 7.2,
4.9 Hz, 1 H), 2.81 (td, J = 5.0, 3.4 Hz, 1 H), 2.10–1.90 (m, 6 H),
2.53 (d, J = 5.0 Hz, 1 H), 1.19 (d, J = 6.2 Hz, 3 H); 13C NMR
(75 MHz, CDCl3) δ 215.4, 138.3, 128.6, 128.0, 127.9, 76.3, 73.1,
71.3, 66.4, 63.3, 33.0, 32.1, 29.6, 25.5, 15.9; HRMS (ESI): m/z
[M + Na]+ calcd for C17H22NaO3 [M + Na]+: 297.3445; found:
297.3490.
on
a Perkin Elmer IR-881 spectrometer. Microanalyses
were carried out by the Service Commun d’Analyses du CNRS,
Institut de Chimie-Strasbourg.
Cross aldol reaction general procedure
Bicyclo[3.2.0]heptanones (−)-3 and (+)-4
(a) Formation of the silyl enol ether. To
a solution Bicyclo[3.2.0]heptan-6-one 1: 0.300 g (2.72 mmol); NEt3:
of bicyclo[3.2.0]alkanone (1 equiv.) in anhydrous dichloro- 0.95 mL (6.81 mmol); Me3SiOTf: 0.64 mL (3.54 mmol); (R)-2-
methane (∼30 mL/1 mmol) at 0 °C were added successively (benzyloxy)propanal (+)-2: 0.537 g (3.27 mmol); TiCl4 1 M
triethylamine (2.5 equiv.) and trimethylsilyl trifluoromethane- in CH2Cl2: 3.30 mL (3.27 mmol). Purification by column
sulfonate (1.3 equiv.). The reaction mixture was stirred under chromatography afforded compounds (−)-3 and (+)-4 as color-
an argon atmosphere at 0 °C for 2 h and then concentrated to less oils.
afford the crude enoxysilane.
(1S,5R,7S)-7-((1R,2R)-2-(benzyloxy)-1-hydroxypropyl)bicyclo-
(b) Formation of the aldehyde–TiCl4 complex. To a solu- [3.2.0]heptan-6-one (−)-(3). Colorless oil, yield: 0.217 g (30%);
tion of (S)-2-(benzyloxy)propanal (1.2 equiv.) in anhydrous [α]2D0 −71 (c 1.0, CHCl3); 1H NMR, 13C NMR and IR data are
dichloromethane (∼10 mL/10 mmol) at −78 °C was added a identical to those reported for compound (+)-3; HRMS (ESI):
titanium chloride solution (1 M in dichloromethane, 1.2 m/z [M + Na]+ calcd for C17H22NaO3 [M + Na]+: 297.3445;
equiv.) and the solution was stirred for 10 minutes.
found: 297.3448.
(c) Cross aldol reaction. The crude enoxysilane was dis-
(1R,5S,7R)-7-((1R,2R)-2-(benzyloxy)-1-hydroxypropyl)bicyclo-
solved in anhydrous dichloromethane (1 mmol/1 mL) and the [3.2.0]heptan-6-one (+)-(4). Colorless oil, yield: 0.222 g (30%);
resulting solution was added dropwise at −78 °C to the [α]2D0 +49 (c 1.0, CHCl3); 1H NMR, 13C NMR and IR data are
titanium complex. The reaction mixture was stirred at −78 °C identical to those reported for compound (−)-4; HRMS (ESI):
This journal is © The Royal Society of Chemistry 2013
Org. Biomol. Chem., 2013, 11, 4025–4029 | 4027

View Article Online
Paper
Organic & Biomolecular Chemistry
m/z [M + Na]+ calcd for C17H22NaO3 [M + Na]+: 297.3445; 6.4 Hz, 3 H), 1.04 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ 217.4,
found: 297.3478.
138.5, 128.4, 127.9, 127.6, 96.9, 83.8, 76.5, 71.8, 71.5, 67.9,
67.6, 62.9, 59.1, 38.7, 28.3, 27.1, 26.9, 17.3, 11.2; Anal. Calcd
for C22H32O5: C, 70.19; H, 8.57. Found: C, 69.59; H, 8.41;
Methylbicyclo[3.2.0]heptanones (+7) and (−)-8
7-methylbicyclo[3.2.0]heptan-6-one 6: 1.150 g (9.26 mmol); HRMS (ESI): m/z [M + Na]+ calcd for C22H32NaO5 [M + Na]+:
NEt3: 3.23 mL (23.15 mmol); Me3SiOTf: 2.18 mL (12.04 mmol); 399.2147; found: 399.2186.
(S)-2-(benzyloxy)propanal (−)-2: 1.824 g (11.11 mmol); TiCl4 1
M in CH2Cl2: 11.15 mL (11.11 mmol). Purification by column
Compounds 10 and 11
chromatography afforded compounds (+7) and (−)-8.
Hydrogenolysis of compound 9 (0.120 g, 0.32 mmol) was
carried out in ethyl acetate (10 mL) in the presence of 10%
Pd/C (0.010 g) under hydrogen pressure (40 bar) for 15 h. After
filtration and concentration in vacuo, the residue was purified
by chromatography on silica gel with petroleum ether–AcOEt,
40 : 60, as an eluent, yielding a 1 : 2 mixture of inseparable
compounds 10 and 11 (0.091 g, 100%). It was possible to deter-
mine the 1H and 13C chemical shifts for each compound.
However, IR and elemental analyses are given for the mixture
(1R,5S,7R)-7-((1S,2S)-2-(benzyloxy)-1-hydroxypropyl)-7-methyl-
bicyclo[3.2.0]heptan-6-one (+)-(7). Colorless oil, yield: 1.048 g
(39%); [α]2D0 +56 (c 1.0, CHCl3); IR (CCl4): νmax 1764, 3560 cm−1
;
1H NMR (300 MHz, CDCl3) δ 7.20–7.40 (m, 5 H), δA = 4.46, δB =
4.62 (AB, JAB = 11.2 Hz, Δν = 46.4 Hz, 2 H), 3.68 (qd, J = 6.2;
4.1 Hz, 1 H), 3.61 (t large, J = 8.1 Hz, 1 H), 3.51 (dd, J = 6.0;
4.0 Hz, 1 H), 2.87 (t large, J = 8.2 Hz, 1 H), 2.86 (d, J = 6.0, 1 H),
1.30–2.10 (m, 6 H), 1.28 (d, J = 6.2 Hz, 3 H), 0.98 (s, 3 H);
13C NMR (75 MHz, CDCl3) δ 218.6, 138.0, 128.6, 128.1, 127.9,
78.4, 74.5, 71.0, 67.7, 63.2, 38.0, 28.5, 27.2, 27.0, 17.8, 10.9;
Anal. Calcd for C18H24O3: C, 75.00; H, 8.39. Found: C, 74.69;
H, 8.46; HRMS (ESI): m/z [M + Na]+ calcd for C18H24NaO3
[M + Na]+: 311.1623; found: 311.1607.
of compounds 10 and 11. IR (CCl4): 1758, 3360, 3600 cm−1
;
Anal. Calcd for C15H26O5: C, 62.91; H, 9.15. Found: C, 63.12;
H, 9.19.
(1R,5S,7R)-7-((1S,2S)-2-hydroxy-1-((2-methoxyethoxy)methoxy)-
propyl)-7-methylbicyclo[3.2.0]heptan-6-one (10). 1H NMR
(300 MHz, CDCl3) δ δA = 4.80, δB = 4.62 (AB, JAB = 7.1 Hz, Δν =
53.6 Hz, 2 H), 3.61–3.81 (m, 4 H), 3.51–3.57 (m, 2 H), 3.48 (d,
J = 5.1 Hz, 1 H), 3.36 (s, 3 H), 2.78 (t, J = 8.2 Hz, 1 H), 2.65
(large d, J = 10.0 Hz, 1 H), 2.10–1.30 (m, 6 H), 1.22 (d, J =
6.4 Hz, 3 H), 0.99 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ 218.5,
98.0, 88.0, 71.7, 68.4, 67.8, 67.6, 62.4, 59.1, 38.6, 28.6, 27.1,
26.9, 20.7, 14.4, 9.7.
(1S,5R,7S)-7-((1S,2S)-2-(benzyloxy)-1-hydroxypropyl)-7-methyl-
bicyclo[3.2.0]heptan-6-one (−)-(8). Colorless oil, yield: 0.947 g
(35%); [α]D20 −59 (c 1.0, CHCl3); IR (CCl4): νmax 1766,
3560 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.20–7.40 (m, 5 H), δA
= 4.42, δB = 4.65 (AB, JAB = 11.4 Hz, Δν = 68.1 Hz, 2 H), 3.71
(qd, J = 6.3; 3.2 Hz, 1 H), 3.60 (t large, J = 8.1 Hz, 1 H), 3.53
(dd, J = 7.4; 4.0 Hz, 1 H), 3.05 (t large, J = 8.1 Hz, 1 H), 2.79 (d,
J = 7.3, 1 H), 1.30–2.10 (m, 6 H), 1.26 (d, J = 6.2 Hz, 3 H), 0.92
(s, 3 H); 13C NMR (75 MHz, CDCl3) δ 219.6, 138.0, 128.6, 128.0,
127.9, 77.6, 74.1, 70.7, 67.8, 63.2, 37.7, 28.6, 27.4, 27.1, 16.9,
10.5; HRMS (ESI): m/z [M + Na]+ calcd for C18H24NaO3 [M +
Na]+: 311.1623; found: 311.1609.
(1R,5S,7R)-7-methyl-7-((3S,4S)-3-methyl-1-phenyl-2,5,7,10-tetra-
oxaundecan-4-yl) bicyclo[3.2.0]heptan-6-one (9). To a solution
of compound (+)-7 (0.100 g, 0.35 mmol) in anhydrous
dichloromethane (5 mL) were added successively N,N-diisopro-
pylethylamine (0.09 mL, 0.52 mmol) and 2-methoxyethoxy-
methyl chloride (0.06 mL, 0.52 mmol). The reaction mixture
was stirred under reflux for 48 h and the same equivalents of
Tricyclo derivative (11). 1H NMR (300 MHz, CDCl3) δ δA
=
4.75, δB = 4.64 (AB, JAB = 7.1 Hz, Δν = 53.6 Hz, 2 H), 4.19 (qd,
J = 6.4, 4.1 Hz, 1 H), 3.61–3.81 (m, 2 H), 3.79 (d, J = 4.0 Hz,
1 H), 3.54 (t, J = 4.7 Hz, 2 H), 3.38 (s, 3 H), 2.72 (s large, 1 H);
2.69 (t, J = 7.9 Hz, 1 H), 2.61 (t, J = 7.8 Hz, 1 H), 2.10–1.30 (m,
6 H), 1.27 (d, J = 6.4 Hz, 3 H), 0.99 (s, 3 H); 13C NMR (75 MHz,
CDCl3) δ 105.3, 95.2, 87.8, 76.5, 71.8, 67.4, 59.2, 52.7, 49.4,
34.1, 28.0, 27.0, 26.6, 14.5, 9.7.
(1R,5S,7R)-7-((S)-1-((2-methoxyethoxy)methoxy)-2-oxopropyl)-7-
methylbicyclo[3.2.0]heptan-6-one (12)
reagents were added approximately every 12 h. After cooling To a solution of compound 10 + 11 (0.110 g, 0.384 mmol) in
and adding dichloromethane (10 mL) the resulting mixture anhydrous dichloromethane (5 mL) at 0 °C was added Dess
was quenched with water (5 mL). The aqueous layer was Martin Periodinane (0.212 g, 0.499 mmol). The reaction
extracted with CH2Cl2 (10 mL) and Et2O (10 mL). The com- mixture was stirred for 2 hours at room temperature. Dess
bined organic extracts were washed with brine (15 mL), dried Martin Periodinane (0.212 g, 0.499 mmol) was added again.
over Na2SO4 and concentrated in vacuo. Purification of the After an additional stirring of 15 hours the resulting mixture
resulting residue by chromatography on a silica gel column was quenched with a saturated solution of Na2S2O3 (10 mL)
with petroleum ether–AcOEt (80 : 20) as an eluent afforded and stirred for 5 minutes. The solution was hydrolyzed with a
compound 9 (0.114 g, 87%). Colorless oil; [α]2D0 +65 (c 1.0, saturated aqueous solution of NaHCO3 (10 mL).. The aqueous
1
CHCl3); IR (CCl4): νmax 1770 cm−1; H NMR (300 MHz, CDCl3) layer was extracted with CH2Cl2 (10 mL) and Et2O (10 mL). The
δ 7.25–7.35 (m, 5 H), δA = 4.73, δB = 4.89 (syst AB, JAB = 7.2 Hz, combined organic extracts were washed with brine (15 mL),
Δν = 48.9 Hz, 2 H), δA = 4.46, δB = 4.58 (syst AB, JAB = 11.6 Hz, dried over Na2SO4 and concentrated in vacuo. Purification of
Δν = 34.4 Hz, 2 H), 3.65–3.78 (m, 3 H), 3.71 (d, J = 4.7 Hz, 1 H), the resulting residue by chromatography on a silica gel
3.70 (t large, J = 8.1 Hz, 1 H), 3.48 (t, J = 4.6 Hz, 2 H), 3.36 (s, 3 column with petroleum ether–AcOEt (70 : 30) as an eluent
H), 2.83 (t large, J = 8.3, 1 H), 1.30–2.05 (m, 6 H), 1.25 (d, J = afforded compound 12 (0.064 g, 59%).
4028 | Org. Biomol. Chem., 2013, 11, 4025–4029
This journal is © The Royal Society of Chemistry 2013

View Article Online
Organic & Biomolecular Chemistry
Paper
Colorless oil; [α]D20 −12 (c 1.0, CHCl3); IR (CCl4): νmax 1715,
2 G. R. Clark, J. Lin and M. Nikaido, Tetrahedron Lett., 1984,
25, 2645–2648.
1
1772 cm−1; H NMR (300 MHz, CDCl3) δ 4.74 (s, 2 H), 4.02 (s,
1 H), 3.64–3.79 (m, 3 H), 3.51 (t, J = 4.6 Hz, 2 H), 3.37 (s, 3 H),
2.93 (t, J = 8.3 Hz, 1 H), 2.20 (s, 3 H), 1.20–2.10 (m, 6 H), 0.93
(s, 3 H). 13C NMR (75 MHz, CDCl3) δ 216.8, 209.0, 96.2, 86.8,
71.8, 68.3, 65.5, 63.5, 59.2, 38.5, 28.6, 27.6, 27.2, 27.1, 10.7;
HRMS (ESI): m/z [M + Na]+ calcd for C15H24NaO5 [M + Na]+:
307.1521; found: 307.1527.
3 B. Ernst, A. de Mesmaeker, H. Greuter and S. J. Veenstra,
Strain and its implications in organic chemistry: organic stress
and reactivity, ed. A. de Meijere and S. Blechert, Springer
Verlag, New York, 1989, pp. 207–234.
4 L. Miesch, T. Welsch, V. Rietsch and M. Miesch,
Chem.–Eur. J., 2009, 15, 4394–4401.
5 (a) D. Bellus and B. Ernst, Angew. Chem., Int. Ed., 1988, 27,
797–827; (b) J. C. Namyslo and D. E. Kaufmann, Chem.
Rev., 2003, 103, 1485–1537; (c) M. Miesch, Curr. Org. Synth.,
2006, 3, 327–340.
6 (a) M. Le Liepvre, J. Ollivier and D. J. Aitken, Eur. J. Org.
Chem., 2009, 5953–5962 and references cited therein;
(b) H. L. Deak, S. S. Stokes and M. L. Snapper, J. Am. Chem.
Soc., 2001, 123, 5152–5153; (c) H. L. Deak, M. J. Williams
and M. L. Snapper, Org. Lett., 2005, 7, 5785–5788;
(d) A. J. Leyhane and M. L. Snapper, Org. Lett., 2006, 8,
5183–5186.
7 (a) D. J. Cram and F. A. Elhafez, J. Am. Chem. Soc., 1952, 74,
5828–5835; (b) A. Mengel and O. Reiser, Chem. Rev., 1999,
99, 1191–1223.
8 (a) We assumed that the formation of bicyclo[3.2.0]hepta-
none 5 took place without epimerization; (b) CCDC-767591
contains the supplementary crystallographic data for
bicyclo[3.2.0]heptanone 5. Unit cell parameters: a 9.2220(10),
b 10.0520(14), c 9.8200(12).
Tricyclo[5.3.0.02,6]decane (13)
To a solution of compound 12 (0.049 g, 0.172 mmol) in
benzene (4 mL) was added a solution of NaOMe (1 M in
methanol, 0.86 mL). The reaction mixture was stirred at room
temperature under an argon atmosphere for 1 hour. The
mixture was quenched with a saturated aqueous solution of
NaHCO3 (5 mL). The aqueous layer was extracted with CH2Cl2
(5 mL) and Et2O (5 mL). The combined organic extracts were
washed with brine (10 mL), dried over Na2SO4 and concen-
trated in vacuo. Purification of the resulting residue by chrom-
atography on a silica gel column with petroleum ether–AcOEt,
60 : 40, as an eluent afforded compound 13 (0.027 g, 55%). Col-
orless oil; [α]2D0 −71 (c 1.0, CHCl3); IR (CCl4): νmax 1757, 3471,
3606 cm−1 1H NMR (300 MHz, CDCl3) δ δA = 4.81, δB = 4.94
;
(syst AB, JAB = 7.0 Hz, Δν = 41.3 Hz, 2 H), 4.33 (d, J = 2.6 Hz,
1 H), 3.75–3.79 (m, 2 H), 3.53–3.57 (m, 2 H), 3.38 (s, 3 H), 2.77
(dd, J = 16.0; 2.7 Hz, 1 H), 2.33–2.53 (m, 3 H), 1.40–1.90 (m,
7 H), 1.19 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ 211.1, 95.5,
86.5, 74.2, 71.8, 67.3, 59.2, 49.8, 49.0, 48.6, 35.2, 28.2, 28.1,
26.6, 13.8; HRMS (ESI): m/z [M + Na]+ calcd for C15H24NaO5
[M + Na]+: 307.1521; found: 307.1519.
9 (a) M. Franck-Neumann, P. Bissinger and P. Geoffroy, Tetra-
hedron Lett., 1997, 38, 4473–4476; (b) M. Franck-Neumann,
L. Miesch-Gross and C. Gateau, Tetrahedron Lett., 1999, 40,
2829–2832; (c) M. Franck-Neumann, L. Miesch-Gross and
C. Gateau, Eur. J. Org. Chem., 2000, 3693–3702.
Acknowledgements
10 D. B. Dess and J. C. Martin, J. Org. Chem., 1983, 48, 4155–
4156.
We gratefully acknowledge Université de Strasbourg and the
CNRS for financial support.
11 (a) V. Sampath, E. C. Lund, M. J. Knudsen, M. N. Olmstead
and N. E. Schore, J. Org. Chem., 1987, 52, 3595–3603;
(b) M. Miesch, A. Cotté and M. Franck-Neumann, Tetra-
hedron Lett., 1993, 34, 8085–8086; (c) M. Tanaka,
K. Tomioka and K. Koga, Tetrahedron, 1994, 50, 12829–
12842; (d) M. Miesch, A. Cotté and M. Franck-Neumann,
Tetrahedron Lett., 1994, 35, 7031–7032; (e) M. Harmata
and P. Rashatasakhon, Tetrahedron Lett., 2001, 42, 5593–
5595; (f) E. Kleinpeter, H. K. Lämmermann and
Notes and references
1 (a) Modern Aldol Reactions, ed. R. Mahrwald, Wiley-VCH,
Weinheim, 2004; (b) L. M. Geary and P. G. Hultin, Tetrahe-
dron: Asymmetry, 2009, 20, 131–173; (c) K.-S. Yeung and
I. Paterson, Angew. Chem., Int. Ed., 2002, 41, 4632–4653;
(d) K.-S. Yeung and I. Paterson, Chem. Rev., 2005, 105,
4237–4313; (e) B. Schetter and R. Mahrwald, Angew. Chem.,
Int. Ed., 2006, 45, 7506–7525; (f) T. Brodmann, M. Lorenz,
R. Schäckel, S. Simsek and M. Kalesse, Synlett, 2009, 174–
192; (g) J. Li and D. Menche, Synthesis, 2009, 2293–2315.
H.
Kühn,
Tetrahedron,
2011,
67,
2596–2604;
(g) B. A. Kowalczyk, T. C. Smith and W. G. Dauben,
J. Org. Chem., 1998, 63, 1379–1389 and references cited
therein; (h) T. Bach and J. P. Hehn, Angew. Chem., Int.
Ed., 2011, 50, 1000–1045.
This journal is © The Royal Society of Chemistry 2013
Org. Biomol. Chem., 2013, 11, 4025–4029 | 4029