Enantioselective synthesis of bicyclo[4.4.1]undecane-2,7-dione via samarium(II)-mediated fragmentation of a cyclopropane precursor

Article abstract of DOI:10.1055/s-2006-941599

An efficient six-step synthesis of bicyclo[4.4.1]undecane-2,7-dione was elaborated. Key steps include an enantioselective oxazaborolidine-catalyzed borane reduction (CBS reduction) of 2,3,4,6,7,8-hexahydronaphthalene-1,5-dione to the corresponding diol, a

Full text of DOI:10.1055/s-2006-941599

LETTER
1527
Enantioselective Synthesis of Bicyclo[4.4.1]undecane-2,7-dione via
Samarium(II)-Mediated Fragmentation of a Cyclopropane Precursor
E
nantioselecti
h
ve Synthesis
e
of Bicyclo
r
[4.4.1]un
i
decane
f
-2,7-dione El Sheikh, Nina Kausch, J. Lex, J.-M. Neudörfl, Hans-Günther Schmalz*
Institut für Organische Chemie, Universität zu Köln, Greinstr. 4, 50939 Köln, Germany
Fax +49(221)4703064; E-mail: schmalz@uni-koeln.de
Received 4 April 2006
Abstract: An efficient six-step synthesis of bicyclo[4.4.1]unde-
cane-2,7-dione was elaborated. Key steps include an enantioselec-
tive oxazaborolidine-catalyzed borane reduction (CBS reduction)
of 2,3,4,6,7,8-hexahydronaphthalene-1,5-dione to the correspond-
ing diol, and a subsequent (syn-diastereoselective) cyclopropana-
tion. Oxidation then gives tricyclo[4.4.1.01,6]undecane-2,7-dione
(>99% ee) which on treatment with two equivalents of samarium(II)
iodide undergoes cleavage of the central cyclopropane bond to yield
the target compound without any loss of stereochemical informa-
tion.
Equation 1 Norcaradiene-cycloheptatriene rearrangement
While the electrocyclic approach is perfectly suitable for
the synthesis of structures like 1, it cannot easily be ap-
plied to the synthesis of products with a more complex
substitution pattern and/or a higher degree of saturation.
Especially, the conditions commonly employed to build
up the required norcaradiene precursors (DDQ or
bromination/dehydrobromination)3,4 are not necessarily
compatible with a range of functional groups.
Key words: asymmetric synthesis, chirality, cyclopropane, frag-
mentation, samarium diiodide
Recently, we became interested in functionalized bicyc-
lo[4.4.1]undecanes such as 4 and 5. While 5 can be con-
sidered as a model compound for 2, we were particularly
interested in the synthesis of the C2-symmetric compound
4 (Scheme 1). Due to the inherent chirality of this com-
pound we consider it to represent a valuable building
block for the elaboration of new chiral ligands. The lower
homologues of 4, bicyclo[3.3.1]nonane-2,6-dione and
bicyclo[2.2.1]heptane-2,5-dione have already found suc-
cessful application as building blocks for chiral ligands.7,8
Among the group of small bridged bicyclic molecules, the
bicyclo[4.4.1]undecane substructure is quite rarely en-
countered. Naturally occuring examples include the ma-
rine natural products spiniferin1 (1) and isocyclocitrinol2
(2). The most famous non-natural representative of this
ring system is E. Vogel’s 1,6-methano[10]annulene3 (3,
R = H, Figure 1).4
OH
HO
H
O
H
O
HO
X
O
O
4
5
O
O
1
2
O
O
6
7
2e–
R
3
Scheme 1 Concept for the synthesis of compounds 4 and 5 via
reductive fragmentation
Figure 1 Compounds containing the bicyclo[4.4.1]undecane
substructure
The reason why chiral bicyclo[4.4.1]undecanes have
never found application in enantioselective chemistry was
certainly the lack of an efficient synthetic entry to this
class of compounds.9
The only common synthetic approach to bicyc-
lo[4.4.1]undecane derivatives with an unfunctionalized
C1-bridge is based on the norcaradiene-cycloheptatriene
rearrangement, i.e., a 6p-electrocyclic ring-opening.
Thus, tricyclo[4.4.1.01,6]undeca-2,4-diene precursors
yield bicyclo[4.4.1]undecatrienes as depicted in
Equation 1.3,5,6
As a new strategy we envisioned that appropriately
functionalized tricyclic systems of type 6 should undergo
fragmentation of the central bond upon treatment with
reducing agents such as zinc or samarium(II)-iodide
(Scheme 2). Therefore, we decided to prepare tri-
cyclo[4.4.1.01,6]undecane-2,7-dione (6a, X = O) to inves-
tigate its reductive fragmentation using samarium(II)-
iodide.10
SYNLETT 2006, No. 10, pp 1527–1530
2
1
.0
6
.2
0
0
6
Advanced online publication: 12.06.2006
DOI: 10.1055/s-2006-941599; Art ID: G12106ST
© Georg Thieme Verlag Stuttgart · New York

1528
S. El Sheikh et al.
LETTER
O
Retrosynthetic analysis of 6 suggests enedione 7 as a pre-
cursor. The common synthesis of 7 by perhydrogenation
of napththalene-1,5-diol followed by two oxidation
steps11 is of limited practical value due to low overall
yields, costly reagents, and long reaction times. This
prompted us to elaborate a new synthesis of this com-
pound.
7
O
Me3SOI, NaH
10–25%
O
O
Our synthesis of enedione 7, which allows easy access to
multigram quantities of the compound, is shown in
Scheme 2. At first, base-catalyzed Michael addition of the
protected 4-nitrobutanal (9)12 to cyclohexenone (8) af-
forded 10 in 59% yield as a mixture of stereoisomers.
Subsequent acid-catalyzed cyclization proceeded with
virtually quantitative yield to give nitroketone 11, again as
a mixture of stereoisomers. The final conversion of 11 to
the enedione 7 was achieved employing modified Nef
conditions13 and subsequent isomerization with DBU. It
proved to be important to conduct the hydrolysis of the in-
termediate nitronate at low temperature under anhydrous
conditions to prevent decomposition of the product that
was observed under classical (aqueous) conditions.
SmI2 (2 equiv)
98%
O
O
4 (rac)
6a (rac)
Scheme 3 Synthesis of racemic diketone 4
For this purpose, enedione 7 was subjected to an ox-
azaborolidine-catalyzed borane reduction (CBS reduc-
tion)15 furnishing the cis-diol 13 in 92% yield as a single
stereoisomer (Scheme 4). While attempts to cyclopropan-
ate 13 under Simmons–Smith conditions (Zn/Cu couple,
CH2I2) failed due to complete decomposition, we finally
succeeded to achieve the desired transformation using the
diethylzinc/chloroiodomethane reagent.16 The tricyclic
diol 14, which was again obtained as a single diastereo-
mer, could be converted to the rather unstable diketone 6
either by Jones oxidation (84%) or with
dimethyldioxirane17 (100%). The optically active dike-
tone was then also subjected to the established fragmenta-
tion conditions (2 equiv SmI2, THF, r.t.) to give
bicyclo[4.4.1]undecane-2,7-dione (4), again in almost
quantitative yield (Scheme 4). The enantiomeric purity of
O
O
O
O
O
H
O
t-BuOK, t-BuOH, 65 °C
+
59%
NO2
NO2
8
9
10
THF, HCl, 80 °C
quant.
O
O
1. NaOMe, MeOH
2. H2SO4, MeOH, –50 °C
3. DBU
20
this product ([a]D –105.0, c 0.765, CHCl3) was deter-
mined to >99% ee by gas chromatography using a chiral
stationary phase.
96%
H
O
NO2
11
7
The proven stereospecificity of the reductive fragmenta-
tion (Scheme 4) is remarkable since the chirality centers
of tricycle 6 are destroyed during the fragmentation. Ob-
viously, the intermediate dienolate 14 retains the absolute
stereochemical information due to its inherent non-planar
(chiral) nature.18 At this point it should be mentioned that
unsymmetrically substituted bicyclo[4.4.1]undecanes in
which both bridgehead carbons are planarized by being
part of a double bond (e.g., 3, R ºH) are configurationally
stable planar chiral molecules.18
Scheme 2 A practical synthesis of enedione 7
While all our attempts to convert 7 into the tricycle rac-6a
under various Simmons–Smith-type conditions failed, we
succeeded to obtain the desired cyclopropane at least in
low yields (10–25%) by treatment of 7 with dimethylsulf-
oxonium methylide.14 With compound rac-6a in hand we
were ready to probe the key fragmentation. Indeed,
reaction of rac-6a with two equivalents of samarium(II)
iodide in THF at room temperature furnished bicyc-
lo[4.4.1]undecane-2,7-dione (rac-4) in virtually quantita-
tive yield (Scheme 3).
The absolute configuration of the synthesized compounds
was assigned as follows: based on the reliable model of
Corey for the CBS reduction15 we were confident that the
configuration of the diol 13, prepared using the (S)-pro-
line-derived catalyst 12, was R,R as shown in Scheme 4.
The syn-directing effect of allylic hydroxyl groups in
Simmons–Smith-type cyclopropanations is well estab-
lished.16 The relative configuration of the cyclopropana-
tion product 14 obtained from 13 was also confirmed by
NOE measurements. Thus, the absolute configuration of
the oxidation product 6 must be S,S. For geometrical rea-
sons, the stereospecific reductive fragmentation of (S,S)-6
can only lead to 4 with the shown R,R-configuration. This
Having thus demonstrated the general feasibility of the
concept, we turned our attention towards the elaboration
of a more efficient and, in particular, enantioselective syn-
thesis of the key intermediate 6a. We envisioned that the
introduction of the methylene bridge could be achieved
after reduction of both carbonyl groups of 7. Using a
chiral reducing agent to prepare the C2-symmetric diol 13,
the directing and activating effect of the two cis-oriented
hydroxyl groups could possibly be utilized for a syn-dia-
stereoselective cyclopropanation.
Synlett 2006, No. 10, 1527–1530 © Thieme Stuttgart · New York

LETTER
Enantioselective Synthesis of Bicyclo[4.4.1]undecane-2,7-dione
1529
O
OH
12 (0.3 equiv)
BH3·SMe2 (1 equiv)
92%
O
OH
7
13
Ph
H
Ph
O
N
B
ClCH2I, Et2Zn
DCE–THF, 0 °C
90%
12
O
OH
O O
100%
O
OH
Figure 3 Structure of 4 in the crystalline state (H atoms not shown)
14
6
≥99% ee
≥99% de
In conclusion, we have elaborated a novel and fully enan-
tioselective synthesis of the C2-symmetric diketone 4,
which proceeds in only six steps starting from cyclohex-
enone. Current research in this laboratory is directed to-
wards further development of this chemistry and in
particular towards the synthesis of new C2-symmetric
ligands derived from 4 (or ent-4) and their application in
enantioselective catalysis.
SmI2
(2 equiv)
I2SmO
O
98%
OSmI2
O
4
15
≥99% ee
Scheme 4 Enantioselective synthesis of diketone 4
(1S,2R,6S,7R)-Tricyclo[4.4.1.01,6]undecane-2,7-diol (14)
A 1 M solution of Et2Zn in hexane (87 mL, 87 mmol) was added to
1,2-dichloroethane (135 mL) at 0 °C under Ar. Then, ICH2Cl (13
mL, 178 mmol) was added over 5 min and the resulting cloudy so-
lution was stirred for an additional 5 min after which a solution of
diol 13 (2.44 g, 14.5 mmol) in 45 mL of THF was added all at once.
The cooling bath was removed and the reaction mixture was stirred
overnight. Sat. NH4Cl solution (25 mL) was added, the organic
phase was separated, washed with H2O (2 ꢀ 50 mL) and brine
(2 ꢀ 50 mL), dried over MgSO4 and evaporated, leaving 2.35 g
(90%) of 14 as a colorless crystalline solid.
assignment is supported by the CD spectrum of compound
4, which displays a pronounced negative Cotton effect at
about 300 nm (Figure 2).19
An X-ray crystal structure analysis of 4 reveals that this
compound adopts a conformation in which the two carbo-
nyl groups point ‘downward’ (away from the methylene
bridge). The distance between the two oxygen atoms is
only 4.4 Å (Figure 3). This not only suggests that stereo-
selective addition reactions could be possible but also that
diimine or dioxime derivatives of 4 may be interesting
chiral chelate ligands for metal complexation.
1
Mp 126–127 °C. H NMR (300 MHz, CDCl3): d = 3.77 (dd, 2 H,
3J1 = 9.4 Hz, 3J2 = 5.7 Hz), 1.59–1.82 (m, 6 H), 1.40–1.52 (m, 2 H),
1.34 (br s, 2 H, OH), 1.12–1.27 (m, 2 H), 0.90–1.03 (m, 2 H), 0.57
(s, 2 H, H-11) ppm. 13C NMR (75 MHz, CDCl3): d = 74.6 (d, C-2
and C-7), 46.3 (t), 30.5 (t), 30.0 (t), 20.4 (t), 15.9 (t, C-11) ppm. IR
(ATR): 3326 (s), 2927 (s), 2856 (s), 1452 (m), 1322 (w), 1267 (m),
1206 (w), 1152 (m), 1060 (s), 1024 (s), 952 (m), 936 (m), 902 (m),
831 (m), 734 (m) cm–1. MS (EI, 70 eV): m/z (%) = 182 (1) [M]+, 164
(20) [M – H2O]+, 149 (25), 131 (35), 117 (35), 105 (40), 91 (100),
79 (80), 67 (40), 55 (40), 39 (60). HRMS (EI): m/z calcd for
12
C H18 16O2 [M]+: 182.1307; found: 182.131.
11
(1S,6S)-Tricyclo[4.4.1.01,6]undecane-2,7-dione (6)
Method A: with Dimethyldioxirane
Diol 14 (20 mg, 0.11 mmol) was dissolved in acetone (0.7 mL). To
this was added a 0.7 M solution of dimethyldioxirane in acetone (7
mL) portion wise over 8 h. After stirring overnight, the reaction
mixture was evaporated under reduced pressure, leaving 19.5 mg
(100%) of 6 as a colorless crystalline solid.
Figure 2 CD spectrum of 4 in MeOH
Method B: with Chromic Acid
Diol 14 (250 mg, 1.37 mmol) was dissolved in 20 mL of acetone,
cooled to 0 °C and treated with Jones reagent until an orange color
persisted. After stirring the mixture for an additional 10 min, i-
PrOH (10 mL) was added and the reaction mixture was evaporated
to a volume of 5 mL under reduced pressure. Then, H2O (100 mL)
was added, and the solution was extracted with MTBE (4 ꢀ 100
Synlett 2006, No. 10, 1527–1530 © Thieme Stuttgart · New York

1530
S. El Sheikh et al.
LETTER
mL). The combined organic layers were dried over MgSO4 and
evaporated to yield 206 mg (84%) of 6 as colorless crystals.
References and Notes
(1) Cimino, G.; De Stefano, S.; Minale, L.; Trivellone, E.
Tetrahedron Lett. 1975, 3727.
(2) Amagata, T.; Amagata, A.; Tenney, K.; Valeriote, F. A.;
Lobkovsky, E.; Clardy, J.; Crews, P. Org. Lett. 2003, 5,
4393.
Compound 6 was essentially pure according to GC, TLC and NMR
analysis. Further purification was achieved by column chromatog-
raphy (SiO2), albeit with substantial loss of material due to decom-
position on the column.
Mp 119–120 °C. 1H NMR (300 MHz, CDCl3): d = 2.24–2.41 (m, 4
H), 1.95–2.14 (m, 4 H), 1.51–1.83 (m, 6 H) ppm; the cyclopropane
protons resonate at 1.70 ppm as a singlet. 13C NMR (75 MHz,
CDCl3): d = 207.2 (s), 39.4 (s), 36.2 (t), 21.9 (t), 17.9 (t), 17.7 (t)
ppm. IR (ATR): 3079 (w), 2941 (m), 2871 (m), 1682 (s), 1636 (w),
1484 (w), 1447 (m), 1411 (w), 1382 (w), 1342 (m), 1248 (m), 1234
(m), 1202 (w), 1144 (m), 1085 (w), 871 (s), 859 (s), 829 (m), 646
(w) cm–1. MS (EI, 70 eV): m/z (%) = 178 (20) [M]+, 164 (5), 150
(90), 135 (85), 120 (60), 112 (50), 93 (55), 79 (100), 64 (30), 55
(3) Vogel, E.; Roth, H. D. Angew. Chem. 1964, 76, 145.
(4) The bicyclo[4.4.1]undecane ring system (with a function-
alized C1-bridge) also occurs as a substructure in some other
more complex polycyclic natural products such as ingenol.
For a leading reference, see: Montalt, J.; Linker, F.; Ratel, F.;
Miesch, M. J. Org. Chem. 2004, 69, 6715.
(5) Vogel, E.; Klug, W.; Breuer, A. Org. Synth., Coll. Vol. VI
1988, 731.
(6) Marshall, J. A.; Conrow, R. E. J. Am. Chem. Soc. 1983, 105,
5679.
(7) (a) Otomaru, Y.; Kina, A.; Shintani, R.; Hayashi, T.
Tetrahedron: Asymmetry 2005, 16, 1673. (b) Otomaru, Y.;
Tokunaga, N.; Shintani, R.; Hayashi, T. Org. Lett. 2005, 7,
307.
(8) Berkessel, A.; Schröder, M.; Sklorz, C. A.; Tabanella, S.;
Vogl, N.; Lex, J.; Neudörfl, J. M. J. Org. Chem. 2004, 69,
3050.
(9) For a synthesis of rac-4 by Pb(OAc)4-mediated cleavage of
a pinacol, see: Kakiuchi, K.; Kumanoya, S.; Kobiro, K.;
Tobe, Y.; Odaira, Y. Bull. Chem. Soc. Jpn. 1990, 63, 3358.
(10) For the reductive fragmentation of 1,4-diketones using
samarium(II) iodide, see: (a) Williams, D. B. G.; Blann, K.;
Holzapfel, C. W. J. Chem. Soc,. Perkin Trans. 1 2001, 219.
For the reductive cleavage of cyclopropyl ketones, see also:
(b) Batey, R. A.; Motherwell, W. B. Tetrahedron Lett. 1991,
32, 6649. (c) Kim, Y. H.; Lee, I. S. Heteroat. Chem. 1992, 3,
509. (d) Batey, R. A.; Harling, J. D.; Motherwell, W. B.
Tetrahedron 1996, 52, 11421. (e) Molander, G. A.; Alonso-
Alija, C. Tetrahedron 1997, 53, 8067. (f) Lee, P. H.; Lee, J.;
Kim, H.-C. Bull. Korean Chem. Soc. 2000, 21, 207.
(g) Aulenta, F.; Hölemann, A.; Reißig, H.-U. Eur. J. Org.
Chem. 2006, 7, 1733.
12
(65), 39 (60). HRMS (EI): m/z calcd for C11H1416O2 [M]+:
178.0994; found: 178.099. [a]D20 –46.3 (c 1.0, CHCl3).
(1R,6R)-Bicyclo[4.4.1]undecane-2,7-dione (4)
To of a freshly prepared 0.1 M solution of SmI2 in THF (8.6 mL,
0.86 mmol) was added, dropwise and with stirring, a solution of
diketone 6 (77 mg, 0.43 mmol) in THF (7 mL) at r.t. The initially
deep blue solution turned brownish-yellow immediately. After 2
min, sat. NH4Cl solution (15 mL) was added and the reaction mix-
ture was extracted with MTBE (3 ꢀ 30 mL). The combined organic
layers were washed with brine (3 ꢀ 30 ml), dried over MgSO4 and
evaporated under reduced pressure. The crude product was filtered
over SiO2 (EtOAc) to afford 76 mg (98%) of a colorless, crystalline
solid. Mp 124–126 °C. 1H NMR (300 MHz, CDCl3): d = 2.77–2.82
(m, 2 H), 2.60–2.69 (m, 2 H), 2.31–2.52 (m, 6 H), 1.70–1.80 (m, 2
H), 1.35–1.61 (m, 4 H) ppm. 13C NMR (75 MHz, CDCl3): d = 212.6
(s), 49.0 (d), 42.8 (t), 30.2 (t), 29.0 (t), 21.4 (t) ppm. IR (ATR): 2940
(m), 2874 (w), 2840 (w), 1689 (s), 1461 (w), 1449 (m), 1434 (w),
1317 (m), 1214 (w), 1181 (m), 1151 (w), 1127 (w), 1058 (w), 1044
(w), 992 (m), 928 (m), 886 (w), 782 (w) cm–1. MS (EI, 70 eV): m/z
(%) = 180 (40) [M]+, 162 (10), 152 (2), 139 (35), 125 (25), 111 (35),
97 (45), 84 (80), 69 (50), 55 (100), 41 (70). [a]D20 –105, [a]546
20
20
20
20
–130.6, [a]405 –376.0, [a]365 –659.5, [a]334 1599.2 (c 0.765,
CHCl3). GC (Agilent HP-6890 system, 6-T-2,3-Me-b-cyclodextrin
25 m fused silica capillary column, 250 mm diameter, gas type: H2
(0.6 bar), inlet temperature 150 °C, detector temperature 220 °C,
temperature program: 40 °C (10 min) to 150 °C (75 min): tR
(1R,6R) = 68.114 min (99.62%), tR (1S,6S) = 69.361 min (0.38%),
(11) McChesney, J. D. J. Pharm. Sci. 1979, 68, 1116.
(12) Horni, A.; Hubacek, I.; Hesse, M. Helv. Chim. Acta 1994,
77, 579.
(13) (a) Chamakh, A.; M’hirsi, M.; Villiéras, J.; Lebreton, J.;
Amri, H. Synthesis 2000, 295. (b) Pinnick, H. K. Org.
React. 1990, 38, 655.
12
99% ee. HRMS (EI): m/z calcd for C11H1616O2 [M]+: 180.1150;
(14) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1962, 84,
867.
found: 180.115; Anal. Calcd for C, 73.3; H, 8.95. Found: C, 72.98;
H, 8.98.
(15) (a) Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc.
1987, 109, 5551. (b) For a review, see: Corey, E. J.; Helal,
C. J. Angew. Chem., Int. Ed. Engl. 1986, 15, 37.
(16) (a) Miyano, S.; Hashimoto, H. Bull. Chem. Soc. Jpn. 1973,
46, 892. (b) Miyano, S.; Izumi, Y.; Fujii, H.; Hashimoto, H.
Synthesis 1977, 700. (c) Denmark, S. E.; Edwards, J. P. J.
Org. Chem. 1991, 56, 6974.
Acknowledgment
This work was supported by the Fonds der Chemischen Industrie.
We thank Dr. Mathias Schäfer for mass spectrometric measure-
ments and Andreas Adler for assistance in gas chromatographic and
HPLC analytic techniques.
(17) (a) Murray, R. W.; Singh, M. Org. Synth., Coll. Vol. IX 1998,
288. (b) Adam, W.; Bialas, J. Chem. Ber. 1991, 124, 2377.
(18) Kuffner, U.; Schlögl, K. Tetrahedron Lett. 1971, 21, 1773.
(19) The homologous (1R,5R)-bicyclo[3.3.1]nonane-2,6-dione
also displays a negative Cotton effect: (a) Berg, U.; Butkus,
E. J. Chem. Res., Synop. 1993, 116. (b) Application of the
octant rule to compound 4 also predicts a negative Cotton
effect for the R,R-enantiomer, see: (b) Moffitt, W.;
Woodward, R. B.; Moscowitz, A.; Klyne, W.; Djerassi, C.
J. Am. Chem. Soc. 1961, 83, 4013.
Synlett 2006, No. 10, 1527–1530 © Thieme Stuttgart · New York