Novel Route to Functionalized Cyclooctanoids via [5+3] Cycloaddition

Article abstract of DOI:10.1021/jo0353583

The self-dimerization of 3-oxidopyrylium leading to stereocontrolled formation of highly functionalized cyclo-octanoids is described. Different functionalities were introduced on the dimer (3) and the stereochemical outcome was determined by single-crysta

Full text of DOI:10.1021/jo0353583

SCHEME 1
Novel Rou te to F u n ction a lized
Cycloocta n oid s via [5+3] Cycloa d d ition
Urlam Murali Krishna,† Kodand D. Deodhar,*,†
Girish K. Trivedi,*,† and Shaikh M. Mobin‡
Department of Chemistry, National Single-Crystal X-ray
Diffraction Facility, Indian Institute of Technology Bombay,
Mumbai 400076, India
SCHEME 2
chgktia@chem.iitb.ac.in
Received September 15, 2003
Abstr a ct: The self-dimerization of 3-oxidopyrylium leading
to stereocontrolled formation of highly functionalized cyclo-
octanoids is described. Different functionalities were intro-
duced on the dimer (3) and the stereochemical outcome was
determined by single-crystal X-ray analysis. It is noteworthy
that the hydrogenation of 3 in ethanol solvent gave the
transannulated product 5, whereas the expected dihydro
product 4 was obtained when the reaction was run in nonnu-
cleophilic solvents. The mechanistic pathway is discussed.
none (1) with triethylamine and spontaneously proceeded
to the thermal [5+3] cycloaddition reaction to afford
dimerized product 3 (60%, Scheme 1). After having
sufficient quantities of dimer in hand, first we attempted
to presaturate the R,â-unsaturated olefinic double bond
in the dimer. Dimer 3 was therefore subjected to the
typical hydrogenation conditions over activated Pd/C in
ethanol solvent. The reaction outcome was quite unusual.
Instead of forming the dihydro product 4, interestingly
an unanticipated reaction occurred to provide compound
5 (Scheme 2). The 1H NMR spectra of the resultant
product displayed a triplet at δ 1.15 (3 protons) and a
pair of doublets of a quartet centered at δ 3.8 (1H) and
3.48 (1H). The presence of a single carbonyl group in the
13C NMR instead of the two initially present in the dimer
helped us in ruling out the formation of the expected
dihydro product (4) or the tetrahydro product. The
structure of 5 was assigned on the basis of single-crystal
X-ray analysis. The structure thus secured shared the
The development of efficient and novel synthetic routes
to medium-sized carbocycles is a worthy endeavor due
to the presence of such systems in many biologically and
structurally interesting natural products.1 Because of
well-known entropic and enthalpic factors associated with
the formation of medium-sized rings, the application of
carbon-carbon bond-forming reactions to medium-size
ring synthesis is not always straightforward and thus
entry into these ring systems is considered quite chal-
lenging.2,3
In 1980 Hendrickson reported that 3-oxidopyrylium,
a reactive species, readily undergoes self-dimerization to
produce a dimer 3 (Scheme 1).4 The dimer thus formed
is a doubly bridged eight-membered carbocycle5-10 en-
dowed with diverse functionalities around the ring. It is
rather surprising that despite its synthetic potential, the
dimer (3) has not received due attention from synthetic
chemists. This observation naturally prompted us to
undertake synthetic study of the said dimer.
(5) For reviews of the construction of cyclooctanoid systems, see: (a)
Mehta, G.; Singh, V. Chem. Rev. 1999, 99, 881. (b) Petasis, N. A.;
Patane, M. A. Tetrahedron 1992, 48, 5757.
(6) (a) Wender, P. A.; Ihle, N. C. J . Am. Chem. Soc. 1986, 108, 4678.
(b) Wender, P. A.; Snapper, M. L. Tetrahedron Lett. 1987, 28, 2221.
(c) Wender, P. A.; Ihle, N. C. Tetrahedron Lett. 1987, 28, 2451. (d)
Wender, P. A.; Ihle, N. C.; Correia, C. R. D. J . Am. Chem. Soc. 1988,
110, 5904. (e) Wender, P. A.; Tebbe, M. J . Synthesis 1991, 1089. (f)
Wender, P. A.; Nuss, J . M.; Smith, D. B.; Suarez-Sobrino, A.; Vagberg,
J .; Decosta, D.; Bordner, J . J . Org. Chem. 1997, 62, 4908 and references
therein.
In this note, we will describe our exploratory investiga-
tions for stereocontrolled transformations of the dimer.
Our studies began with efficient preparation of dimer 3
using the method reported by Hendrickson et al.4 3-Oxi-
dopyrylium (2) was formed by treatment of acetoxypyra-
(7) (a) Sieburth, S. M.; McGee, K. F., J r.; Al-Tel, T. H. J . Am. Chem.
Soc. 1998, 120, 587. (b) Sieburth, S. M.; Cunard, N. T. Tetrahedron
1996, 52, 6251.
(8) (a) Molander, G. A.; Etter, J . B.; Harring, L. S.; Thorel, P.-J . J .
Am. Chem. Soc. 1991, 113, 8036. (b) Molander, G. A.; Brown, G. A.;
deGracia, I. S. J . Org. Chem. 2002, 67, 3459.
(9) (a) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413. (b) Fu,
G. C.; Grubbs, R. H. J . Am. Chem. Soc. 1992, 114, 5426. (c) Fu. G. C.;
Grubbs, R. H. J . Am. Chem. Soc. 1992, 114, 7324. (d) Fu, G. C.; Nguyen,
S. T.; Grubbs, R. H. J . Am. Chem. Soc. 1993, 115, 9856. (e) Grubbs, R.
H.; Miller, S. J .; Fu, G. C. Acc. Chem. Res. 1995, 28, 446.
(10) (a) Schmalz, H.-G. Angew. Chem., Int. Ed. Engl. 1995, 34, 1833.
(b) Martin, S. F.; Chen, H.-J .; Courtney, A. K.; Liao, Y.; Patzel, M.;
Ramser, M. N.; Wagman, A. S. Tetrahedron 1996, 52, 7251. (c)
Schneider, M. F.; J unga, H.; Blechert, S. Tetrahedron 1995, 51, 13003.
(d) Furstner, A.; Muller, T. Synlet 1997, 1010.
* To whom correspondence should be addressed. Phone: (+91)-022-
25767169. Fax: (+91)-022-25723480.
† Department of Chemistry.
‡ National Single-Crystal X-ray Diffraction Facility.
(1) (a) Oishi, T.; Ohtsuks, Y. In Studies in Natural Products
Synthesis; Atta-ur-Rahman, Ed.; Elsevier: Amsterdam, The Nether-
lands, 1989; Vol. 3, p 73. (b) Rigby, J . H. In Studies in Natural Products
Synthesis; Atta-ur-Rahman, Ed.; Elsevier: Amsterdam, The Nether-
lands, 1993; Vol. 12, p 233.
(2) Illuminati, G.; Mandoline, L. Acc. Chem. Res. 1981, 14, 95.
(3) Molander, G. A. Acc. Chem. Res. 1998, 31, 603.
(4) (a) Hendrickson, J . B.; Farina, J . S. J . Org. Chem. 1980, 45, 3361.
(b) Sammes, P. G.; Street, L. J . J . Chem. Soc., Perkin Trans. 1 1983,
1261. (c) For a review of oxidopyrylium cycloadditions see: Sammes,
P. G. Gazz. Chim. Ital. 1986, 51, 1573.
10.1021/jo0353583 CCC: $27.50 © 2004 American Chemical Society
Published on Web 12/31/2003
J . Org. Chem. 2004, 69, 967-969
967

SCHEME 3
SCHEME 4
SCHEME 5
presence of an ethoxy group and formation of a new
carbon-carbon bond (C4-C9).
In view of the above results the conditions for hydro-
genation were changed such that the solvent participa-
tion was eliminated, i.e., to undergo the reduction in a
nonparticipating, nonnucleophilic solvent. Hydrogenation
of 3 was, therefore, run in toluene and ethyl acetate,
respectively. In both cases, the required hydrogenation
product 4 was formed, which was confirmed by its
spectroscopic data.
To better understand the reaction pathway for the
formation of the unexpected product 5, two simple
experiments were performed. When compound 4 was
treated with Pd/C in ethanol it furnished a product that
was found identical with 5, whereas no reaction occurred
when dimer 3 was subjected to the above reaction
conditions (Scheme 2). In light of these observations the
mechanism depicted in Scheme 3 seems tenable. The
acidic nature of the reaction medium appears to be
responsible for the formation of this unexpected product
through the transannular cationic cyclization of 4. The
transient carbocation 6 was then trapped by the solvent
(ethanol) to generate the observed product. The estab-
lishment of a carbon-carbon bond during hydrogenation
is rather unique and unanticipated.
We next turned our attention to sodium borohydride
reduction of compound 4. Since such a reduction is going
to develop two new stereogenic centers, the formation of
four products is possible. However, the reaction proceeded
stereoselectively to produce diol 7 as the sole product.
The stereochemistry of the diol was established through
the single-crystal X-ray analysis of the corresponding
diacetate. The diacetate was characterized as 8 and hence
the stereostructure 7 is assigned to the diol.
Our next objective was to open the heavily encumbered
pyranyl ether moiety while still maintaining the geo-
metrical rigidity imparted by the oxa-bridge to the deeply
embedded eight-membered ring in the structure. The
hydroxyl groups in 7 are protected as benzyl ethers
(BnBr/NaH), and the resultant bis-benzyl ether (9) was
then hydrated with use of acedic resins (Dowex 50W X
4) in the presence of water to furnish the aldehyde 10
(νmax 1719 cm-1),11 which was further converted into other
cyclooctanoid derivatives (11-13, Scheme 5) following
literature procedures.
transforming furans to functionalized cyclooctanoids. The
results described herein may pave the way for further
studies on the dimer leading to the polyhydroxy cyclooc-
tanoids. Efforts toward preparation of various bicyclic
systems are currently underway.
Exp er im en ta l Section
(3,6-Bisben zyloxy-4-h yd r oxy-9-oxa -bicyclo[3.3.1]n on -2-
yl)a ceta ld eh yd e (10). To a solution of 9 (0.5 g, 1.37 mmol) and
lithium bromide (0.36 g) in acetonitrile (15 mL) were added
Dowex 50W X 4 resin (H+ form,11 0.2 g) and water (0.45 mL).
The mixture was stirred at room temperature for 0.5 h. The
solution was filtered, neutralized with Et3N, and evaporated to
dryness. The residue was dissolved in CH2Cl2, washed succes-
sively with water, ice-cold HCl (5%), and saturated NaHCO3,
and dried (Na2SO4). The crude reaction mixture was filtered and
concentrated under reduced pressure and used directly in the
next step.
4-Allyl-3,8-b isb en zyloxy-9-oxa -b icyclo[3.3.1]n on a n -2-ol
(13). To a suspension of phosphonium salt in anhydrous THF
(0.5 M) was added n-BuLi (0.6 mL, 15% in hexane, 2 mmol)
dropwise at -20 °C. The reaction mixture was stirred at -20
°C to room temperature until the entire solid disappeared
(∼0.5-1 h). A solution of 10 (0.48 g, 1.36 mmol, coevaporated
with anhydrous benzene 3 × 25 mL before use) in THF (20 mL)
was added to the reaction mixture at -20 °C, and the solution
was stirred for 16 h at room temperature. An excess of reagent
grade acetone was added and the mixture was extracted with
diethyl ether. The precipitated solid was filtered off and the ether
extracts were washed with saturated NaHCO3 solution, water,
and brine. The organic phase was dried (Na2SO4) and evaporated
under reduced pressure. Purification of the resultant residue by
flash chromatography afforded compound 13 (0.36 g, 72%) as
pale yellow oil.
IR (neat) νmax 3482, 1640 cm-1; 1H NMR (300 MHz, CDCl3) δ
7.2 (m, 10H), 5.76-5.63 (m, 1H), 5.12 (d, J ) 11.4 Hz, AB system,
1H), 4.96 (m, 2H), 4.74 (d, J ) 11.4 Hz, AB system, 1H), 4.60
(m, benzylic, 2H), 4.28 (m, 1H), 4.20-4.10 (m, 2H), 3.96 (m, 1H),
3.82 (m, 1H), 3.66 (dd, J ) 8, 10.6 Hz, 1H), 2.20 (m, 2H), 2.7 (m,
1H), 1.87-1.60 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 139.1,
137.2, 136.3, 128.7, 128.4, 128.2, 127.9, 127.6, 116.3, 83.2, 78.5,
77.8, 74.7, 71.8, 70.0, 69.6, 44.8, 33.8, 26.9, 23.4; HRMS calcd
for C25H30O4 417. 2042 (MNa+), found 417.2027.
In conclusion the thermal [5+3] cycloaddition of 3-oxi-
dopyrylium appears to provide a convenient method of
Ack n ow led gm en t. We thank the Department of
Science and Technology (New Delhi, India) for the
financial support of this work and the National Single
(11) Sabesan, S.; Neira, S. J . Org. Chem. 1991, 56, 5468.
968 J . Org. Chem., Vol. 69, No. 3, 2004

1
data including copies of H and 13C NMR spectra of all new
Crystal X-ray Diffraction facility at IITB for the X-ray
data of 5 and 8.
compounds (4-13). This material is available free of charge
via the Internet at http://pubs.acs.org.
Su p p or tin g In for m a tion Ava ila ble: Crystallographic
information files (CIF) of compounds 5 and 8; characterization
J O0353583
J . Org. Chem, Vol. 69, No. 3, 2004 969