New silicon-mediated, sequential ring expansions of n-sized 2-cycloalkenones into hydroxyolefinic n + m + p medium-sized lactones: Short synthesis of (-)-phoracantholide-J

Article abstract of DOI:10.1021/ol051854x

(Chemical Equation Presented) In only four steps from 2-cyclopentenone and 2-cyclohexenone, sequential three- or four-atom and then one- to three-atom ring enlargements produce nine- to 12-membered hydroxyolefinic lactones on a gram scale. 2-Cyclopentenon

Full text of DOI:10.1021/ol051854x

ORGANIC
LETTERS
2005
Vol. 7, No. 19
4301-4303
New Silicon-Mediated, Sequential Ring
Expansions of n-Sized 2-Cycloalkenones
into Hydroxyolefinic n
Medium-Sized Lactones: Short
Synthesis of ( )-Phoracantholide-J
+ m + p
−
Gary H. Posner,* Mark A. Hatcher, and William A. Maio
Department of Chemistry, School of Arts and Sciences, The Johns Hopkins UniVersity,
Baltimore, Maryland 21218
ghp@jhu.edu
Received August 2, 2005
ABSTRACT
In only four steps from 2-cyclopentenone and 2-cyclohexenone, sequential three- or four-atom and then one- to three-atom ring enlargements
produce nine- to 12-membered hydroxyolefinic lactones on a gram scale. 2-Cyclopentenone undergoes this serial 5 2 process to form
10-membered ring natural ( )-phoracantholide-J in six linear steps and 26% overall yield.
+
3 +
−
Organic chemistry is still being enriched by new synthetic
methods for converting simple reactants into more complex
compounds.1 Specifically, transforming readily available
carbocycles into much less common medium-sized rings
remains an important goal, in part as an intellectual challenge
and in part because many valuable natural products possess
medium-sized rings.2 Although many ring-expansion pro-
cesses work well,3 we have recently described a new three-
step protocol using simple epoxides for overall homologous
Baeyer-Villiger ring expansion of five- to seven-membered
2-cycloalkenones into eight- to 10-membered homoallylic
lactones.4 Now we report the first examples of oxetanes being
opened by ketone enolate nucleophiles as well as significant
enhancement of our carbocycle-to-heterocycle methodology
using functionalized epoxides allowing preparation of more
diverse, complex, and valuable medium-sized lactones.5
Specifically, â-silyl n-sized cyclic ketone enolates open
O-protected hydroxy-epoxides6 or hydroxy-oxetanes to pro-
duce intermediate hemiketals that undergo oxidative frag-
mentation to form three-atom or four-atom ring-enlarged
homoallylic or bis-homoallylic lactones; after release of the
pendant free hydroxyl group, intramolecular reorganization
then leads to the final, serially ring-expanded, medium-sized
n + m + p lactones.
In a seminal report on oxetane opening by cyclohexanone
imine salts, Hudrlik and Wan indicated that cyclohexanone
enolate failed to open oxetane, even in the presence of
(1) Larock, R. C. ComprehensiVe Organic Transformations, 2nd ed., John
Wiley: New York, 1999.
(2) Hesse, M. Ring Enlargements in Organic Chemistry; VCH: Wein-
heim, Germany, 1991.
(3) Paterson, I.; Mansuri, M. M. Tetrahedron 1985, 41, 3569.
(4) Hatcher, M. A.; Borstnik, K.; Posner, G. H. Tetrahedron Lett. 2003,
44, 5407-5409.
(5) Nubbemeyer, U. Top. Curr. Chem. 2001, 216, 126.
(6) Posner, G. H.; Maxwell, J. P.; Kahraman, M. J. Org. Chem. 2003,
68, 3049-3054.
10.1021/ol051854x CCC: $30.25
© 2005 American Chemical Society
Published on Web 08/17/2005

aluminum and boron Lewis acids.7 Now we have found that
boron trifluoride-etherate does in fact assist rapid oxetane
opening by â-silyl cycloalkanone enolates 2 at low temper-
ature in THF solvent to give γ-hydroxysilane intermediates
3a, 3b, and 5a in 54-67% yields (Scheme 1). These
Scheme 2. Translactonizations to Nine- to 12-Membered Ring
Lactones
Scheme 1. Ketone Enolate Opening of Oxetanes Followed by
Oxidative Clevage
silyl ethers 9 liberates the corresponding primary hydroxyl
group that spontaneously causes translactonization to form
n + 3 + p lactones 1011 in 70-100% yields,12 except for
10, p ) 3. To assist translactonization in the difficult case
of lactone 9 when p ) 3, involving a seven-membered vs a
six-membered (p ) 2) or a five-membered (p ) 1) tetrahedral
intermediate, a gem-dialkyl side chain was incorporated into
eight-membered lactone 9a (Scheme 3); fluoride-induced
γ-hydroxysilane intermediates exist as a mixture of the
hemiketal form (as shown) and the corresponding hydroxy
ketone.
Oxidative cleavage of 3, using the oxidant ceric am-
monium nitrate (CAN),8,9 produces the n + 4 ring-enlarged
lactones 4a and 4b exclusively with cis-olefin geometry.
When the oxetane carries a silyl ether protected alcohol side
chain, mild and fast nucleophilic opening of the oxetane
(61% yield) followed by simultaneous oxidative cleavage
and silyl ether hydrolysis using CAN produces nine-
membered olefinic lactone 6a (70% yield, 1.25/1.0 E/Z).
Palladium-catalyzed hydrogenation and then acid-promoted
translactonization10 finally provides 11-membered lactone 7a
via this serial 5 + 4 + 2 ring expansion. For practical
considerations, it should be noted that stock solutions of
distilled enol silyl ethers 1a and 1b can be stored neat under
inert atmosphere at -5 °C for several days without hydroly-
sis.
Scheme 2 illustrates silicon-mediated n + 3 + p ring-
enlargement reactions using functionalized epoxides to form
medium-sized lactones. The following two observations are
noteworthy: (1) n + 3 lactones 9 are formed in 49-59%
overall yields from both five- and six-membered â-silyl enol
ethers 1, except for lactone 9, n ) 6, p ) 1 (23% overall
yield); (2) fluoride-promoted O-desilylation of the primary
Scheme 3. Thorpe-Ingold Effect in Eight- to 11-Membered
Ring Translactonization
desilylation led directly and spontaneously, aided by the
Thorpe-Ingold effect,13 to the desired 11-membered lactone
10a in 51% overall yield via this serial 5 + 3 + 3 ring-
enlargement process. To improve the poor yield in the case
of lactone 9, n ) 6, p ) 1 (Scheme 2), we used a benzyl
group instead of a TBS group for glycidol O-protection.
Epoxide opening in this case proceeded more satisfactorily,
giving 6 + 3 lactone 9b in 50% overall yield after oxidative
fragmentation (Scheme 4). Thus, in only four steps from
readily available 2-cyclopentenone and 2-cyclohexenone,
(11) Because of the nature of medium-ring lactones (ref 5), some NMR
spectra may be broad due to the presence of conformational isomers.
(12) Some medium-ring lactones in Scheme 2 are a mixture of ring sizes
due to incomplete translactonization and are inseparable by column
chromatography. As a result, yields reported for 10, n ) 6, p ) 1 and p )
2 reflect the actual isolated yield of 6 + 3 + p lactones 10 based on their
1H NMR ratios.
(7) Hudrlik, P. F.; Wan, C. N. J. Org. Chem. 1975, 40, 2963-2965.
(8) Wilson, S. R.; Zucker, P. A.; Kim, C. W.; Villa, C. A. Tetrahedron
Lett. 1985, 26, 1969-1972.
(9) Trahanovsky, W. S.; Himstedt, A. L. J. Am. Chem. Soc. 1974, 96,
7974-7976.
(10) Corey, E. J.; Brunelle, D. J.; Nicolaou, K. C. J. Am. Chem Soc.
1977, 99, 7359.
(13) Beesley, R. M.; Ingold, C. K.; Thorpe, J. F. J. Chem. Soc. 1915,
107, 1080-1106.
4302
Org. Lett., Vol. 7, No. 19, 2005

radical deoxygenation to yield natural (-)-phoracantholide-J
(15, [R]23 -40.3; lit.18 [R]22 -36.8) in six linear steps and
26% overall yield from 2-cyclopentenone.
Scheme 4. 6 + 3 + 1 Ring Expansion Using Glycidyl Benzyl
Ether
In conclusion, we present here a four-step protocol
involving three- or four-atom and subsequent one- to three-
atom ring expansions of 2-cyclopentenones and 2-cyclohex-
enones. These n + m + p sequential ring-enlargement
reactions produce medium-sized lactones with a homoallylic
or bis-homoallylic hydroxyl group at a specific position in
the new oxygen heterocycle.21 Incorporation of different p
units in this n + m + p methodology is expected to produce
diverse and even more complex and useful lactones. We are
actively exploring this issue as well as mechanistic under-
standing of the oxidative fragmentation step as part of our
long-standing interest in sequential, multicomponent, ring-
forming reactions.22,23
nine- to 12-membered, regiospecifically unsaturated, geomet-
ically pure, cis-olefinic hydroxy lactones 10 are formed in
good overall yields in most cases.
Phoracantholide-J (15) is a natural 10-membered ring
olefinic lactone that is part of the defense secretion of the
insect eucarypt longicorn, Phoracantha synonyma. This
medium-sized lactone, having one stereogenic center, has
been synthesized in racemic form in three different ways.14-19
The only reported previous synthesis of (-)-phoracantholide-
J (15) required 12 linear steps and proceeded in only 14%
overall yield via initial yeast stereoselective reduction of ethyl
acetoacetate.18 Scheme 5 features our new 5 + 3 + 2 ring-
Acknowledgment. We thank NSF for seed support of
this project and Dr. R. Larsen for a helpful discussion.
Supporting Information Available: Experimental pro-
cedures and spectral data for all compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL051854X
(21) Typical Gram-Scale Experimental Protocol. Formation of
Hemiketal 8, n ) 5, p ) 1. Silylenol-ether 1a4 (2.50 g, 10.9 mmol) and
THF (20.0 mL) were added to a flame-dried 100 mL flask and then cooled
to 0 °C. MeLi (7.01 mL, 11.3 mmol, 1.6 M in Et2O) was added dropwise,
turning the solution bright yellow. After 5 min, the flask was removed from
the ice bath and cooled to -78 °C before a solution of tert-butyldimethylsilyl
glycidol ether (1.04 g, 5.50 mmol) in THF (5.0 mL) was cannulated into
the reaction. This mixture was stirred for 5 min before BF3‚OEt2 (0.693
mL, 5.50 mmol, neat) was added very slowly (1 drop/4 s) while cooling
the needle with a piece of dry ice. The reaction was quenched after 30 min
of stirring with phosphate buffer (15.0 mL, pH 7.0) and warmed to room
temperature. The mixture was extracted with Et2O (3 × 50 mL), and the
combined organics were dried over MgSO4 and concentrated in vacuo. The
crude product was purified by silica gel chromatography (90% hexanes,
10% ethyl acetate, ∼1% TEA) to give the desired hemiketal (1.39 g, 73%)
as a colorless oil. Formation of Lactone 9, n ) 5, p ) 1. Hemiketal 8, n
) 5, p ) 1 (1.39 g, 4.04 mmol) was placed in a 250 mL flask with CH2Cl2
(100.0 mL) and cooled to 0 °C. PhI(OAc)2 (1.43 g, 4.44 mmol) and then
I2 (1.02 g, 4.04 mmol, crystals) were added. The reaction immediately turned
a dark purple color. The reaction was stirred for 5 h at 0 °C before quenching
with a saturated solution of sodium thiosulfate. The mixture was extracted
with CH2Cl2 (3 × 50 mL), and the combined organics were dried over
MgSO4 and concentrated in vacuo. The crude product was purified by silica
gel chromatography (90% hexanes, 10% ethyl acetate) to give lactone (0.73
g, 67%) as a colorless oil: 1H NMR (CDCl3) δ 5.81-5.73 (m, 2H), 4.64-
4.58 (m, 1H), 3.73 (dq, J ) 10.4, 4.8 Hz, 2H), 2.89-2.72 (m, 2H), 2.55-
2.47 (m, 1H), 2.38-2.30 (m, 1H), 2.20-2.90 (m, 2H), 0.901 (s, 9H), 0.073
(d, J ) 4.4 Hz, 6H); 13C NMR (CDCl3) δ 176.76, 132.67, 128.13, 77.84,
64.88, 37.94, 30.59, 25.87, 18.30, -5.32, -5.35; IR (neat, cm-1) 3025,
2955, 2931, 2849, 1755, 1467, 1249, 1208, 1149, 1055, 832, 779; HRMS
(CI) m/z (M+Na) calcd 293.1543 for C14H26O3SiNa+, found 293.1532.
Formation of Lactone 10, n ) 5, p ) 1. Lactone 9, n ) 5, p ) 1 (0.73
g, 2.70 mmol) was placed in a 50 mL flask with THF (15.0 mL). To this
mixture was added TBAF (6.75 mL, 6.75 mmol, 1.0 M in THF) at room
temperature. The reaction was quenched after 2 h by the addition of H2O
(10 mL), extracted with Et2O (2 × 50 mL), and washed with brine (1 × 50
mL), and the combined organics were dried over MgSO4 and concentrated
in vacuo. The crude product was purified by silica gel chromatography
(70% hexanes, 30% ethyl acetate) to give the desired lactone (0.376 g, 89%)
as a colorless oil: 1H NMR (CDCl3) δ 5.68-5.61 (m, 2H), 4.59-4.55 (m,
1H), 4.14-4.04 (m, 2H), 2.64-2.54 (m, 2H), 2.36-2.43 (m, 1H), 2.34-
2.022 (m, 3H), 1.98 (s, 1H); 13C NMR (CDCl3) δ 174.66, 129.21, 128.11,
70.47, 68.62, 33.87, 32.12, 30.28, 29.67, 24.12; IR (neat, cm-1) 3410.7,
2925.0, 2854.8, 1741.6, 1458.1, 1235.2, 1089.1, 730.2: HRMS (CI) m/z
(2M+Na) calcd 335.1465 for C16H24O6Na+, found 335.1443.
Scheme 5. Total Synthesis of (-)-Phoracantholide-J
expansion protocol for a short synthesis of (-)-phoracan-
tholide-J (15). The tert-butyl dimethylsilyl ether 11 of the
known (R)-4-hydroxy-1-pentene oxide20 and cyclopentenone
enol silyl ether 1a produce hemiketal 12, which undergoes
oxidative fragmentation to afford geometrically pure cis-
olefinic eight-membered ring lactone 13 as a diastereomeric
mixture. Fluoride-induced desilylation liberates the pendant
secondary alcohol that spontaneously translactonizes into 10-
membered ring olefinic hydroxylactone 14, which undergoes
(14) Gerlach, H.; Kunzler, P.; Oertle, K. HelV. Chim. Acta 1978, 61,
1226-1231.
(15) Petrzilka, M. HelV. Chim. Acta 1978, 61, 3075-3078.
(16) Trost, B. M.; Verhoeven, T. R. J. Am. Chem. Soc. 1979, 101, 1595-
1597.
(17) Trost, B. M.; Verhoeven, T. R. J. Am. Chem. Soc. 1980, 102, 4743-
4763.
(18) Kitahara, T.; Koseki, K.; Mori, K. Agric. Biol. Chem. 1983, 47,
389-393.
(19) Malherbe, R.; Rist, G.; Bellus, D. J. Org. Chem. 1983, 48, 860-
869.
(22) Posner, G. H.; Webb, K. S.; Asirvatham, E.; Jew, S.-S.;
Degl’Innocenti, A. J. Am. Chem. Soc. 1988, 110, 4754-4762.
(23) Posner, G. H. Chem. ReV. 1986, 86, 831-844.
(20) Barrett, A. G. M.; Sheth, H. G. J. Org. Chem. 1983, 48, 5017-
5022.
Org. Lett., Vol. 7, No. 19, 2005
4303