Ring-closing metathesis/fragmentation route to geometrically defined medium-ring cycloalkenes: Total synthesis of (±)-periplanone C

Article abstract of DOI:10.1021/ol049875z

The combination of alkene metathesis and β-fragmentation offers an efficient entry into (Z)-configured medium-ring cycloalkenes. The versatility of this method is demonstrated by the total synthesis of Periplanone C, a semiochemical of Periplaneta america

Full text of DOI:10.1021/ol049875z

ORGANIC
LETTERS
2004
Vol. 6, No. 8
1221-1224
Ring-Closing Metathesis/Fragmentation
Route to Geometrically Defined
Medium-Ring Cycloalkenes: Total
Synthesis of (±)-Periplanone C
Aleksandar Ivkovic, Radomir Matovic, and Radomir N. Saicic*
Faculty of Chemistry, UniVersity of Belgrade, Studentski trg 16, P.O. Box 158,
11000 Belgrade, Serbia and Montenegro, and ICTM-Centre for Chemistry,
NjegoseVa 12, 11000 Belgrade, Serbia and Montenegro
rsaicic@chem.bg.ac.yu
Received January 21, 2004
ABSTRACT
The combination of alkene metathesis and â-fragmentation offers an efficient entry into (Z)-configured medium-ring cycloalkenes. The versatility
of this method is demonstrated by the total synthesis of Periplanone C, a semiochemical of Periplaneta americana.
Ring-closing metathesis (RCM) has rapidly evolved into one
of the most versatile approaches for the synthesis of cyclic
systems of various sizes and has found widespread applica-
tion in the synthesis of complex organic compounds.1
Continuous efforts in the field have resulted in a steady
improvement of the catalyst performance in terms of
functional group tolerance, increased reactivity and stability
toward oxygen and moisture, and in the development of
polymer-supported reagents. Recently, enantioselective vari-
ants of RCM have also been reported.2
controlled, profoundly influenced by the ring size and
substituents. Thus, even cyclooctene ring closure, normally
expected to occur with (Z)-selectivity, under certain condi-
tions can afford an (E)-derivative exclusively.4 Numerous
examples are known where metathetic closures of medium-
sized rings proceed with (E)-selectivity, both in the carbo-
and heterocyclic series.5 In larger rings, (E)-products are
usually favored, where the degree of selectivity may depend
on the reaction temperature6 and solvent.7 While the ap-
(3) For a short review on the application of RCM in the synthesis of
medium-sized rings, see: Maier, M. E. Angew. Chem., Int. Ed. 2000, 39,
2073.
(4) Bourgeois, D.; Pancrazi, A.; Ricard, L.; Prunet, J. Angew. Chem.,
Int. Ed. 2000, 39, 726.
(5) For some examples of (E)-selective RCM of 10-membered rings,
see the following. (a) Cycloalkene: Nevalainen, M.; Koskinen, A. M. P. J.
Org. Chem. 2002, 67, 1554. (b) Lactam: Fink, B. E.; Kym, P. R.;
Katzenellenbogen, J. A. J. Am. Chem. Soc. 1998, 120, 4334. (c) Ester:
Furstner, A.; Radkowski, K.; Wirtz, C.; Goddard, R.; Lehmann, C.; Mynott,
R. J. Am. Chem. Soc. 2002, 124, 7061. (d) For examples of both (E)- and
(Z)-selective 11-membered ring formation, see: Nicolaou, K. C.; Vassil-
ikogiannakis, G.; Montagnon, T. Angew. Chem., Int. Ed. 2002, 41, 3276.
(6) Furstner, A.; Langemann, K. Synthesis 1997, 792.
However, the control of alkene geometry in the medium-
and large-ring cycloalkene products remains an unsolved
problem.3 The (E/Z) outcome is difficult to predict and almost
impossible to modify. Most often it appears to be substrate
(1) For review articles on RCM, see: (a) Grubbs, R. H.; Chang, S.
Tetrahedron 1998, 54, 4413. (b) Schrock, R. R. Tetrahedron 1999, 55,
8141.
(2) For some recent reviews on the developments in RCM and the use
of the last-generation catalysts, see: (a) Schrock, R. R., Hoveyda, A. H.
Angew. Chem., Int. Ed. 2003, 42, 4592. (b) Trnka, T. M.; Grubbs, R. H.
Acc. Chem. Res. 2001, 34, 18. (c) Furstner, A. Angew. Chem., Int. Ed. 2000,
39, 3012. (d) See also: Blechert, S.; Connon, S. J. Angew. Chem., Int. Ed.
2003, 42, 1900.
(7) Nakashima, K.; Ito, R.; Sono, M.; Tori, M. Heterocycles 2000, 53,
301.
10.1021/ol049875z CCC: $27.50 © 2004 American Chemical Society
Published on Web 03/17/2004

Scheme 1. Metathesis/Fragmentation Approach to
Medium-Ring (Z)-Cycloalkenes
Scheme 2
plication of RCM in the synthesis of (E)-alkene units in
cyclic natural products has been recently reviewed,8 (Z)-
selective RCM remains elusive.9
An indirect method, which circumvents the selectivity
problem, relies on ring-closing alkyne metathesis; the mac-
rocyclic alkynes thus obtained can often be further reduced
selectively to (Z)-cycloalkenes.10 The catalysts for this type
of transformation are, however, less developed than those
for the alkene RCM.
We set out to devise a method that would allow for a
general, stereoselective synthesis of medium-ring (Z)-cy-
cloalkenes, based on RCM. Our approach, delineated in
Scheme 1, involves RCM of a cyclic substrate followed by
fragmentation of a central bond in a condensed bicyclic
intermediate. Several features of this indirect procedure
should contribute to its efficiency: (a) the stereochemical
constraints associated with small-ring closure could secure
the (Z)-configuration of the new alkene bond; (b) a RCM
reaction that led to a five-, six-, or seven-membered ring
could be expected to proceed in a better yield, as compared
to a direct medium-sized ring closure; (c) given the vast
number of methods for small-ring formation, as well as for
nucleophilic and electrophilic introduction of alkenyl units,
the RCM precursors should be readily available; (d) the
fragmentation step could be performed under various condi-
tions (anionic, radical), which adds to the versatility of the
overall sequence.
Upon submission to the cyclization/fragmentation cascade,
compounds 1a-c were expected to yield 9-11-membered
cycloalkenones with an additional exo-methylene double
bond. On exposure to Ru catalyst 4, all the substrates
afforded bicyclic products in almost quantitative yields.
Reduction of the esters, followed by selective mesylation of
the primary hydroxyl groups in 2, set the stage for the Grob
fragmentation, which proceeded without event to give the
expected cycloalkenones 3. The overall yield from 1 was
35-59%, which we found to be acceptable for an unopti-
mized four-step procedure. Notably, regio- and stereochem-
ical integrity of the endocyclic double bond in the final
products 3 was not affected under the basic conditions of
the latter reaction.
These preliminary results encouraged us to apply the
RCM/fragmentation method in the synthesis of more com-
plex systems. We turned our attention toward a group of
cyclic sesquiterpenes known as periplanones, sex pheromones
of the American cockroach, Periplaneta americana, which
have proven to be of considerable interest of synthetic
chemists.12 Periplanone C 5 appeared to us as a challenging
target for the application of our method, as this germacrene
derivative possesses four alkene units of both (Z)- and (E)-
configuration, as well as a highly activated, conjugated exo-
The annulation/fragmentation principle is well precedented
and has been used in the synthesis of many complex natural
products. However, we are aware of only two, relatively
specific, examples of the RCM-based stereoselective ring
expansion approach to medium-sized rings.11
To test the feasibility of the envisaged protocol, several
model compounds were prepared according to Scheme 2.
(8) Prunet, J. Angew. Chem., Int. Ed. 2003, 42, 2826.
(9) Examples from the epothilone syntheses: (a) Meng, D.; Bertinato,
P.; Balog, A.; Su, D.-S.; Kamenecka, T.; Sorensen, E. J.; Danishefsky, S.
J. J. Am. Chem. Soc. 1997, 119, 10073. (b) Yang, Z.; He, Y.; Vourloumis,
D.; Vallberg, H.; Nicolaou, K. C. Angew. Chem., Int. Ed. Engl. 1997, 36,
166. (c) Schinzer, D.; Limberg, A.; Bauer, A.; Bohm, O. M.; Cordes, M.
Angew. Chem., Int. Ed. Engl. 1997, 36, 523.
(10) (a) Furstner, A.; Mathes, C.; Grela, K. Chem. Commun. 2001, 1057.
(b) Furstner, A.; Grela, K. Angew. Chem., Int. Ed. 2000, 39, 1234.
(11) (a) Mehta, G.; Kumaran, R. S. Chem. Commun. 2002, 1456. (b)
Rodriguez, J. R.; Castedo, L.; Mascarenas, J. L. Chem. Eur. J. 2002, 8,
2923.
(12) (a) Persoons, C. J.; Ritter, F. J.; Verwiel, P. E.; Hauptmenn, H.;
Mori, K. Tetrahedron Lett. 1990, 31, 1747, and the references therein. (b)
Nicolaou, K. C.; Sorensen, E. J. Classics in Total Synthesis; VCH:
Weinheim, 1996; Chapters 13 and 21.
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Org. Lett., Vol. 6, No. 8, 2004

Scheme 3. Retrosynthetic Analysis of Periplanone C
Scheme 4. Synthesis of Periplanone C
methylene group.13 In addition, the total synthesis of
periplanone C would also constitute formal syntheses of
periplanones A14 and D.15
Our retrosynthetic analysis of periplanone C is outlined
in Scheme 3. Mannich disconnection and selective alkene
isomerization in 5 pave the way for application of the
fragmentation transform, which converts the 10-membered
ring into the unsaturated condensed bicycle 6, itself poten-
tially obtainable by RCM. Our precursor for the metathesis
reaction could possibly be prepared by C-allylation of the
unsaturated â-ketoester 7. The latter compound could be
assembled from the aromatic ester 8 by an alkylative Birch
reduction.
Our synthesis, displayed in Scheme 4, commenced with a
regioselective ortho-lithiation of the anisole derivative 9,
which, after carboxylation and esterification, gave ester 8.16
The Birch reduction of 8 with potassium gave the required
cyclic â-ketoester 7 as a mixture of diastereoisomers in a
7:1 ratio, after quenching of the corresponding lithium
enolate with allyl bromide17 and in situ hydrolysis. Allylation
of the carbonyl group in 7 was best performed with the
allylzinc reagent, prepared in situ in DMF, and gave the RCM
precursor 10 as a single stereoisomer.18 Upon exposure to 3
mol % of the first-generation Ru-catalyst 4, diene 10 was
smoothly converted into the bicyclic intermediate 6. Scission
of the central bond in the condensed bicycle 6 was envisioned
to occur via Grob fragmentation. To this end, ester 6 was
reduced to 11 with lithium aluminum hydride and its primary
hydroxyl group was O-mesylated. Mesylate 12 was not
purified but was submitted directly to the action of powdered
potassium hydroxide in benzene, in the presence of 18-
crown-6. The required cyclodecadienone intermediate 13 was
obtained as a single geometrical isomer.
The sensitive nature of 13 severely restricted the choice
of methods available for effecting the penultimate synthetic
step, namely, regioselective isomerization of the (Z)-double
bond of the conjugated diene moiety. Clearly, both basic and
acidic reagents had to be avoided, as the nonconjugated (Z)-
olefinic bond would most probably suffer positional isomer-
ization into the thermodynamically more stable conjugated
enone. Not unexpectedly, under conditions of photochemical
isomerization, 13 underwent transannular [2 + 2] photocy-
(13) Total syntheses of Periplanone C: (a) Shizuri, Y.; Matsunaga, K.;
Tamaki, K.; Yamaguchi, S.; Yamamura, S. Tetrahedron Lett. 1988, 29,
1971. (b) McMurry, J. E.; Siemers, N. O. Tetrahedron Lett. 1994, 35, 4505.
(c) Nishii, Y.; Watanabe, K.; Yoshida, T.; Okayama, T.; Takahashi, S.;
Tanabe, Y. Tetrahedron 1997, 53, 7209.
(14) Hofmeister, P.; Krieg, W.; Neudert, R.; Hauptmann, H. U.S. Patent
4939275.
(15) Biendl, M.; Hauptmann, H.; Sass, H. Tetrahedron Lett. 1989, 30,
2367.
(16) Shirley, D. A.; Harmon, T. E.; Cheng, C. F. J. Organomet. Chem.
1974, 69, 323.
(17) Hook, J. M.; Mander, L. N.; Woolias, M. Tetrahedron Lett. 1982,
23, 1095.
(18) The stereochemical outcome of the allylation reaction can be
predicted according to the model proposed by Molander: Molander, G.
A.; Harris, C. R. J. Am. Chem. Soc. 1995, 117, 3705.
Org. Lett., Vol. 6, No. 8, 2004
1223

cloaddition to yield 8-exo-methylene tricyclo[4.4.0.07,10]-
decan-3-one. Therefore, we envisaged accomplishing the
necessary transformation through use of reversible thiyl
radical addition. Although extensively studied theoretically,
such radical isomerizations have seldom been employed in
synthesis.19 Much to our pleasure, the irradiation of 13 with
visible light in the presence of a catalytic amount of diphenyl
disulfide brought about a smooth conversion into 14.
Although a 1:1 ratio of isomers 13 and 14 was established
at equilibrium, these were easily separated by column
chromatography on silver nitrate-impregnated silica gel
(SNIS).20 Compound 14 was isolated in 38% yield, and 13
was recovered in 58% yield.
lithium enolate of 14 was treated with an excess of
Eschenmoser’s reagent at -78 °C, aminomethylation pro-
ceeded, followed by spontaneous elimination of dimethy-
lamine to give periplanone C.22 Its transformation into
periplanones A and D has been reported previously.14,15
In summary, we have shown that the RCM/fragmentation
sequence offers an expedient, stereoselective entry into
unsaturated medium-sized ring compounds.
Acknowledgment. We dedicate this work to Professor
Pierre Potier. This research was partially supported by the
Ministry of Science, Technology and Development of the
Republic of Serbia (Project No. 1719).
The final step in the synthesis, the regioselective Mannich
methylenation of the nonsymmetrical ketone 14, was ac-
complished via the preformed metal enolate.21 When the
Supporting Information Available: Experimental pro-
cedures and spectral data for compounds 6-14. This material
is available free of charge via the Internet at http://pubs.acs.org.
(19) Review article on the alkene (E)-(Z) isomerization: Dugave, C.;
Demange, L. Chem. ReV. 2003, 103, 2475.
OL049875Z
(20) Review article on SNIS: Williams, C. M.; Mander, L. N. Tetra-
hedron 2001, 57, 425.
(22) 1H NMR and IR spectra identical to those reported for the naturally
occurring compound in ref 15; 13C NMR spectrum identical to the spectrum
previously reported in ref 13c.
(21) Roberts, J. L.; Borromeo, P. S.; Poulter, C. D. Tetrahedron Lett.
1977, 1621.
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Org. Lett., Vol. 6, No. 8, 2004