Ring closing metathesis/fragmentation route to (Z)-configured medium ring cycloalkenes. Total synthesis of (±)-periplanone C

Article abstract of DOI:10.1021/jo061790j

(Chemical Equation Presented) The combination of ring closing metathesis and β-fragmentation offers an efficient entry into (Z)-configured medium ring cycloalkenes. The fragmentation step can be effected under anionic or radical conditions. The versatilit

Full text of DOI:10.1021/jo061790j

Ring Closing Metathesis/Fragmentation Route to (Z)-Configured
Medium Ring Cycloalkenes. Total Synthesis of (()-Periplanone C
Radomir Matovic, Aleksandar Ivkovic, Marija Manojlovic, Zorana Tokic-Vujosevic, and
Radomir N. Saicic*
Faculty of Chemistry, UniVersity of Belgrade, Studentski trg 16, P.O.B. 158, 11000 Belgrade, Serbia; I. C.
T. M. Centre for Chemistry, NjegoseVa 12, 11000 Belgrade; and Faculty of Pharmacy, UniVersity of
Belgrade, Bul. Stepe StepanoVica 450, 11000 Belgrade
rsaicic@chem.bg.ac.yu
ReceiVed August 30, 2006
The combination of ring closing metathesis and â-fragmentation offers an efficient entry into (Z)-configured
medium ring cycloalkenes. The fragmentation step can be effected under anionic or radical conditions.
The versatility of this method is demonstrated by the total synthesis of (()-periplanone Csa macrocyclic
pheromone of Periplaneta americana.
Introduction
intermediate;4 the overall transformation results in the extension
of the initial ring system and avoids complications associated
with the macrocyclization.
Due to unfavorable enthalpic and entropic effects, the
formation of medium- and large-sized rings is, in general, a
more complex synthetic task, as compared to small and common
ring closures.1 As these structural units represent a frequent motif
in numerous natural products and biologically active compounds,
much effort has been invested in circumventing this problem.2
Two principal synthetic approaches have been developed, which
could be designated as the direct and the indirect one. The direct
approach has been successfully applied using organotransition
metal complexes, which are able to function, under mechanisti-
cally diverse conditions, as both reagents and templates, bringing
the reacting centers (the termini) of the cyclization precursor
into spatial proximity.3 Alternatively, the indirect route, also
known as the ring expansion method, involves the annulation
of a new (small or common) ring to a monocyclic precursor,
followed by the fragmentation of the central bond in the bicyclic
The recent advent of catalysts for metathesis has had a
considerable impact on the synthesis of medium- and large-
sized rings.5 Notably, the ruthenium and molybdenum carbene
complexes of new generations proved capable of effecting
traditionally difficult ring closures.6 This property, combined
with increased reactivity, improved functional group tolerance
and stability toward oxygen and moisture, makes ring closing
metathesis (RCM) an almost ideal tool for the direct macrocy-
clizations.7 However, one important issue remained unsolved,
(4) Review articles on radical methods: (a) Yet, L. Tetrahedron 1999,
55, 9349. (b) Dowd, P.; Zhang, W. Chem. ReV. 1993, 93, 2091.
(5) Reviews on the development and various applications of the alkene
metathesis reaction: (a) Grubbs, R. H. Tetrahedron 2004, 60, 7117. (b)
Schrock, R. R., Hoveyda, A. H. Angew. Chem., Int. Ed. 2003, 42, 4592.
(c) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18. (d) Furstner,
A. Angew. Chem., Int. Ed. 2000, 39, 3012. (e) Blechert, S.; Connon, S. J.
Angew. Chem., Int. Ed. 2003, 42, 1900.
(6) For review articles on RCM, see: (a) Grubbs, R. H.; Chang, S.
Tetrahedron 1998, 54, 4413. (b) Schrock, R. R. Tetrahedron 1999, 55, 8141.
(c) Phillips, A. J.; Abell, A. D. Aldrichimica Acta 1999, 32, 75.
(7) For a short review on the application of RCM in the synthesis of
medium-sized rings, see: (a) Maier, M. E. Angew. Chem., Int. Ed. 2000,
39, 2073. Review on the application of RCM macrocyclizations in the total
synthesis of natural products: (b) Gradillas, A.; Perez-Castells, J. Angew.
Chem., Int. Ed. 2006, 45, 6086.
(1) (a) Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Compounds;
Wiley: New York, 1994; pp 675-685. (b) Illuminati, G.; Mandolini, L.
Acc. Chem. Res. 1981, 14, 95.
(2) Review articles: (a) Molander, G. Acc. Chem. Res. 1998, 31, 603.
Eight-Membered carbocycles: (b) Petasis, N. A.; Patane, M. A. Tetrahedron
1992, 48, 5757. (c) Mehta, G.; Singh, V. Chem. ReV. 1999, 99, 881. Eight-
and nine-membered carbocycles: (d) Oishi, T.; Ohtsuka, Y. In Studies in
Natural Products Synthesis; Atta-ur-Rahman, Ed.; Elsevier: Amsterdam,
1989; Vol. 3, p 73. Lactones: (e) Rousseau, G. Tetrahedron 1995, 51, 2777.
(3) Yet, L. Chem. ReV. 2000, 100, 2963.
10.1021/jo061790j CCC: $33.50 © 2006 American Chemical Society
Published on Web 11/16/2006
J. Org. Chem. 2006, 71, 9411-9419
9411

Ivkovic et al.
SCHEME 1
which is the control of alkene geometry in medium-sized and
macrocyclic products. The stereochemical outcome of the
reaction (i.e., E/Z ratio) is difficult to predict and, in general,
impossible to modify. Most often, it appears to be substrate
controlled, profoundly influenced by the ring size and substitu-
tion pattern.8 Thus, even cyclooctene ring closure, which is
normally expected to occur with (Z)-selectivity, under certain
conditions, can afford an (E)-derivative exclusively.9 Numerous
examples are known where metathetic closures of medium-sized
rings proceeded with (E)-selectivity, or nonselectively, both in
the carbo- and heterocyclic series.10 In some cases, it was shown
that the stereochemical outcome of the reaction depends on the
catalyst employed, where the more reactive, new generation
catalysts favor the formation of thermodynamically controlled
products; the less reactive ones promote the irreversible RCM,
resulting in the kinetic control and, occasionally, inverted (E/
Z)-ratio.11 In larger rings (E)-products are usually favored,12
where the degree of selectivity may depend on the reaction
temperature13 and solvent.14 Although the application of RCM
in the synthesis of (E)-alkene units in cyclic natural products
has been recently reviewed,15 (Z)-selective RCM remains
elusive.
transformation are, however, less developed than those for the
alkene RCM.17
Results and Discussion
We set out to devise a method that would allow for a general,
stereoselective synthesis of medium-sized (Z)-cycloalkenes,
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
should secure the (Z)-configuration of the new alkene bond;
(b) a RCM reaction that leads 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 conditionssanionic,
radicalswhich adds to the versatility of the overall sequence.
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.18 In a preliminary report, we
disclosed our initial results on the RCM-based annulation/
fragmentation route to medium-sized (Z)-cycloalkenes.19 Here
we wish to provide a full account of this study, together with
some additional observations on the reactivity of intermediates.
An indirect method, which circumvents the selectivity
problem, relies on ring closing alkyne metathesis; the macro-
cyclic alkynes thus obtained can often be further reduced
selectively to (Z)-cycloalkenes.16 The catalysts for this type of
(8) However, attempts to generalize these observations have not met
success; see, for example: Vassilikogiannakis, G.; Margaros, I.; Tofi, M.
Org. Lett. 2004, 6, 205. Compare the conclusions from this reference to
the following: Nicolaou, K. C.; Vassilikogiannakis, G.; Montagnon, T.
Angew. Chem., Int. Ed. 2002, 41, 3276.
(9) Bourgeois, D.; Pancrazi, A.; Ricard, L.; Prunet, J. Angew. Chem.,
Int. Ed. 2000, 39, 726.
(10) (E)-selective RCM of 10-membered rings. Cycloalkene: (a) Nev-
alainen, M.; Koskinen, A. M. P. J. Org. Chem. 2002, 67, 1554. Cycloalk-
ene: (b) Castoldi, D.; Caggiano, L.; Panigada, L.; Sharon, O.; Costa, A.
M.; Gennari, C. Angew. Chem., Int. Ed. 2005, 44, 588. Lactam: (c) Fink,
B. E.; Kym, P. R.; Katzenellenbogen, J. A. J. Am. Chem. Soc. 1998, 120,
4334. Lactone: (d) Furstner, A.; Radkowski, K.; Wirtz, C.; Goddard, R.;
Lehmann, C.; Mynott, R. J. Am. Chem. Soc. 2002, 124, 7061. 11-Membered
rings: (e) El Sukkari, H.; Gesson, J. P.; Renoux, B. Tetrahedron Lett. 1998,
39, 4043. (f) Winkler, J. D.; Holland, J. M.; Kasparec, J.; Axelsen, P. H.
Tetrahedron 1999, 55, 8199. (g) Arisawa, M.; Kato, C.; Kaneko, H.; Nishida,
A.; Nakagawa, M. J. Chem. Soc., Perkin Trans 1, 2000, 1873. (h) Furstner,
A.; Muller, C. Chem. Commun. 2005, 5583. 12-Membered rings: (i) Snider,
B. B.; Song, F. Org. Lett. 2001, 3, 1817. (j) Wu, Y.; Liao, X.; Wang, R.;
Xie, X.-S.; De Brabander, J. K. J. Am. Chem. Soc. 2002, 124, 3245. (k)
Couladouros, E. A.; Mihou, A. P.; Bouzas, E. A. Org. Lett. 2004, 6, 977.
14-Membered rings: (l) Furstner, A.; Thiel, O. R.; Kindler, N.; Bartkowska,
B. J. Org. Chem. 2000, 65, 7990. (m) Goldring, W. P. D.; Hodder, A. S.;
Weiler, L. Tetrahedron Lett. 1998, 39, 4955.
The practical value of a synthetic method depends on the
accessibility of the precursors. Scheme 2 represents, in a
retrosynthetic format, several ways of assembling various types
of cyclization/fragmentation precursors, in a few steps, starting
from commercially available compounds. Variations in relative
positions of the leaving group and the alkene bond formed by
RCM give rise to diverse structural patterns of the expected
cycloalken(on)e products.
(11) (a) Furstner, A.; Radkowski, K.; Wirtz, C.; Goddard, R.; Lehman,
C. W.; Minott, R. J. Am. Chem. Soc. 2002, 124, 7061. (b) Lee, C. W.;
Grubbs, R. H. Org. Lett. 2000, 2, 2145. (c) Furstner, A.; Schlede, M. AdV.
Synth. Catal. 2002, 344, 657.
To test the feasibility of the envisaged protocol, we endeav-
ored to prepare several model compounds, and we first turned
our attention toward the transformation of type 1, according to
Scheme 2. A series of precursors were prepared in a straight-
forward way according to Scheme 3: allylation (or butenylation)
(12) Numerous examples in the 16-membered series come from synthetic
studies toward epothilones, where undesired (E)-products usually predomi-
nate: (a) Nicolaou, K. C.; He, Y.; Vourloumis, D.; Vallberg, H.; Roschangar,
F.; Saurabia, F.; Ninkovic, S.; Yang, Z.; Trujillo, J. I. J. Am. Chem. Soc.
1997, 119, 7960. (b) Rivkin, A.; Cho, Y. S.; Gabarda, A. E.; Yoshimura,
F.; Danishefsky, S. J. J. Nat. Prod. 2004, 67, 139. (c) Schinzer, D.; Limberg,
A.; Bauer, A.; Bohm, O. M.; Cordes, M. Angew. Chem., Int. Ed. 1997, 36,
523.
(13) Furstner, A.; Langemann, K. Synthesis 1997, 792.
(14) Nakashima, K.; Ito, R.; Sono, M.; Tori, M. Heterocycles 2000, 53,
301.
(15) Prunet, J. Angew. Chem., Int. Ed. 2003, 42, 2826. Corrigendum:
Prunet, J. Angew. Chem., Int. Ed. 2003, 42, 3322.
(16) (a) Furstner, A.; Turet, L. Angew. Chem., Int. Ed. 2005, 44, 3462.
(b) Furstner, A.; Mathes, C.; Grela, K. Chem. Commun. 2001, 1057. (c)
Furstner, A.; Grela, K. Angew. Chem., Int. Ed. 2000, 39, 1234.
(17) A review article on alkyne metathesis: Furstner, A.; Davies, P. W.
Chem. Commun. 2005, 2307.
(18) (a) Mehta, G.; Kumaran, R. S. Chem. Commun. 2002, 1456. (b)
Rodriguez, J. R.; Castedo, L.; Mascarenas, J. L. Chem.sEur. J. 2002, 8,
2923. See also: (c) Balskus, E. P.; Mendez-Andino, J.; Arbit, R. M.;
Paquette, L. A. J. Org. Chem. 2001, 66, 6695. (d) Mendez-Andino, J.;
Paquette, L. A. Org. Lett. 2000, 2, 1263.
(19) Ivkovic, A.; Matovic, R.; Saicic, R. N. Org. Lett. 2004, 6, 1221.
9412 J. Org. Chem., Vol. 71, No. 25, 2006

Total Synthesis of (()-Periplanone C
SCHEME 2
SCHEME 4
SCHEME 3
products 3a-d in high yields. Upon submission to the cycliza-
tion/fragmentation cascade, the compounds 2a-c were expected
to yield 9-11-membered cycloalkenones with an additional exo-
methylene double bond. Therefore, esters 3a-c were reduced
with lithium aluminum hydride into diols 4a-c, thus setting
the stage for the Grob fragmentation.
Diols 4a-c were converted into the fragmentation precursors
6a-c by regioselective mesylation and further used without
purification (Scheme 4). After some experimentation, it was
found that KOH in benzene, in the presence of 18-crown-6,
gives clean fragmentation reactions with 6.24 It turned out that
the outcome of the reaction depends on the relative stereochem-
istry of the hydroxyl and the leaving group in 6a-c. Thus, 6a-c
trans all afforded the desired cycloalkenone products 7a-c in
good yields. No positional, nor stereochemical, isomerization
of the alkene bond was observed. On the contrary, under the
same reaction conditions, 6b-c cis underwent cyclization, which
gave rise to propellane-type oxetanes 8b,c. This outcome is not
surprising given that, as a rule, an anti-periplanar conformation
of the reaction centers is required for the Grob fragmentation
to proceed successfully.25 The conclusion that can be drawn
from these experiments is the following: if the fragmentation
step is envisaged to be accomplished by Grob fragmentation,
the synthesis of the fragmentation precursors has to be stereo-
selective, as, although the two stereocenters in 2-4 are not
retained in the final products, the trans-configuration is required
for the successful second step.
Alternatively, the fragmentation step can be accomplished
under retro-aldol conditions. In this way, the mechanistic
bifurcation associated with diastereoisomeric fragmentation
precursors (as shown in Scheme 4) is avoided. Thus, when
submitted to the action of potassium hexamethyldisilazide at
-78 °C, 3d afforded the macrocyclic product 9 in good yield
(Scheme 5).26 However, this possibility is restricted to large
of cyclic â-ketoesters of various sizes,20 followed by allylation
of carbonyl group in 1, afforded the required dienes 2a-d in
good yields. Cyclododecanone derivative 1d proved unreactive
toward the allylzinc reagent, and the Grignard reagent had to
be used instead. With the exception of 2a,21 all the other dienes
2b-d were obtained as mixtures of diastereoisomers, which
were separated by column chromatography. No attempt was
made to improve the stereoselectivity of the allylation, as the
relationship between stereochemistry and reactivity of compound
2 was also one of the issues to be studied. On exposure to Ru
catalyst 5a22 or 5b,23 all the substrates afforded the bicyclic
(23) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953.
(24) Other bases, such as DBU, NaH, or metal alkoxides, were not
successful.
(25) However, examples are known where the fragmentation is successful
even when this stereoelectronic requirement is not fulfilled; for a review
article on Grob fragmentation, see: Weyerstahl, P.; Marschall, H. In
ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon
Press: Oxford, U.K., 1991; Vol. 6, p 1041.
(26) Other bases, such as potassium ethoxide, potassium tert-butoxide,
sodium hydride, DBU, potassium carbonate/18-crown-6, or potassium
hydroxide/18-crown-6, were unsuccessful.
(20) (a) Aburel, P. S.; Romming, C.; Ma, K.; Undheim, K. J. Chem.
Soc., Perkin Trans. 1 2001, 1458. (b) Fraga, C. A. M.; Teixeira, L. H. P.;
Menezes, C. M.; Sant’Anna, C. M. R.; Conceicao, M.; Ramos, K. V.; de
Aquino Neto, F.; Barreiro, E. J. Tetrahedron 2004, 60, 2745.
(21) Molander, G. A.; Harris, C. R. J. Am. Chem. Soc. 1995, 117, 3705.
(22) Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1996,
118, 110.
J. Org. Chem, Vol. 71, No. 25, 2006 9413

Ivkovic et al.
SCHEME 5
SCHEME 7
SCHEME 6
diol 12 was first oxidized to ketol 15 (Scheme 7). Upon
submission to the conditions of the hypoiodite reaction, 15 was
smoothly converted into the iodo-derivative 16. Importantly,
no isomerization of the alkene double bond took place under
the reaction conditions.
These preliminary results encouraged us to apply the RCM/
fragmentation method in the synthesis of more complex systems,
such as macrocyclic semiochemicals.32 We turned our attention
toward a group of cyclic sesquiterpenes known as periplanoness
sex pheromones of the American cockroach, Periplaneta
americanaswhich attracted considerable interest from synthetic
chemists.33 The periplanone C 17 appeared to us as a challenging
rings, where the equilibrium between the bicyclic precursor and
the retro-aldol product favors the latter.27
For transformation 2, Scheme 2, the model compound 12 was
prepared as displayed in Scheme 6. The reaction of cyclohex-
anone silylenol ether with crotonaldehyde, under modified
Mukaiyama conditions, afforded the diastereomeric mixture of
silylated aldol products 10 syn and 10 anti.28 Allylation of these
compounds proceeded stereoselectively to give dienes 11.29
Upon submission to the first generation Grubbs’ catalyst 5a,
both isomers of 11 cyclized to give, after deprotection, diols
12 syn and 12 anti.29 Surprisingly, when submitted to the
conditions of Grob fragmentation, both diastereoisomers of 13
afforded the same oxetane derivative, 14. Apparently, the allylic
mesylate gave rise to a carbocation, which underwent substitu-
tion much faster than â-fragmentation.30
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-
methylene group.34 In addition, the total synthesis of periplanone
(30) These results were obtained with the stereochemically defined
isomers 12 syn and 12 anti, purified by column chromatography and
separately characterized. The whole sequence of reactions was also
performed with the diastereomeric mixture, without the separation of the
isomers, with similar results.
(31) (a) Saicic, R. N. Tetrahedron Lett. 1997, 38, 295. (b) Saicic, R. N.;
Cekovic, Z. J. Serb. Chem. Soc. 1997, 62, 727.
Therefore, in this case, we recurred to free-radical means to
effect the fragmentation step (path 3, Scheme 2).31 To this aim,
(32) Czyzewska, E.; Oehlschlager, A. C. In Studies in Natural Products
Chemistry; Atta-ur-Rahman, Ed.; Elsevier: Amsterdam, 1991; Vol. 8, p.
219.
(33) (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, Germany, 1996; Chapters 13 and 21.
(34) 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.
(27) In the case of compounds 3a-c, the bicyclic system is thermody-
namically favored and the fragmentation step cannot be performed as a
simple retro-aldol reaction.
(28) Hirama, M.; Noda, T.; Takeishi, S.; Ito, S. Bull. Chem. Soc. Jpn.
1988, 61, 2645.
(29) The stereochemistry of compounds 11 and 12 was established in
the following way: on oxidation with PDC both 12 syn and 12 anti were
converted into the same ketone (15); this compound was then subjected to
hydrogenation of the alkene bond over Pd/C to give the trans-decalone
derivative described in the literature: Wharton, P. S.; Hiegel, G. A. J. Org.
Chem. 1965, 30, 3254. See the Supporting Information for details.
9414 J. Org. Chem., Vol. 71, No. 25, 2006

Total Synthesis of (()-Periplanone C
SCHEME 8. Retrosynthetic Analysis of Periplanone C
Although the stereochemical information contained in 23 and
24 are not transferred to the final product (the methoxycarbonyl
bearing stereocenters in 23-26, as well as the tertiary alcohol
stereocenter in 24-26, are destroyed in the fragmentation step),
the stereochemical outcome of both reactionssBirch reductive
alkylation of 22 and carbonyl allylation of 23sis important for
the success of synthesis. The predominant stereoisomer 23 in
the Birch allylation reaction arises from the attack of the allyl
bromide to the less hindered (trans to the isopropyl group) face
of the intermediate ester enolate. The stereochemistry of the
carbonyl allylation reaction of 23 can be predicted according
to the model proposed by Molander.21 Notably, of all four
theoretically possible stereoisomeric products for 24 of the two
reactions, only the stereoisomer 24 represented in Scheme 9
can be transformed into the desired macrocycle 28. The model
studies with the compound lacking the isopropyl side chain have
shown that isomer 30, with the cis stereochemistry of the
hydroxyl and mesyloxy groups, affords the oxetane type product
31 under the conditions of the Grob fragmentation (Scheme
10).39 In turn, when subjected to the conditions of RCM, 24
epi did not undergo cyclization, even after prolonged reaction
times, as the trans-diaxial configuration of the two allyl groups
precludes the cyclization of this diastereoisomer.
The sensitive nature of 28 severely restricted the choice of
methods available for effecting the penultimate synthetic steps
the regioselective isomerization of the (Z)-double bond of the
conjugated diene moiety (Scheme 9). 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.
C would also constitute formal syntheses of the periplanones
A35 and D.36
Our retrosynthetic analysis of periplanone C is outlined in
Scheme 8. Mannich disconnection and selective alkene isomer-
ization in 17 pave the way for the application of the fragmenta-
tion transform that converts the 10-membered ring into the
unsaturated condensed bicycle 18, on its turn obtainable by
RCM. The precursor for the metathesis reaction could be
prepared by the allylation of the carbonyl group in the
unsaturated â-ketoester 19; this latter compound would be
assembled from the aromatic ester 20 by the alkylative Birch
reduction.
The synthesis, displayed in Scheme 9, commenced with
regioselective ortho-lithiation of the anisole derivative 21, which,
after carboxylation and esterification, gave ester 22.37 The Birch
reduction of 22 with potassium, followed by quenching of the
corresponding lithium enolate with allyl bromide38 and in situ
hydrolysis, furnished the required cyclic â-ketoester 23, as a
mixture of diastereoisomers in a 7:1 ratio. The allylation of the
carbonyl group in 23 was performed with the allyl zinc reagent,
prepared in situ in DMF, to give the RCM precursor 24 as a
single stereoisomer. Upon exposure to 3 mol % of the first
generation Ru-catalyst 5a, diene 24 was smoothly converted
into the bicyclic intermediate 25. The scission of the central
bond in the condensed bicycle 25 was envisioned to occur via
Grob fragmentation (under ionic conditions). To this end, ester
25 was reduced with lithium aluminum hydride, followed by
the regioselective mesylation of the primary hydroxyl group in
26. Mesylate 27 was not purified but was submitted directly to
the action of powdered potassium hydroxide in benzene, in the
presence of 18-crown-6, to give the required cyclodecadienone
intermediate 28 as a single geometrical isomer.
Not unexpectedly, under the conditions of photochemical
isomerization, 28 underwent transannular [2+2] photocycload-
dition to yield the 8-exo-methylenetricyclo[4.4.0.07,10]decan-3-
one derivative 32 (Scheme 11). Therefore, we envisaged to
accomplish the necessary transformation by using a free radical
methodology. Although extensively studied theoretically, radical
isomerizations of alkenes have seldom been used in synthesis.40
The exo-methylene group in 28 being the most reactive site for
the radical attack, we hoped that the selective (E) f (Z)
isomerization of the 1,3-butadiene unit would take place by a
reversible addition/elimination of thiyl radicals, via the corre-
sponding allylic radical. This approach was not devoid of
pitfalls, however, as the related systems were reported to
undergo positional and geometrical isomerization of noncon-
jugated olefinic bonds via the reversible radical addition, or
hydrogen atom abstraction.41 The latter reaction was especially
threatening, in light of the known propensity of thiyl radicals
to effect polarity reversal catalysis in hydrogen abstraction
reactions.42 In addition, the intermediary allylic radical could
engage into a transannular cyclization, leading to unwanted
isomerization of the nonconjugated alkene through the cyclo-
propylmethyl/butenyl rearrangement. Much to our pleasure, the
(39) In this case, the fragmentation step could be performed under radical
conditions, which would require some additional steps though.
(40) A review article on the alkene (E)-(Z) isomerization: Dugave, C.;
Demange, L. Chem. ReV. 2003, 103, 2475.
(41) Ferreri, C.; Costantino, C.; Perrotta, L.; Landi, L.; Mulazzani, Q.
G.; Chatgilialoglu, C. J. Am. Chem. Soc. 2001, 123, 4459.
(42) Triene 28 possesses four allylic hydrogen atoms sterically available
for the abstraction, both electron-deficient (R to the carbonyl group) and
electron-rich (R to the exo-methylene group). For a review article on polarity
reversal catalysis in hydrogen abstraction reactions, see: Roberts, B. P.
Chem. Soc. ReV. 1999, 28, 25.
(35) Hofmeister, P.; Krieg, W.; Neudert, R.; Hauptmann, H. U.S. Patent
4,939,275.
(36) Biendl, M.; Hauptmann, H.; Sass, H. Tetrahedron Lett. 1989, 30,
2367.
(37) Shirley, D. A.; Harmon, T. E.; Cheng, C. F. J. Organometal. Chem.
1974, 69, 323.
(38) Hook, J. M.; Mander, L. N.; Woolias, M. Tetrahedron Lett. 1982,
23, 1095.
J. Org. Chem, Vol. 71, No. 25, 2006 9415

Ivkovic et al.
SCHEME 9. Synthesis of Periplanone C
SCHEME 10
with compound 29 should be secured by the synergetic action
of two effects: the allylic activation of the R-position and the
deactivation of the R′-position by the steric hindrance of the
adjacent isopropyl group. Much to our disappointment, 29
proved unreactive toward TAMAsthe reagent reported to effect
methylenation under essentially neutral conditions.44 Therefore,
notwithstanding the risk of side reactions, the reaction had to
be performed with the preformed metal enolate,45 where the
positional and configurational integrity of the (Z)-double bond
was hoped to be preserved by operating at low temperature.
Indeed, when the lithium enolate of 29 was treated with an
excess of the Eschenmoser’s reagent at -78 °C, the aminom-
ethylation was followed by spontaneous elimination of dim-
ethylamine to give periplanone C.46 Its transformation into
periplanones A and D has been reported previously.35,36
To summarize, we have shown that the combination of RCM
and â-fragmentation offers an expedient, stereoselective entry
into medium-sized (Z)-cycloalkenes. The fragmentation step can
be effected under either anionic or radical conditions, which
adds to the versatility of the procedure, whose applicability is
demonstrated in the total synthesis of (()-periplanone C.
SCHEME 11
Experimental Section
irradiation of 28 with visible light in the presence of a catalytic
amount of diphenyl disulfide brought about a smooth conversion
into 29. Although the equilibrium established at the isomer ratio
28:29 was 3:2, the yield calculated on the basis of the converted
28 was virtually quantitative, and the isomers could be easily
separated by column chromatography on silver nitrate impreg-
nated silica gel (SNIS).43
Ethyl cis- and trans-2-Hydroxy-1,2-bis(2-propenyl)cyclodode-
canecarboxylate (2d cis and 2d trans). To a cold (-78 °C) solution
of ethyl 1-(2-propenyl)-2-oxocyclododecanecarboxylate (400 mg,
1.36 mmol) in diethyl ether (8 mL) was added a solution of
allylmagnesium bromide (3.36 g, 23 mmol) in diethyl ether (20
mL) dropwise with stirring under an argon atmosphere. Upon
completion of the reaction, water (10 mL) was added, and the
To the best of our knowledge, the regioselective Mannich
methylenation of nonsymmetrical ketones possessing methylene
groups in both R- and R′-positions was without literature
precedent. We believed that the regioselectivity of the reaction
(44) (a) Gras, J.-L. Tetrahedron Lett. 1978, 2111. (b) Gras, J.-L. Org.
Synth. Coll. Vol. VII, 332.
(45) Roberts, J. L.; Borromeo, P. S.; Poulter, C. D. Tetrahedron Lett.
1977, 1621.
(46) 1H NMR and IR spectra identical to those reported for the naturally
occurring compound (ref 36). 13C NMR spectrum identical to the spectrum
previously reported in ref 34c.
(43) A review article on SNIS: Williams, C. M.; Mander, L. N.
Tetrahedron 2001, 57, 425.
9416 J. Org. Chem., Vol. 71, No. 25, 2006

Total Synthesis of (()-Periplanone C
reaction mixture was allowed to reach room temperature (rt).
Extraction with dichloromethane (3 × 50 mL), followed by drying
over anhydrous magnesium sulfate, concentration under reduced
pressure, and purification by low-pressure liquid chromatography
(LPLC) (eluent: 1.25% ethyl acetate in petroleum ether, with 0.75%
triethylamine added to the eluent) afforded 140 mg (37%) of trans-
ethyl 1,2-diallyl-2-hydroxycyclododecanecarboxylate (2d trans)
(eluted first), followed by 240 mg (46%) of cis-ethyl 1,2-diallyl-
2-hydroxycyclododecanecarboxylate (2d cis).
Ethyl trans-12-Hydroxybicyclo[10.4.0]hexadec-14-ene-1-car-
boxylate (3d trans). To a solution of 2d trans (150 mg, 0.446
mmol) in deaerated dichloromethane (3 mL) was added catalyst
5a (11 mg, 13.4 µmol), and the reaction mixture was stirred at rt
for 4 h under an argon atmosphere. Lead tetraacetate (9 mg, 0.02
mmol) was added, and the mixture was stirred at rt overnight. The
suspension was filtered through a short pad of silica, the pad was
washed with dichloromethane, and the combined organic extract
was concentrated under reduced pressure and purified by dry-flash
chromatography (eluent: petroleum ether:ethyl acetate ) 975:25)
to give 120 mg (87%) of the title compound 3d trans.
Physical data for 2d trans. Colorless oil. IR (film, cm-1): 2977,
1
2927, 2863, 1696, 1446, 1221, 1161, 913. H NMR (δ): 5.83-
6.07 (m, 2H); 4.99-5.14 (m, 4H); 4.18 (q, J ) 7.1, 2H); 3.74 (s,
1H, OH); 2.27-2.69 (m, 4H); 1.88-1.16 (m, 23H). 13C NMR (δ):
176.7 (C); 136.3 (CH); 134.9 (CH); 117.7 (CH2); 117.1 (CH2); 77.7
(C); 60.7 (CH2); 57.1 (C); 42.3 (CH2); 38.1 (CH2); 34.3 (CH2);
33.5 (CH2); 26.9 (CH2); 26.4 (CH2); 24.8 (CH2); 24.5 (CH2); 23.5
(CH2); 23.3 (CH2); 23.0 (CH2); 21.5 (CH2); 14.1 (CH3). HRMS
(ESI): calcd for C21H36O3Na, 359.2562; found, 359.2563.
Physical data for 3d trans. Colorless oil. IR (film, cm-1): 2929,
1
2862, 1725, 1180. H NMR (δ): 5.77-5.65 (m, 1H); 5.49-5.61
(m, 1H); 4.10 (q, J ) 7.1, 2H); 2.42-2.68 (m, 2H); 2.16-2.32
(m, 1H); 0.92-2.07 (m, 25H). 13C NMR (δ): 174.9 (C); 126.4
(CH); 124.8 (CH); 73.2 (C); 60.0 (CH2); 52.8 (C); 37.3 (CH2); 35.5
(CH2); 33.7 (CH2); 32.9 (CH2); 26.8 (CH2); 26.2 (CH2); 26.1 (CH2);
23.7 (CH2); 23.4 (CH2); 23.1 (CH2); 22.1 (CH2); 21.4 (CH2); 14.2
(CH3). HRMS (ESI): calcd for C19H32O3Na, 331.2249; found,
331.2241.
Physical data for 2d cis. Colorless oil. IR (film, cm-1): 2980,
1
2929, 2864, 1721, 1471, 1446, 1220, 1160, 1029, 1001, 915. H
NMR (δ): 6.05-5.68 (m, 2H); 5.18-4.98 (m, 4H); 4.15, (J )
6.8, 2H); 3.09 (s, 1H, OH); 2.65-2.84 (dd, J1 ) 14.3, J2 ) 7.2,
1H); 2.44-2.60 (dd, J1 ) 14.3, J2 ) 7.2, 1H); 2.30-2.44 (dd, J1
) 14.3, J2 ) 7.2, 1H); 1.90-2.20 (m, 2H); 1.14-1.89 (m, 22H).
13C NMR (δ): 176.5 (C); 135.5 (CH); 134.5 (CH); 118.0 (CH2);
117.8 (CH2); 77.2 (C); 60.8 (CH2); 58.2 (C); 41.9 (CH2); 34.7
(CH2); 34.6 (CH2); 30.2 (CH2); 26.6 (CH2); 26.4 (CH2); 24.1 (CH2);
24.0 (CH2); 23.0 (CH2); 22.6 (CH2); 21.4 (CH2); 20.9 (CH2); 14.1
(CH3). HRMS (ESI): calcd for C21H36O3Na, 359.2562; found,
359.2547.
(Z)-6-Methylenecyclonon-3-ene-1-one (7a) (Ring Expansion
by Grob Fragmentation). Mesyl chloride (56 µL, 0.71 mmol) was
added to a cold (-15 °C) solution of 4a (100 mg, 0.59 mmol) and
triethylamine (125 µL, 0.89 mmol) in dichloromethane (4.3 mL)
with stirring under an argon atmosphere. After 25 min, diethyl ether
(6 mL) and saturated aqueous NaHCO3 (6 mL) were added and
vigorous stirring was continued for 10 min. The aqueous layer was
extracted with ether, the combined organic extract was washed with
brine, dried over anhydrous MgSO4, and concentrated under reduced
pressure to give the crude mesylate 6a trans, which was used in
the next step without purification.
Ethyl cis- and trans-Bicyclo[4.4.0]dec-3-en-6-ol-1-carboxylate
(3b cis and 3b trans) (Ring Closing Metathesis of 2b). To a
solution of compound 2b (660 mg, 2.62 mmol) in dichloromethane
(15.6 mL), previously deaerated in an ultrasonic bath under a stream
of argon, was added catalyst 5a (22.2 mg, 26 µmol, 0.75 mol %),
and the reaction mixture was heated to reflux under an argon
atmosphere. After 1.5 h, an additional amount of catalyst 5a (15.2
mg, 18 µmol) was added, and after 2.5 h, a second supplementary
amount of catalyst 5a (15.2 mg, 18 µmol) was added. After 6 h,
the reaction was complete. The reaction was allowed to cool, lead
tetraacetate (46.6 mg, 0.105 mmol) was added, and the mixture
was stirred at rt for 7 h. The suspension was filtered through a
short pad of silica, the pad was washed with dichloromethane and
ethyl acetate, and the combined organic extract was concentrated
under reduced pressure and purified by dry-flash chromatography
(eluent: toluene:ethyl acetate ) 97:3) to give 293 mg (50%) of
the title compound 3b as a mixture of diastereoisomers. The
diastereoisomers were separated by LPLC (eluent: petroleum ether:
ethyl acetate ) 95:5) to give 128 mg of 3b cis and 146 mg of 3b
trans.
18-Crown-6 (550 mg, 2.1 mmol) was added to a benzene (15.4
mL) solution of mesylate 6a trans from the previous step. To this
solution was added finely powdered KOH (84.6 mg, 1.51 mmol),
and the mixture was stirred for 4.5 h at rt. Upon dilution with
dichloromethane and water, the layers were separated, the aqueous
layer was extracted with dichloromethane, and the combined organic
extract was dried over anhydrous MgSO4 and carefully concentrated
under reduced pressure (the compound is highly volatile). The
mixture was purified by dry-flash chromatography (eluent: pentane:
diethyl ether ) 95:5) to give 51 mg (57%) of the title compound
7a. An analytical sample of 7a was obtained by preparative gas
chromatography.
Physical data for 7a. Light yellow oil. IR (film, cm-1) 3071,
3023, 2931, 2860, 1704, 1602, 1444. 1H NMR (δ): 5.63-5.79 (m,
2H); 4.82 (d, J ) 1.1, 2H); 3.18 (dd, J1 ) 15.4, J2 ) 9.2, 2H);
2.92 (dd, J1 ) 15.4, J2 ) 9.2, 2H); 2.47-2.53 (m, 2H); 2.10-2.20
(m, 2H) 1.80-1.92 (m, 2H). 13C NMR (δ): 147.0 (C); 131.9 (CH);
123.4 (CH); 113.6 (CH2); 42.6 (CH2); 42.6 (CH2); 35.0 (CH2); 34.2
(CH2); 24.6 (CH2); the peak corresponding to the carbonyl group
was not detected under the recording conditions. HRMS (ESI):
calcd for C10H14ONa, 173.0942; found, 173.0945.
When the reaction was performed with catalyst 5b, in boiling
benzene, the title compound was isolated in 88% yield (as a mixture
of diastereoisomers).
11-Oxatricyclo[4.4.2.01,6]dodec-3-ene (8b). Mesyl chloride (50
µL, 0.66 mmol) was added to a cold (-15 °C) solution of 4b cis
(100 mg, 0.55 mmol) and triethylamine (115 µL, 0.82 mmol) in
dichloromethane (3.9 mL) with stirring under an argon atmosphere.
After 30 min, diethyl ether (6 mL) and saturated aqueous NaHCO3
(6 mL) were added and the mixture was vigorously stirred for 10
min. The aqueous layer was extracted with ether, the combined
organic extract was washed with brine, dried over anhydrous
MgSO4, and concentrated under reduced pressure to give the crude
mesylate 6b cis, which was used in the next step without
purification.
18-Crown-6 (461 mg, 1.75 mmol) was added to a benzene (12.9
mL) solution of mesylate 6b cis from the previous step. To this
solution was added finely powdered KOH (70 mg, 1.25 mmol),
and the mixture was stirred for 4.5 h at rt. Upon dilution with
dichloromethane and water, the layers were separated, the aqueous
layer was extracted with dichloromethane, and the combined organic
Physical data for 3b cis. Colorless oil. Anal. Calcd for
C13H20O3: C, 69.61; H, 8.99. Found: C, 70.04; H, 9.29. IR (film,
cm-1): 3510, 3028, 2942, 2866, 1702, 1451, 1394, 1299. 1H NMR
(δ): 5.52-5.64 (m, 2H); 4.48 (bs, 1H); 4.18 (q, J ) 7.0, 2H); 2.22-
2.62 (m, 4H); 1.98-2.10 (m, 2H); 1.72-1.78 (m, 2H); 1.35-1.64
(m, 4H); 1.27 (t, J ) 7.0, 3H). 13C NMR (δ): 178.6 (C); 124.6
(CH); 123.0 (CH); 70.6 (C); 60.7 (CH2); 49.1 (CH2); 34.8 (2 ×
CH2); 31.8 (CH2); 30.6 (CH2); 21.7 (2 × CH2); 14.0 (CH3).
Physical data for 3b trans. Colorless oil. Anal. Calcd for
C13H20O3: C, 69.61; H, 8.99. Found: C, 69.20; H, 9.31. IR (KBr,
1
cm-1): 3545, 3026, 2958, 2933, 2860. H NMR (δ): 5.54-5.70
(m, 2H), 4.11 (q, J ) 7.0, 1H); 4.09 (q, J ) 7.0, 1H); 2.75-2.90
(m, 1H); 2.45 (dd, J1 ) 16.8, J2 ) 4.0, 1H); 1.52-2.24 (m, 11H);
1.23 (t, J ) 7.0, 3H). 13C NMR (δ): 175.0 (C); 125.3 (CH); 124.9
(CH); 70.1 (C); 60.1 (CH2); 49.5 (C); 38.4 (CH2); 34.2 (CH2); 33.1
(CH2); 32.1 (CH2); 22.8 (CH2); 21.3 (CH2); 14.1 (CH3).
J. Org. Chem, Vol. 71, No. 25, 2006 9417

Ivkovic et al.
extract was dried over anhydrous MgSO4 and carefully concentrated
under reduced pressure (the compound is highly volatile). The
mixture was purified by dry-flash chromatography (eluent: pentane:
diethyl ether ) 9:1) to give 41 mg (50%) of the title compound
8b.
temperature, and then the cooling bath was removed and the
ammonia left to evaporate. The reaction mixture was diluted with
a saturated aqueous NH4Cl solution (30 mL) and extracted with
dichloromethane (3 × 50 mL). The organic extract was dried over
anhydrous Na2SO4, filtered off, and concentrated under reduced
pressure. The crude residue (967 mg) was purified by dry-flash
chromatography (eluent: petroleum ether:acetone ) 985:15) to
obtain the corresponding enol ether (methyl 1-allyl-4-isopropyl-2-
methoxycyclohexa-2,5-dienecarboxylate, 714 mg). This compound
was dissolved in acetone (5 mL), cooled to 4 °C, and concentrated
HCl (1 mL) was added with stirring. After 1 min, the reaction
mixture was neutralized by careful addition of NaHCO3 (990 mg),
concentrated under reduced pressure, diluted with water, and
extracted with dichloromethane (3 × 50 mL). The organic extract
was dried over anhydrous Na2SO4, filtered off, and concentrated
under reduced pressure. Purification of the crude product (675 mg)
by dry-flash chromatography (eluent: petroleum ether:diethyl ether
) 96:4) afforded the title compound 23 (408 mg, 39%), followed
by the more polar trans-isomer (methyl cis-1-allyl-r-4-isopropyl-
6-oxocyclohex-2-enecarboxylate, 60 mg, 6%).
Physical data for 8b. Light yellow liquid. Anal. Calcd for
C11H16O: C, 80.44; H, 9.82. Found: C, 80.21; H, 10.06. IR (film,
1
cm-1): 3034, 2918, 2869, 1452, 1382, 1343, 1269. H NMR (δ):
5.94-6.10 (m, 2H); 4.35 (d, J ) 5.5, 1H); 4.12 (d, J ) 5.5, 1H);
2.16-2.26 (m, 1H); 1.19-2.06 (m, 11H). 13C NMR (δ): 128.2
(CH); 127.0 (CH); 87.4 (C); 75.5 (CH2); 47.3 (C); 36.0 (CH2); 33.3
(CH2); 32.9 (CH2); 29.9 (CH2); 17.8 (CH2); 17.0 (CH2).
(Z)-Ethyl 6-Oxocyclohexadec-3-enecarboxylate (9) (Ring Ex-
pansion by a Retro-aldol Reaction). KHMDS (130 µL of the 0.5
M solution in THF, 64.8 µmol, 2 equiv) was added to a cold (-78
°C) solution of 3d (10 mg, 32.4 µmol, equimolar mixture of cis
and trans isomers) and 18-crown-6 (catalytic amount) in THF (1
mL), and the resulting solution was stirred for 20 min under an
argon atmosphere. The reaction was quenched by the addition of
water (1 mL) and extracted with dichloromethane (3 × 10 mL);
the organic layer was washed with water (10 mL), dried over
anhydrous MgSO4, concentated under reduced pressure, and the
residue was purified by dry-flash chromatography (eluent: petro-
leum ether:ethyl acetate ) 95:5) to give 7.4 mg (74%) of the title
compound 9.
Alternatively, the transmetalation with LiBr can be omitted (the
rest of the experimental procedure remains identical), which results
in an improved overall yield (56%) but with lower stereoselectivity
(cis:trans ) 4:1).
Physical data for 23. Pale-yellow oil. Anal. Calcd for C14H20O3:
Physical data for 9. Colorless oil. Anal. Calcd for C19H32O3: C,
C, 71.16; H, 8.53. Found: C, 70.93; H, 8.74. IR (film, cm-1): 2960,
73.98; H, 10.46. Found: C, 74.25; H, 10.59. IR (film, cm-1): 2931,
1
2876, 1740, 1722, 1642, 1435, 1233, 1133. H NMR (δ): 5.94
1
2859, 1726, 1454, 1374, 1266, 1172, 1038. H NMR (δ): 5.48-
(dd, J1 ) 10.0, J2 ) 2.2, 1H); 5.24 (dd, J1 ) 10.0, J2 ) 2.2, 1H);
5.72-5.55 (m, 1H); 5.13-5.02 (m, 2H); 3.71 (s, 3H); 2.71 (dd, J1
) 13.7, J2 ) 7.5, 1H); 2.58 (dd, J1 ) 13.7, J2 ) 6.9, 1H); 2.53-
2.35 (m, 3H); 1.81-1.68 (m, 1H); 0.94 (d, J ) 2.0, 3H); 0.91 (d,
J ) 2.1, 3H). 13C NMR (δ): 206.4 (C); 170.9 (C); 132.8 (CH);
132.7 (CH); 128.0 (CH); 118.8 (CH2); 59.7 (C); 52.5 (CH3); 43.8
(CH); 41.0 (CH2); 38.7 (CH2); 31.8 (CH); 19.1 (CH3); 18.6 (CH3).
5.75 (m, 2H); 4.16 (q, J ) 7.0, 2H); 3.36 (dd, J1 ) 17.0, J2 ) 8.2,
1H); 3.06 (dd, J1 ) 17.0, J2 ) 5.2, 1H); 2.22-2.51 (m, 5H); 1.40-
1.80 (m, 4 H); 1.30-1.40 (br s, 14H); 1.27 (t, J ) 7.0, 3H). 13C
NMR (δ): 208.9 (C); 175.7 (C); 130.0 (CH); 123.4 (CH); 60.2
(CH2); 44.4 (CH); 41.7 (CH2); 41.2 (CH2); 30.2 (CH2); 29.4 (CH2);
26.9 (CH2); 26.8 (CH2); 26.1 (CH2); 25.8 (CH2); 25.6 (CH2); 25.4
(CH2); 22.6 (CH2); 14.2 (CH3); two peaks of methylene carbon
atoms are superimposed.
Methyl cis-1-trans-6-Diallyl-6-hydroxy-r-4-isopropylcyclohex-
2-enecarboxylate (24). To a solution of 23 (194 mg, 0.822 mmol)
and allyl bromide (149 mg, 1.23 mmol) in DMF (0.64 mL) was
added Zn powder (80 mg, 1.22 mmol) in one portion with stirring.
The reaction mixture was stirred for 20 h, then diluted with saturated
aqueous NH4Cl (10 mL), and extracted with dichloromethane (3
× 50 mL). The organic extract was washed with water, dried over
anhydrous Na2SO4, filtered off, and concentrated under reduced
pressure. Purification of the crude residue (225 mg) by dry-flash
chromatography (eluent: petroleum ether:ethyl acetate ) 97:3)
afforded the title compound 24 (204 mg, 89%).
Physical data for 24. Colorless oil. Anal. Calcd for C17H26O3:
C, 73.34; H 9.41. Found: C, 73.16; H, 9.15. IR (film, cm-1): 3539,
2957, 1725, 1640, 1438, 1218, 1001. 1H NMR (δ): 6.01-5.60 (m,
4H); 5.21-5.08 (m, 4H); 3.67 (s, 3H); 2.87 (dd, J1 ) 13.9, J2 )
5.8, 1H); 2.61 (dd, J1 ) 14.2, J2 ) 6.7, 1H); 2.37 (dd, J1 ) 13.9,
J2 ) 8.8, 1H); 2.19-2.05 (m, 2H); 1.98 (s, 1H); 1.84-1.66 (m,
2H); 1.57 (dd, J1 ) 13.7, J2 ) 10.0, 1H); 0.94 (s, 3H); 0,91 (s,
3H). 13C NMR (δ): 174.0 (C); 134.8 (CH); 133.6 (CH); 131.5 (CH);
126.8 (CH); 119.1 (CH2); 118.7 (CH2); 73.5 (C); 55.4 (C); 51.9
(CH3); 41.5 (CH2); 38.5 (CH); 36.9 (CH2); 32.6 (CH2); 31.4 (CH);
19.5 (CH3); 19.4 (CH3).
trans-1-Hydroxy-cis-6-methoxycarbonyl-r-9-isopropyl-bicyclo-
[4.4.0]deca-3,7-diene (25). Benzylidenebis(tricyclohexylphosphine)-
dichlororuthenium (5a) (6 mg, 7.2 µmol) was added to a solution
of 24 (204 mg, 0.734 mmol) in dichloromethane (3.7 mL), and the
resulting mixture was stirred at room temperature for 15 h. A new
portion of 5a (12 mg, 14.4 µmol) was added, and the mixture was
stirred for an additional 8 h, when TLC indicated that the reaction
was complete. Lead tetraacetate (14.6 mg, 32.9 µmol) was added,
and the resulting suspension was stirred for 12 h. The reaction
mixture was filtered through a plug of silica (1 g), the plug was
washed with dichloromethane (4 × 3 mL), and the organic extract
was concentrated under reduced pressure. Purification by dry-flash
(Z)-10-Iodocyclodec-2-ene-1,5-dione (16) (Ring Expansion by
Radical Fragmentation). Mercuric oxide (88.5 mg, 0.41 mmol)
and iodine (104 mg, 0.41 mg) were added to a solution of 15 (34
mg, 0.205 mmol) in benzene (8 mL). The reaction mixture was
deaerated with a stream of argon and irradiated with a Xenophot
250 W focalized light with vigorous stirring. After 20 min, the
reaction mixture was filtered, diluted with dichloromethane (70 mL),
washed with aqueous sodium thiosulfate (2 × 5 mL) and water
(10 mL), dried over anhydrous MgSO4, and concentrated under
reduced pressure. Purification of the residue by dry-flash chroma-
tography (eluent: 20% ethyl acetate in hexanes) gave 39 mg (65%)
of the title compound 16.
Physical data for 16. Colorless plates, mp 93.5-94 °C. Anal.
Calcd for C10H13IO2: C, 41.12; H, 4.49. Found: C, 41.08; H, 4.29.
IR (KBr, cm-1): 2939, 2858, 1713, 1690, 1626, 1464, 1395, 1292,
1
1243, 1198, 1137, 1102. H NMR (δ): 7.12 (d, J ) 12.0, 1H);
6.11-6.22 (m, 1H); 4.53 (dd, J1 ) 3.7, J2 ) 10.8, 1H); 3.68 (dd,
J1 ) 10.4, J2 ) 15.8, 1H); 3.20 (dd, J1 ) 7.1, J2 ) 15.8, 1H);
2.16-2.58 (m, 4H); 1.56-1.68 (m, 4H). 13C NMR (δ): 200.7;
200.2; 134.7; 129.7; 41.8; 39.2; 33.7; 31.2; 28.3; 21.5.
Total Synthesis of (()-Periplanone C Methyl cis-1-Allyl-r-
4-isopropyl-6-oxocyclohex-2-enecarboxylate (23) (Reductive Alky-
lation of 22).47 To a cold (-68 °C) solution of 22 (916 mg, 4.4
mmol) in liquid ammonia (36 mL), THF (18 mL), and tert-butanol
was added potassium metal (400 mg, 10.256 mmol) in small pieces
with stirring. After the addition was complete, the reaction mixture
was stirred for an additional 15 min, and then LiBr (840 mg, 9.66
mmol) was added in one portion when the reaction turned from
deep blue to yellow. After 15 min, allyl bromide (2.12 g, 17.6
mmol) was added, the reaction mixture was stirred 30 min at that
(47) Hook, J. M.; Mander, L. N.; Woolias, M. Tetrahedron Lett. 1982,
23, 1095.
9418 J. Org. Chem., Vol. 71, No. 25, 2006

Total Synthesis of (()-Periplanone C
chromatography (eluent: petroleum ether:ethyl acetate ) 95:5)
afforded the title compound 25 (148 mg, 81%).
Physical data for 29. Colorless liquid. IR (film, cm-1): 3078,
3023, 2962, 2876, 1709, 1655, 1615, 1448, 1314, 1257, 1118, 1082,
978. 1H NMR (δ): 5.90 (d, J ) 16.2, 1H); 5.67 (dd, J1 ) 15.9, J2
) 10.1, 1H); 5.71-5.45 (m, 2H); 4.97 (d, J ) 1.3, 1H); 4.76 (d, J
) 1.4, 1H); 3.53 (dd, J1 ) 15.9, J2 ) 10.5, 1H); 3.25-3.14 (m,
1H); 2.80-2.36 (m, 4H); 2.21-2.04 (m, 1H); 1.70-1.53 (m, 1H);
0.93 (d, J ) 4.2, 3H); 0.90 (d, J ) 4.2, 3H). 13C NMR (δ): 211.7
(C); 144.7 (C); 134.8 (CH); 131.0 (CH); 129.7 (CH); 123.4 (CH);
113.0 (CH2); 49.8 (CH2); 47.6 (CH); 43.7 (CH); 35.9 (CH); 32.2
(CH2); 20.1 (CH3); 20.0 (CH3).
Physical data for 25. Colorless oil. Anal. Calcd for C15H22O3:
C, 71.97; H, 8.86. Found: C, 71.79; H, 8.97. IR (film, cm-1): 3525,
1
2957, 1732, 1648, 1462, 1440, 1373, 1277, 1176, 1030. H NMR
(δ): 5.83-5.77 (m, 1H); 5.75-5.58 (m, 2H); 5.48 (dd, J1 ) 10.0,
J2 ) 2.2, 1H); 3.61 (s, 3H); 2.79-2.57 (m, 2H); 2.39-1.97 (m,
5H); 1.79-1.63 (m, 2H); 0.91 (d, J ) 5.5, 3H); 0.87 (d, J ) 5.5,
3H). 13C NMR (δ): 132.9 (CH); 127.9 (CH); 125.9 (CH); 125.2
(CH); 70.4 (C); 51.9 (CH3); 49.8 (C); 39.0 (CH); 37.0 (CH2); 33.3
(CH2); 31.5 (CH); 31.4 (CH2); 19.4 (CH3); 19.0 (CH3). The peak
of the ester carbonyl was not observed under the recording
conditions.
Periplanone C (17) (Regioselective Methylenation of 29).45
To a cold (-20 °C) solution of diisopropylamine (50 mg, 0.492
mmol) in THF (630 µL) was added the solution of n-butyllithium
in hexane (294 µL of the 1.67 M solution, 0.491 mmol). The
solution was stirred for 15 min at that temperature, then cooled to
-78 °C, and the solution of compound 29 (91.3 mg, 0.447 mmol)
in THF (400 µL) was added. HMPA (319 mg, 1.78 mmol) was
added to the solution of the lithium enolate, and the resulting
solution was transferred via cannula to a cold (-78 °C) suspension
of the Eschenmoser’s salt (200 mg, 1.08 mmol) in THF (1 mL).
(In order to secure the quantitative transfer of the enolate, the first
flask was washed with two 250 µL portions of THF.) The reaction
mixture was allowed to reach rt with stirring, when the yellow
suspension went into solution. The reaction was quenched with
saturated aqueous NaHCO3 (10 mL), and the product was extracted
with ethyl acetate (4 × 25 mL). The organic extract was washed
with brine, dried over anhydrous MgSO4, filtered off, and concen-
trated under reduced pressure. The crude residue (430 mg) was
dissolved in diethyl ether (3 mL), methyl iodide (1 mL, 2.275 g,
16.28 mmol) was added, and the reaction mixture was stirred at rt
for 2 h. The solution of NaOAc (1.2 g) in water (7 mL) was added,
and the reaction mixture was vigorously stirred for 1 h. The mixture
was diluted with n-hexane (80 mL) and water (10 mL), the phases
were separated, and the aqueous phase was extracted with n-hexane
(2 × 10 mL). The combined extract was thoroughly washed with
water, dried over anhydrous MgSO4, filtered off, and concentrated
under reduced pressure. Purification of the crude organic residue
(107 mg) by column chromatography (gradient elution with
n-hexane:diethyl ether ) 95:5f9:1) afforded periplanone C 17
(35.3 mg, 36.5%, 53% based on the recovered 29) followed by the
starting compound 29 (28 mg). (The yield of 17, determined by
1H NMR of the crude reaction mixture, calculated on the basis of
the recovered 29, was 84%.)
(3Z,7Z)-9-Isopropyl-6-methylenecyclodeca-3,7-dienone (28).
Methanesulfonyl chloride (49 mg, 0.426 mmol) was added to a
cold (-15 °C) solution of 26 (70 mg, 0.355 mmol) and triethy-
lamine (54 mg, 0.532 mmol) in dichloromethane (1.8 mL) with
stirring. After 1 min, saturated aqueous NaHCO3 (0.5 mL) was
added and the reaction mixture was diluted with diethyl ether (100
mL). The organic extract was thoroughly washed with saturated
aqueous NaHCO3 (4 × 10 mL, 10 min every washing), water, and
brine; dried over anhydrous MgSO4; filtered off; and evaporated
under reduced pressure. The crude product 27 (colorless oil, 109
mg) was used in the next step without further purification. To a
solution of 27 and 18-crown-6 (332 mg; 1.26 mmol) in benzene
(8.8 mL) was added powdered KOH (50.4 mg, 0.9 mmol) with
stirring. After 90 min, saturated aqueous NH4Cl (8 mL) was added,
the reaction mixture was extracted with dichloromethane (5 × 20
mL), and the organic extract was washed with water, dried over
anhydrous Na2SO4, filtered off, and concentrated under reduced
pressure. Purification of the crude residue (100 mg) by dry-flash
chromatography (eluent: petroleum ether:acetone ) 96:4) afforded
the title compound 28 (53.7 mg, 74%).
Physical data for 28. Colorless liquid. Anal. Calcd for C14H22O2
(204.31): C, 75.63; H 9.97. Found: C, 75.17; H, 9.49. IR (film,
cm-1): 3081, 3023, 2961, 2874, 1709, 1656, 1626, 1598, 1465,
1427, 1391, 1317, 897. 1H NMR (δ): 5.85 (d, J ) 11.9, 1H); 5.80-
5.65 (m, 1H); 5.53-5.44 (m, 1H); 5.23 (dd, J1 ) J2 ) 11.6, 1H);
5.10 (s, 1H); 4.98 (s, 1H); 3.85 (dd, J1 ) 15.6, J2 ) 10.7, 1H);
3.34 (dd, J1 ) 16.3, J2 ) 6.3, 1H); 3.20-3.02 (m, 1H); 2.89 (dd,
J1 ) 16.3, J2 ) 6.6, 1H); 2.70-2.48 (m, 2H); 2.22 (dd, J1 ) 13.4,
J2 ) 10.4, 1H); 1.56 (hept, J ) 7.0, 1H); 0.97 (d, J ) 3.2, 3H);
0.93 (d, J ) 3.2, 3H). 13C NMR (δ): 210.6 (C); 144.4 (C); 133.8
(CH); 130.9 (CH); 128.9 (CH); 124.6 (CH); 115.7 (CH2); 50.2
(CH2); 41.2 (CH); 38.4 (CH2); 36.5 (CH2); 33.0 (CH); 20.5 (CH3);
20.4 (CH3).
The compound 17 had IR and 1H and 13C NMR spectra identical
to those described in the literature.36,34c
(3Z,7E)-9-Isopropyl-6-methylenecyclodeca-3,7-dienone (29).
In a Pyrex vessel with external water cooling, a solution of 28 (260
mg, 1.272 mmol) and diphenyl disulfide (5.6 mg, 26 µmol) in
benzene (2.4 mL) was irradiated with a Xenophot 250 W sunlamp
for 10 min. The solvent was evaporated under reduced pressure,
and the residue was purified by dry-flash chromatography on silver
nitrate impregnated silica gel (10% AgNO3 on SiO2, eluent:
petroleum ether:ethyl acetate ) 9:1) to give 28 (eluted first, 150
mg), followed by the title compound 29 (100 mg, 38.5%, 91% based
on the recovered 28) as a colorless liquid. In the repeated
experiments, the yields varied from 85 to 100% with a ratio of
isomers of 29:28 ) 1.2:1-1:1.5.
Acknowledgment. This work was financially supported by
the Ministry of Science and Environmental Protection (project
no. 142021). We are grateful to Professor Jovica Badjic for help
in characterization of several compounds.
Supporting Information Available: Experimental procedures,
characterization data, and copies of spectra for all compounds. This
materialisavailablefreeofchargeviatheInternetathttp://pubs.acs.org.
JO061790J
J. Org. Chem, Vol. 71, No. 25, 2006 9419