A three-component coupling approach to cyclopentanoids

Article abstract of DOI:10.1021/jo010593b

A new approach to 2,3-disubstituted cyclopentenones has been developed. This approach consists of a two-step protocol involving the cyclization of a Z-vinyl bromide under Barbier type conditions to form a cyclopentenol, which is then oxidatively rearranged to generate the cyclopentenone. The Z-vinyl bromide is in turn derived from a ruthenium catalyzed three-component coupling of an alkyne, an enone, and a HBr equivalent. A range of 2,3-disubstituted cyclopentenones has been generated, including short syntheses of jasmone and dihydrojasmone. Further applicability of this strategy is shown in the total syntheses of tetrahydrodicranenone B, rosaprostol, and a selective COX-2 inhibitor.

Full text of DOI:10.1021/jo010593b

7714
J . Org. Chem. 2001, 66, 7714-7722
A Th r ee-Com p on en t Cou p lin g Ap p r oa ch to Cyclop en ta n oid s
Barry M. Trost* and Anthony B. Pinkerton
Department of Chemistry, Stanford University, Stanford, California 94305
bmtrost@stanford.edu
Received J une 12, 2001
A new approach to 2,3-disubstituted cyclopentenones has been developed. This approach consists
of a two-step protocol involving the cyclization of a Z-vinyl bromide under Barbier type conditions
to form a cyclopentenol, which is then oxidatively rearranged to generate the cyclopentenone. The
Z-vinyl bromide is in turn derived from a ruthenium catalyzed three-component coupling of an
alkyne, an enone, and a HBr equivalent. A range of 2,3-disubstituted cyclopentenones has been
generated, including short syntheses of jasmone and dihydrojasmone. Further applicability of this
strategy is shown in the total syntheses of tetrahydrodicranenone B, rosaprostol, and a selective
COX-2 inhibitor.
In tr od u ction
synthetic idea is shown in eq 1. Thus, cyclopentenones
then would derive from three simple building blocks: an
enone, an alkyne, and the equivalent of HBr using a
bromide salt and water as a surrogate.
Cyclopentanoid natural products, such as the jasmon-
ates1 and prostaglandins,2 are a diverse and biologically
significant class of compounds in which there has been
considerable interest. Because of these and other natural
products and pharmaceuticals containing cyclopentyl
structures there has been intense development of meth-
odology to construct such moieties.3,4 Cyclopentenones are
particularly useful precursors for the synthesis of various
cyclopentyl compounds due to the versatility of their
functionality. Because of this versatility, there have
been many methods for their synthesis, including more
classical methods such as the aldol reaction,5 as well
as newer methods such as the Nazarov cyclization,6
the Pauson-Khand reaction,7 and other methods.8 This
paper discusses the development of a synthesis of cyclo-
pentenones from Z-vinyl bromides, which in turn are
derived from a ruthenium catalyzed three-component
coupling as illustrated in Scheme 1.10 The general retro-
Cyclop en ten ol F or m a tion . We initially examined
the cyclization of Z-vinyl bromides, with a 1,5 juxtaposi-
tion between the vinyl bromide moiety and the carbonyl
group, to give cyclopentenols (eq 2). The prospect of using
(1) For a recent review, see: Beale, M. H.; Ward, J . L. Nat. Prod.
Rep. 1998, 533.
(2) The Synthesis of Prostaglandins; Mitra, A.; J . Wiley-Interscience:
New York, 1977. Prostaglandin Synthesis; Bindra, J . S., Bindra, R.;
Academic Press: London, 1977.
a lithium-halogen exchange with an organolithium was
unappealing due to concerns of chemoselectivity. A
Barbier type protocol looked more promising. The con-
ditions of Nozaki and Kishi involving CrCl2 and NiCl2
were most appealing because of their mildness.11 Their
(3) For a few recent references, see: Trost, B. M.; Toste, F. D. J .
Am. Chem. Soc. 2000, 122, 714. Hicks, F. A.; Buchwald, S. L. J . Am.
Chem. Soc. 1999, 121, 7026. Sturla, S. J .; Buchwald, S. L. J . Org. Chem.
1999, 64, 5547. Perch, N. S.; Widenhoefer, R. A. J . Am. Chem. Soc.
1999, 121, 6960. Yamamoto, Y.; Matsumi, D.; Hattori, R.; Itoh, K. J .
Org. Chem. 1999, 64, 3224. Yamamoto, Y.; Ohkoshi, N.; Kameda, M.;
Itoh, K. J . Org. Chem. 1999, 64, 2178. Taber, D. F.; Yu, H.; Incarvito,
C. D.; Rheingold, A. L. J . Am. Chem. Soc. 1998, 120, 13285. Sugihara,
T.; Yamaguchi, M. J . Am. Chem. Soc. 1998, 120, 10782. Belanger, D.
B.; Livinghouse, T. Tetrahedron Lett. 1998, 39, 7637, 7641.
(4) For some reviews, see: Trost, B. M.; Krische, M. J . Synlett 1998,
1. Geis, O.; Schmalz, H. G. Angew. Chem., Int. Ed. 1998, 37, 911.
Kirmse, W. Angew. Chem., Int. Ed. Engl. 1997, 36, 1164. Schore, N.
E. In Comprehensive Orgnometallic Chemistry II; Abel, E. W., Stone,
F. G., Wilkinson, G., Eds.; Elsevier: New York, 1995; Vol. 12, p 703.
Padwa, A.; Krumpe, K. E. Tetrahedron. 1992, 48, 5385.
(7) Pauson, P. L. Tetrahedron 1985, 41, 5855. Schore, N. E. In
Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon Press: Oxford, 1991; Vol. 5, Chapter 9.1, pp 1037-1062.
Hicks, F. A.; Buchwald, S. L. J . Am. Chem. Soc. 1999, 121, 7026. See
also: Sturla, S. J .; Buchwald, S. L. J . Org. Chem. 1999, 64, 5547.
Negishi, E.-I. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 5, Chapter 9.5,
pp 1163-1183.
(8) Bu¨chi, G.; Egger, B. J . Org. Chem. 1971, 36, 2021. Hayakawa,
Y.; Yokoyama, K.; Noyori, R. J . Am. Chem. Soc. 1978, 100, 1799. Trost,
B. M. Angew. Chem., Int. Ed. Engl. 1986, 25, 1.
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50, 4681. Pecunioso, A.; Menicagli, R. J . Org. Chem. 1988, 53, 2614.
(6) Santelli-Rouvier, C.; Santelli, M. Synthesis 1983, 429. Denmark,
S. E. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I.,
Eds.; Pergamon Press: Oxford, 1991; Vol. 5, Chapter 6.3, pp 752-
781. Chenard, B. L.; Van Zyl, C. M.; Sanderson, D. R. Tetrahedron
Lett. 1986, 27, 2801. Hiyama, T.; Shinoda, M.; Tsukanaka, M.; Nozaki,
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(9) A portion of this work has been published: Trost, B. M.;
Pinkerton, A. B. Org. Lett. 2000, 2, 1601. See also: Trost, B. M.;
Pinkerton, A. B. Tetrahedron Lett. 2000, 41, 9627.
(10) Trost, B. M.; Pinkerton, A. B. Angew. Chem., Int. Ed. 2000,
39, 360.
(11) (a) For a review, see: Cintas, P. Synthesis 1992, 248. (b) For a
recent intramolecular example and representative procedure, see:
Chen, X.-T.; Bhattacharya, S. K.; Zhou, B.; Gutteridge, C. E.; Pettus,
T. R. R.; Danishefsky, S. J . J . Am. Chem. Soc. 1999, 121, 6563.
10.1021/jo010593b CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/13/2001

Three-Component Coupling Approach to Cyclopentanoids
J . Org. Chem., Vol. 66, No. 23, 2001 7715
Ta ble 1. F or m a tion of Cyclop en ten ols fr om Z-Vin yl
Sch em e 1. A Ru -Ca ta lyzed Th r ee-Com p on en t
Cou p lin g
Br om id es
Sch em e 2. P r op osed Mech a n ism for th e
Noza k i-Kish i Rea ction
a
i. A 1:1 diastereomeric ratio of cyclopentenols was obtained.
ii. A 23% yield of the dehalogenated olefin was also obtained, as
b
a mixture of isomers. Exclusively the Z-isomer. c Trace amounts
of dehalogenated olefin were observed, along with 20% unreacted
starting material.
1 and 3) can be used as substrates, as well as olefins
(entry 4). Silyl-protected alcohols (entry 2) are compat-
ible. Steric hindrance on the vinyl partner is tolerated
(entries 5-7), as well as on the ketone portion (entries 5
and 7). It should be noted that these cyclopentenol
products are quite sensitive, and even mild acid (for
example deuteriochloroform that has not been basified)
will lead to elimination to the cyclopentadiene. However,
they can be subjected to silica gel chromatography with
no apparent decomposition.
reported failure in intermolecular reactions with ketones
seemed ominous; however, the prospect that such an
acceptor might be better if the reaction were intramo-
lecular induced us to at least try the experiment despite
our reservations. In contrast to the intermolecular reac-
tion, the corresponding intramolecular reaction was
found to work well in these studies. A recent report using
a bipyridyl-based ligand to give efficient intermolecular
reaction with ketones has been disclosed,12 but this was
not necessary in our intramolecular case.
The proposed mechanism for this reaction is shown in
Scheme 2. As shown in the scheme, nickel(0) inserts into
the vinyl halide bond to form vinyl nickel 1. This then
transmetalates to chromium(III) to give vinyl chromium
2, which attacks the carbonyl group to form cyclopentenol
3. The nickel(II) is reduced by chromium(II) to reform
the nickel(0) and chromium(III). One of the reasons that
the ketone substrate may be more reactive in this case
is potential coordination as depicted in 2.
In all cases with Z/ E mixtures, some of the dehaloge-
nated E olefin (which cannot cyclize) is observed. How-
ever, only in the case of entry 2 was a substantial amount
of the dehalogenated E olefin obtained. This could be due
to the bulky O-TBS group slowing the cyclization, as
indeed a mixture of E and Z dehalogenated olefin was
seen. This steric effect is seen in entry 7, where a lower
yield of cyclopentenol was obtained. However, in this case
the lower yield could also be attributable to the instability
of this compound due to the electron rich aromatic ring.
The mildness of the reaction conditions is clearly indi-
cated by the ability to form such products at all consider-
ing their extremely sensitive nature, especially in the
cases of entries 5 and 7.
In general, the cyclopentenols were characterized by
the appearance of an alcohol stretch at approximately
-1
3400 cm
in the IR spectrum. Furthermore, there was
As shown in Table 1, the intramolecular Nozaki-Kishi
cyclization works quite well with a range of substrates
under quite standard conditions. Thus, no optimization
was performed. Saturated aliphatic compounds (entries
the appearance of a characteristic olefin resonance at ∼δ
5.5 in the proton NMR and olefin signals at ∼δ 150 and
∼δ 130 as well as the tertiary alcohol carbon (∼δ 85) in
the carbon NMR spectra. Finally, elemental analysis
confirmed the elemental composition and the lack of
bromine.
(12) Chen, C. Synlett 1998, 1311. See also: Chen, C.; Tagami, K.;
Kishi, Y. J . Org. Chem. 1995, 60, 5386.

7716 J . Org. Chem., Vol. 66, No. 23, 2001
Trost and Pinkerton
Ta ble 2. Syn th esis of Cyclop en ten on es
Sch em e 3. P r op osed Mech a n ism for th e
Oxid a tive Rea r r a n gem en t
Oxid a tive Rea r r a n gem en t of Cyclop en ten ols To
Give Cyclop en ten on es. After formation of the cyclo-
pentenols, we investigated the oxidative rearrangement
of the cyclopentenols to give cyclopentenones. As de-
scribed in the literature, chromium oxidations such as
those using pyridinium dichromate (PDC) in methylene
chloride13 typically effect this transformation. The mech-
anism proposed for this reaction is the initial formation
of the chromate ester 18 from the tertiary alcohol
followed by allylic rearrangement to the chromate ester
of the secondary alcohol (19). Typical fragmentation
of the resultant chromate ester delivers the ketone
(Scheme 3).
J apanese moss Leucobryum scabrum that shows anti-
microbial and antihypertensive properties. Earlier syn-
theses of tetrahydrodicranenone B used five-membered
ring precursors such as methyl jasmonate or 6-methoxy-
indanone. Scheme 4 illustrates a retrosynthetic analysis
that derives from this newly developed cyclopentenone
synthesis.
Following the literature method, the reactions were
run according to eq 3, and the results are summarized
in Table 2. As shown in the table, good yields are obtained
in all cases. In general an excess of PDC (1.5-2 equiv)
was employed.
The first subunit synthesized was the known16 enyne
29. Starting from cis-2-penten-1-ol (31), the alcohol was
mesylated in high yield under standard conditions. This
was followed by a copper(I)-mediated displacement17 by
trimethylsilylacetylene to give the TMS-protected enyne
33, albeit as a 3:1 mixture of the desired product and
the regioisomer resulting from SN2′ addition (determined
by NMR spectroscopy). Lowering the amount of copper
iodide used (from 1 equiv) eventually raised the ratio to
9:1, but at the expense of yield (for example, using 10%
copper iodide, a 9:1 ratio was obtained, but only in 40%
yield). Thus, the 3:1 mixture was used in subsequent
steps. The silyl group was removed using TBAF buffered
with acetic acid (when only TBAF was employed, exten-
sive isomerization to the conjugated product was seen)
to give the volatile enyne 29, which was isolated by
extraction into pentane followed by careful removal of
the pentane via distillation (Scheme 5). Attempts to
remove the silyl group under conditions to facilitate
purification, such as sonicating 33 with aqueous KF in a
variety of solvents were unsuccessful.
The cyclopentenones were readily characterized by the
disappearance of an alcohol stretch in the IR spectrum
and the appearance of an enone stretch at approximately
1700 cm -1. The carbon NMR spectra showed signals
indicative of an enone at ∼δ 210, 170, and 140.
This process represents a novel and convergent method
of five-membered ring synthesis that we felt could be
developed into a general entry into cyclopentanoid natu-
ral products. Table 2, entries 2 and 3, illustrate the
synthesis of dihydrojasmone and jasmone, respectively.
We turned our attention to illustrating this potential
more fully.
Tota l Syn th esis of Cyclop en ta n oid Com p ou n d s.
For our first target, we chose tetrahydrodicranenone B
(26),14,15 a cyclopentenone fatty acid isolated from the
Enone 30 was synthesized in a very straightforward
manner from commercially available azelaic acid monom-
ethyl ester. The acid was converted to the acid chloride
under standard conditions and then subjected without
(13) Dauben, W. G.; Michno, D. M. J . Org. Chem. 1977, 42, 682.
Majetich, G.; Song, J .-S.; Leigh, A. J .; Condon, S. M. J . Org. Chem.
1993, 58, 1030. Majetich, G.; Condon, S.; Hull, K.; Ahmad, S.
Tetrahedron Lett. 1989, 30, 1033.
(14) Sakai, K.; Fujimoto, T.; Yamashita, M.; Kondo, K. Tetrahedron
Lett. 1985, 26, 2089. Ichikawa, T.; Namikawa, M.; Yamada, K.; Sakai,
K.; Kondo, K. Tetrahedron Lett. 1983, 24, 337.
(15) For syntheses, see: Ichikawa, T.; Namikawa, M.; Yamada,
K.; Sakai, K.; Kondo, K. Tetrahedron Lett. 1983, 24, 337. Moody,
C. J .; Roberts, S. M.; Toczek, J . J . Chem. Soc., Chem. Commun. 1986,
1292.
(16) Billington, D. C.; Blandon, P.; Helps, I. M.; Pauson, P. L.;
Thomson, W.; Willison, D. J . Chem. Res. 1988, 10, 2601.
(17) Lapitskaya, M. A.; Vasiljeva, L. L.; Pivnitsky, K. K. Synthesis
1993, 65. A method employing Bu4NCl instead of NaI gave similar
results, see: J effrey, T.; Gueugnot, S.; Linstrumelle, G. Tetrahedron
Lett. 1992, 33, 5757.

Three-Component Coupling Approach to Cyclopentanoids
J . Org. Chem., Vol. 66, No. 23, 2001 7717
Sch em e 4. Retr osyn th etic An a lysis of Tetr a h yd r od icr a n en on e B
Sch em e 5. Syn th esis of En yn e 29
Sch em e 6. Syn th esis of Tetr a h yd r od icr a n en on e B
purification to a Stille coupling18 with tributylvinyl tin
to give enone 30 in an 88% yield over two steps (eq 4).
Scheme 6). Subjecting the two subunits to our standard
conditions10 gave bromide 28 in 69% yield with a Z/ E
ratio of 3.6/1, values which are consistent with our earlier
work. The use of (CH3) 4NBr in place of LiBr gave a Z/ E
ratio of 8.0/1, but in a yield of only 28%. Thus, the 3.6/1
mixture was used. The vinyl bromide was then reacted
under Nozaki-Kishi conditions11 to give an intramolecu-
lar cyclization yielding 73% of cyclopentenol 27. Some of
the dehalogenated cis olefin was observed, presumably
coming from the E-vinyl bromide. The allylic alcohol was
oxidatively rearranged13 to give the cyclopentenone 34
(18) For a representative procedure, see: Darwish, I. S.; Patel, C.;
Miller, M. J . J . Org. Chem. 1993, 58, 6072. For a review, see: Farina,
V.; Krishnamurthy, V.; Scott, W. J . The Stille Reaction; Wiley: New
York, 1998.
With the two subunits in hand, the stage was set for
formation of the key vinyl bromide intermediate 28 (see

7718 J . Org. Chem., Vol. 66, No. 23, 2001
Sch em e 7. Retr osyn th esis of Rosa p r ostol
Trost and Pinkerton
Sch em e 8. Syn th esis of Vin yl Br om id e 37 a n d Cycliza tion
in 70% yield. All that remained for completion of the
synthesis was hydrolysis of the ester to the acid, which
proceeded in 74% yield using lithium hydroxide in a
dioxane/water mixture, to give tetrahydrodicranenone B.
The spectral data of this synthetic sample were consistent
with those of the natural product.
We chose the cyclopentanol rosaprostol (35),19 an
antiulcer drug, as our next target. Marketed as the
sodium salt under the name Rosal, it displays gastric
antisecretory activity devoid of many of the side effects
of other prostanoids. Earlier syntheses of rosaprostol
have been reported from several groups.20 Scheme 7
depicts the retrosynthetic analysis based on this new
strategic concept. It is to be noted that rosaprostol is a
diastereomeric mixture at the hydroxyl-bearing carbon.
The two subunits necessary for vinyl bromide forma-
tion were synthesized in a simple fashion. Fischer esteri-
fication of commercially available 8-nonynoic acid pro-
vided a quantitative yield of alkynoate 38. Enone 39
was made from heptanoic acid using the acid chloride
formation/Stille coupling procedure as described in eq 4
and is a known compound made in a similar fashion.21
The two subunits were coupled under our standard
conditions10 to form vinyl bromide 37 in 70% yield with
a Z/ E ratio of 3.7/1 (see Scheme 8). The vinyl bromide
was the reacted under Nozaki-Kishi conditions11 to give
a 71% yield of cyclopentenol 36, with traces of the
dehalogenated E olefin also observed. At this point, 36
was oxidatively rearranged following the known proce-
dure13 to give the cyclopentenone 40 in 81% yield. Initial
attempts to reduce the enone using zinc/acetic acid22 gave
instead deoxygenated products 41 (as a mixture of double
bond isomers), which could be further reduced using
catalytic hydrogenation to give the cis-disubstituted
cyclopentane 42.
Altering the route to rosaprostol, reduction of the olefin
of the cyclopentenone 40 was accomplished using cata-
lytic hydrogenation over Pd/C to give cyclopentanone 43
(19) Valcavi, U.; Caponi, R.; Brambilla, A.; Palmira, M.; Minoja, F.;
Bernini, F.; Musanti, R.; Fumagalli, R. Arzneim-Forsch. 1982, 32, 657.
Foschi, D.; et al. Prostaglandins Leukotrienes Med. 1984, 15, 147.
(20) Mikolajczyz, M.; Zurawinski, R. J . Org. Chem. 1998, 63, 8894.
Tanimori, S.; Kainuki, T.; Nakayama, M. Biosci. Biotech. Biochem.
1992, 56, 1807. Shono, T.; Kise, N.; Fujimoto, T.; Tominaga, N.; Morita,
H. J . Org. Chem. 1992, 57, 7175. Valcavi, U. Chem. Abstr. 1976, 85,
32512q. Valcavi, U.; Innocenti, S.; Bosone, E.; Farina, P.; Marotta, V.;
Zabban, G. B. Eur. Pat. Appl. EP 155,392; Chem. Abstr. 1986, 104,
168263c.
(21) Galatsis, P.; Millan, S. D.; Faber, T. J . Org. Chem. 1993, 58,
1215. Nakahira, H.; Ryu, I.; Ikebe, M.; Oku, Y.; Ogawa, A.; Kambe,
N.; Sonoda, N.; Murai, S. J . Org. Chem. 1992, 57, 17.
(22) Edwards, P. N.; Smith, G. F. J . Chem. Soc. 1961, 152. Mantlo,
N. B.; Danishefsky, S. J . J . Org. Chem. 1989, 54, 2781.

Three-Component Coupling Approach to Cyclopentanoids
J . Org. Chem., Vol. 66, No. 23, 2001 7719
Sch em e 9. Com p letion of th e Syn th esis
Sch em e 10. Ap p r oa ch to Meth yl J a sm on a te
in 83% yield as a 3/1 trans/ cis mixture (Scheme 9). This
vinyl bromide 46 in a modest 49% yield as a 3.2/1 Z/ E
mixture (Scheme 10). This moderate yield is most likely
due to the instability of Nazarov’s reagent to the Lewis
acidic conditions. Unfortunately, none of the desired
cyclopentenol was obtained from the Nozaki-Kishi reac-
tion. Rather, only a low yield of the dehalogenated
E-olefin 47 was obtained. The acidity of the â-ketoester
is a likely culprit for the failure of the Nozaki-Kishi
version of the Barbier reaction. It is also possible that
the initial adduct is unstable to a retro aldol reaction.
Nevertheless, the success of employing the Nazarov re-
agent in the three component coupling is most gratifying.
The last target chosen was the diarylcyclopentenone
48, which was developed by Merck as a potent and selec-
tive inhibitor of the COX-2 enzyme25 and is structurally
related to the osteoarthritis medication Vioxx (Figure 1).
Our synthetic strategy for cyclopentenone 48 focused
on preparation of the requisite vinyl bromide followed
by cyclization then oxidation. The necessary precursors,
alkyne 49 and enone 50, were synthesized in a simple
fashion. The enone 50 was accessed in one pot from the
commercially available acid 51 by first converting it to
the acid chloride and then subjecting it to a Stille type
cross-coupling as before (eq 5). Interestingly, attempts
to perform the Stille cross-coupling with the sulfone
ratio was determined by NMR spectroscopic analysis of
the methine signal R to the carbonyl group at δ 2.34-
2.29. This ratio was, in the end, irrelevant since the next
step, base-catalyzed hydrolysis of the ester, gave rapid
equilibration to the trans substituted acid 44 in quanti-
tative yield. To complete the synthesis, the cyclopen-
tanone was reduced with sodium borohydride following
the published procedure20 to give a 1:1 mixture of the
cis-trans and trans-trans products whose spectral prop-
erties were consistent with literature values.
We next turned to the cyclopentanone natural product
methyl jasmonate. Methyl jasmonate is an extremely
important factor in plant development, as well as a cell-
signaler in the defense response of plants. It is also
commercially valuable as a fragrance. Because of this it
has been the subject of many synthetic efforts.23
Our approach to methyl jasmonate focused (as did the
previous synthesis) on the generation of a cyclopentenone
followed by reduction to the cyclopentanone. This re-
quired the coupling of the previously described alkyne
29 with Nazarov’s reagent 45, whose synthesis employed
the method of Zibuck.24 This compound was quite un-
stable and could not be stored longer than several days.
Nazarov’s reagent and the enyne 29 were then reacted
under our standard vinyl bromide conditions to form
(25) Zhao, D.; Xu, F.; Chen, C.-Y.; Tillyer, R. D.; Grabowski, E. J .
J .; Reider, P. J .; Black, C.; Ouimet, N.; Prasit, P. Tetrahedron 1999,
55, 6001.
(23) See ref 1.
(24) Zibuck, R.; Streiber, J . M. J . Org. Chem. 1989, 54, 4717.

7720 J . Org. Chem., Vol. 66, No. 23, 2001
Trost and Pinkerton
F igu r e 1. Selective COX-2 inhibitors.
Sch em e 11. Com p letion of th e Syn th esis
(instead of the sulfide), to avoid an oxidation step later
in the synthesis, gave only decomposition products. The
known alkyne 49 was synthesized following the published
procedure26 in 68% yield for the two-step protocol of
Sonogashira coupling and desilylation.
to be quite unstable (decomposing after several hours),
probably due to the donating ability of the S-methyl
group on the aryl ring. This additional destabilization
makes the alcohol even more prone to eliminate to form
the cyclopentadiene.
However, if cyclopentenol 53 was reacted immediately
with pyridinium dichromate, cyclopentenone 54 could be
formed in good yield (80%). At this point, our synthesis
intercepts the previously published synthesis of this
compound. All that remained was to oxidize the sulfide
to the sulfone, which proceeded under the published
conditions25 using Oxone in acetone to give the target
compound in 92% yield.
Con clu sion
In conclusion, we have developed a general two-step
procedure for the synthesis of 2,3-disubstituted cyclo-
pentenones from vinyl bromides, which, in turn, are
readily available from the Ru-catalyzed three-component
coupling. The ease of access of both enones27 and alkynes
make this a very straightforward method. Therefore, this
reaction compares quite favorably to the known methods
of cyclopentenone synthesis, especially convergent meth-
ods such as the Pauson-Khand reaction and is a clear
improvement over more linear approaches to cyclopen-
tenones. Several limitations do exist, of course, mainly
the ability to construct only 2,3-disubstituted cyclopen-
The synthesis of the COX-2 inhibitor 48 was then
completed as shown in Scheme 11.9 Alkyne 49 and enone
50 were reacted under the standard vinyl bromide
conditions to form vinyl bromide 52 in 64% yield as
exclusively the Z-isomer, a selectivity that has been seen
with other aryl acetylenes.9 Following the standard
Nozaki-Kishi protocol, vinyl bromide 52 was then cy-
clized to cyclopentenol 53 in 60% yield (80% based on
recovered starting material). This compound was found
(27) For some other methods of enone synthesis, see: Floyd, J . C.
Tetrahedron Lett. 1974, 15, 2877. Kim, B. M.; Guare, J . P.; Hanifin,
C. M.; Arford-Bickerstaff, D. J .; Vacca, J . P.; Ball, R. G. Tetrahedron
Lett. 1994, 35, 5153.
(26) Crisp, G. T.; Flynn, B. L. J . Org. Chem. 1993, 58, 6614.
See also: Neenan, T. X.; Whitesides, G. M. J . Org. Chem. 1988, 53,
2489.

Three-Component Coupling Approach to Cyclopentanoids
J . Org. Chem., Vol. 66, No. 23, 2001 7721
mmol). The reaction was heated to 40° C for 2 h, and then the
volatile materials were removed in vacuo. The acid chloride
was then redissolved in toluene (20 mL) and tributylvinyl tin
(837 mg, 0.77 mL, 2.64 mmol) followed by palladium(II)
bistriphenylphosphinebenzyl chloride (1.6 mg, 0.01mol %) were
added. The mixture was heated to 80 oC for 4 h and then cooled
to room temperature. The toluene was evaporated by rotary
evaporation and the crude mixture subjected directly to
chromatography on silica gel (4/1 petroleum ether/ethyl ether)
to give 348 mg product (81% over two steps).
tenones rather than a full range of substitution patterns.
Furthermore, some functional groups would not be toler-
ated under the Nozaki-Kishi reaction and the oxidative
rearrangement, for example free alcohols.
However, the power of this approach has been exem-
plified by the rapid synthesis of the natural product
tetrahydrodicranenone B, as well as the pharmaceutical
agents rosaprostol and 2-(3,5-difluorophenyl)-3-(4-meth-
anesulfonylphenyl)cyclopent-2-enone. A synthesis of
tetrahydrodicranenone B was accomplished in a seven-
step procedure from simple precursors (cis-2-penten-1-
ol and azelaic acid monomethyl ester) in 14% overall
yield. This compares very well with the other synthesis
of this compound, which started with most of the carbons
and required excessive functional group manipulation,
especially oxidations and reductions.
White solid, mp ) 54-56 °C. Rf ) 0.38 (4/1 petroleum ether/
1
ethyl ether). IR (neat): 1657, 1605, 1589 cm-1. H NMR (500
MHz, CDCl3): δ 7.88 (d, J ) 8.8, 2H), 7.28 (d, J ) 8.3, 2H),
7.15 (dd, J ) 17.1, 10.8, 1H), 6.43 (dd, J ) 17.1, 1.7, 1H), 5.90
(dd, J ) 10.5, 1.7, 1H), 2.53 (s, 3H). 13C NMR (125 MHz,
CDCl3): δ 189.7, 146.0, 133.5, 132.0, 129.8, 129.1, 125.0, 14.8.
Anal. Calcd for C10H10OS: C, 67.38; H, 5.65; S, 17.99. Found:
C, 67.51; H, 5.70; S, 18.13.
P r ep a r a tion of 5-Br om o-5-(3,5-d iflu or op h en yl)-1-(4-
m eth ylsu lfa n ylp h en yl)p en t-4-en -1-on e (52). The alkyne 49
(111 mg, 0.80 mmol) and the vinyl ketone 50 (150 mg, 0.84
mmol) in acetone (reagent grade, not distilled) (1.6 mL) was
added to [CpRu(CH3CN)3]PF6 (34.9 mg, 0.08 mmol), stannic
bromide (52.5 mg, 0.12 mmol), and lithium bromide (104.3 mg,
1.20 mmol) in a pressure tube. The tube was capped and then
heated to 60 °C with stirring for 2 h. The reaction was then
cooled to room temperature and chromatographed directly on
silica gel (8/1 petroleum ether/ethyl ether) to give 204 mg
product (64%).
Rosaprostol was synthesized in seven linear steps in
31% overall yield from simple precursors, 8-nonynoic acid
and hexanoic acid. Although there are several other quite
efficient syntheses and high-yielding syntheses of ro-
saprostol, our synthesis represents a more convergent
approach as opposed to the rather linear approaces.
Finally, COX-2 inhibitor 48 was synthesized in five linear
steps from known compounds in a 30% overall yield.
Although the Merck synthesis for this compound is very
short and high yielding, and thus our synthesis offers
no major advantage besides simpler starting materials,
it is a much more flexible synthesis of this type of
compound considering the wide range of different side
chains that can be incorporated.
In conclusion, then, 2,3-disubstituted cyclopentenones
can now be analyzed retrosynthetically as in eq 6. It
should be noted that the cyclopentenols are also useful
intermediates for a host of other transformations such
as allylic couplings and Claisen rearrangements as well
as simple allylic transposition of the OH group (eq 7).
Thus, this new strategy can offer a general approach to
a diverse range of five-membered ring targets.
Viscous yellow oil. Rf ) 0.35 (8/1 petroleum ether/ethyl
ether). IR (neat): 1682, 1622 cm-1 1H NMR (500 MHz,
.
CDCl3): δ 7.89 (d, J ) 8.6, 2H), 7.26 (d, J ) 8.6, 2H), 7.05 (dd,
J ) 8.6, 2.3, 2H), 6.73 (tt, J ) 8.7, 2.3, 1H), 6.44 (t, J ) 7.1,
1H), 3.16 (t, J ) 7.1, 2H), 2.77 (q, J ) 7.1, 2H), 2.52 (s, 3H).
13C NMR (125 MHz, CDCl3): δ 197.6, 162.5 (dd, J ) 248.9,
12.8), 146.1, 142.6 (t, J ) 9.6), 132.8, 132.4, 128.4, 124.9, 123.6,
110.5 (dd, J ) 20.3, 6.4), 103.6 (t, J ) 25.1), 36.5, 27.0, 14.7.
Anal. Calcd for C15H15BrF2OS: C, 54.42; H, 3.87; S, 8.07.
Found: C, 54.25; H, 3.95; S, 8.21.
P r ep a r a tion of 2-(3,5-Diflu or op h en yl)-1-(4-m eth ylsu l-
fa n ylp h en yl)cyclop en t-2-en ol (53). Chromium(II) chloride
(154 mg, 1.25 mmol) and nickel(II) chloride (65 mg, 0.5 mmol)
were weighed out in a flask in a drybox and placed under
argon. To this flask was added a solution of the vinyl bromide
substrate 52 (100 mg, 0.25 mmol) in DMF (2 mL) and the
reaction stirred overnight at room temperature. The crude
reaction mixture was then applied directly to a silica gel
column (3/1 petroleum ether/ethyl ether) to give 48 mg of
product (60%) as well as 12 mg of unreacted starting material
(20%). This product was found to be very unstable and needed
to be reacted in the next step very quickly in order to prevent
decomposition.
Colorless oil. Rf ) 0.28 (3/1 petroleum ether/ethyl ether).
IR (neat): 3453 cm-1 1H NMR (500 MHz, CDCl3): δ 7.31
.
(d, J ) 8.1, 2H), 7.19 (d, J ) 8.3, 2H), 6.88 (dd, J ) 9.0, 1.7,
2H), 6.58 (tt, J ) 8.8, 2.3, 1H), 6.50 (t, J ) 2.7, 1H), 2.69-2.62
(m, 1H), 2.54-2.51 (m, 2H), 2.47 (s, 3H), 2.39-2.33 (m, 1H),
2.14 (brs, 1H). 13C NMR (125 MHz, CDCl3): δ 162.5 (dd, J )
246.7, 13.9), 142.3 (t, J ) 9.0), 136.7, 133.8, 128.4, 126.5, 125.3,
124.9, 109.7 (dd, J ) 20.3, 6.0), 102.5 (t, J ) 25.6), 87.4, 45.7,
29.3, 15.7. HRMS: Calcd for C18H16CF2OS: 318.0890. Found:
318.0888.
P r ep a r a tion of 2-(3,5-Diflu or op h en yl)-3-(4-m eth ylsu l-
fa n ylp h en yl)cyclop en t-2-en on e (54). To a solution of the
cyclopentenol 53 (15 mg, 0.047 mmol) in CH2Cl2 (2 mL) at 0
°C was added pyridinium dichromate (86 mg, 0.236 mmol).
The reaction was stirred for 1 h, ether (20 mL) was added,
and the mixture was filtered through a pad of Celite. The
solvent was then evaporated by rotary evaporation, and the
residue was purified by silica gel chromatography (3/1 petro-
leum ether/ethyl ether) to give 12 mg of product (80%).
White solid, mp)124-126 °C. Rf ) 0.28 (3/1 petroleum
Exp er im en ta l Section
1
P r ep a r a tion of 1-(4-Meth ylth iop h en yl)p r op en on e (50).
To a solution of 4-(methylthio)benzoic acid (400 mg, 2.4 mmol)
in CH2Cl2 was added oxalyl chloride (640 mg, 0.42 mL, 4.8
ether/ethyl ether). IR (neat): 1698 cm-1. H NMR (500 MHz,
CDCl3): δ 7.24 (d, J ) 9.0, 2H), 7.15 (d, J ) 8.8, 2H), 6.78-
6.75 (m, 3H), 3.06-3.04 (m, 2H), 2.72-2.70 (m, 2H), 2.49 (s,

7722 J . Org. Chem., Vol. 66, No. 23, 2001
Trost and Pinkerton
3H). 13C NMR (125 MHz, CDCl3): δ 206.3, 168.8, 163.0 (dd,
J ) 261.0, 12.0), 142.5, 137.8, 136.1 (t, J ) 11.0), 130.8,
128.4, 125.4, 112.4 (d, J ) 19.2), 103.4 (t, J ) 25.1), 34.6, 29.4,
14.9. This compound has been previously described, and the
data are consistent.25
P r ep a r a tion of 2-(3,5-Diflu or op h en yl)-3-(4-m eth a n e-
su lfon ylp h en yl)cyclop en t-2-en on e (48). Following the lit-
erature procedure,25 oxone (34 mg, 0.11 mmol) was added to a
solution of 54 (12 mg, 0.038 mmol) in acetone/water 9/1 (1 mL).
The reaction was heated to 45 °C and stirred for 2 h at this
temperature. The reaction was then cooled to room tempera-
ture, filtered through a plug a Celite, and then concentrated
in vacuo to give 12 mg of 48 (92%).
This compound has been previously described, and the data
are consistent.25
Ack n ow led gm en t. We thank the National Science
Foundation and the National Institutes of Health,
General Medical Sciences, for their generous support
of our programs. Mass spectra were provided by the
Mass Spectrometry Regional Center of the University
of CaliforniasSan Francisco, supported by the NIH
Division of Research Resources. A.B.P. thanks Abbott
Laboratories, Glaxo-Wellcome, the ACS Division of
Organic Chemistry (sponsored by Bristol-Myers Squibb),
and Eli Lilly for fellowship support.
White solid, mp ) 153-154 °C. Rf ) 0.28 (3/1 petroleum
1
ether/ethyl ether). IR (neat): 1704 cm-1. H NMR (500 MHz,
CDCl3): δ 7.95 (d, J ) 8.8, 2H), 7.52 (d, J ) 8.5, 2H), 6.82
(tt, J ) 8.9, 2.4, 1H), 6.77-6.72 (m, 2H), 3.12-3.10 (m, 5H),
2.81-2.79 (m, 2H). 13C NMR (125 MHz, CDCl3): δ 206.1, 166.8,
163.8 (dd, J ) 249.6, 19.5), 141.6, 140.4, 139.8, 134.5 (t, J )
9.7), 128.7, 127.8, 112.4 (dd, J ) 26.7, 9.7), 104.1 (t, J ) 24.6),
44.3, 34.7, 29.9.
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails for all reactions as well as characterization data are
included (PDF). This material is available free of charge via
the Internet at http://pubs.acs.org.
J O010593B