A new strategy for cyclopentenone synthesis.

Article abstract of DOI:10.1021/ol005853a

[reaction--see text] A new strategy for the synthesis of 2,3-disubstituted cyclopentenones emerges from two key reactions-the ruthenium-catalyzed three-component coupling of an equivalent of HBr, an alkyne, and a vinyl ketone and the Ni-Cr Barbier type reaction. As a result, these important structures are readily accessed from an alkyne and a vinyl ketone (which derive directly from carboxylic acids). Syntheses of tetrahydrodicranenone B and rosaprostol illustrate the new strategy.

Full text of DOI:10.1021/ol005853a

ORGANIC
LETTERS
2000
Vol. 2, No. 11
1601-1603
A New Strategy for Cyclopentenone
Synthesis
Barry M. Trost* and Anthony B. Pinkerton
Department of Chemistry, Stanford UniVersity, Stanford, California 94305-5080
bmtrost@leland.stanford.edu
Received March 23, 2000
ABSTRACT
A new strategy for the synthesis of 2,3-disubstituted cyclopentenones emerges from two key reactionssthe ruthenium-catalyzed three-
component coupling of an equivalent of HBr, an alkyne, and a vinyl ketone and the Ni−Cr Barbier type reaction. As a result, these important
structures are readily accessed from an alkyne and a vinyl ketone (which derive directly from carboxylic acids). Syntheses of
tetrahydrodicranenone B and rosaprostol illustrate the new strategy.
The vast importance of cyclopentyl compounds has led to
numerous methods for their synthesis.1,2 Nevertheless, new
strategies provide enhanced opportunities for increasing
efficiency. Cyclopentenones are particularly useful because
of the versatility of the functionality. The classical method
for their synthesis involves the intramolecular aldol reaction
of a suitable 1,5-diketone. Examination of eq 1 makes the
(1) 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.
(2) 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 Organometallic Chemistry II; Abel, E. W., Stone, F. G.
A., Wilkinson, G., Eds.; Elsevier: New York, 1995; Vol. 12, p 703. Taber,
D. F. Methods of Organic Chemistry; Helmchen, G., Ed.; Georg Thiem
Verlag: Stuttgart, 1995; Vol. E 21, p 1127. Padwa, A.; Krumpe, K. E.
Tetrahedron 1992, 48, 5385.
major issue immediately apparentschemoselectivity. Two
possible aldol products are equally accessible. We report a
new strategy to avoid this ambiguity which we developed
in the context of a synthesis of tetrahydrodicranenone B (1),
a cyclopentenone fatty acid isolated from the Japanese moss
Leucobryum scabrum which shows antimicrobrial and an-
tihypertensive properties.3,4 A facile synthesis of rosaprostol,
a clinically important antiulcer agent, also emerged from this
chemistry.5,6
Scheme 1 illustrates the strategic concept which derives
from the known oxidative rearrangement of tertiary allylic
(3) Ichikawa, T.; Namikawa, M.; Yamada, K.; Sakai, K.; Kondo, K.
Tetrahedron Lett. 1983, 24, 3337.
(4) For syntheses, see: Sakai, K.; Fujimoto, T.; Yamashita, M.; Kondo,
K. Tetrahedron Lett. 1985, 26, 2089. Moody, C. J.; Roberts, S. M.; Toczek,
J. J. Chem. Soc., Chem. Commun. 1986, 1292.
(5) 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.
10.1021/ol005853a CCC: $19.00 © 2000 American Chemical Society
Published on Web 05/06/2000

(TBAF, HOAc, THF, room temperature) provided the known
enyne 4. The yield of this last step mainly reflects difficulties
in isolation due to the volatility of the compound. The vinyl
ketone 5 was prepared from azelaic acid monomethyl ester
(8) via a Stille type cross-coupling11 as shown in eq 3.
Scheme 1. Retrosynthetic Analysis and Synthesis of
Tetrahydrodicranenone B (1)a
Scheme 1 outlines the synthesis of tetrahydrodicranenone
B from the two subunits, 4 and 5. Subjecting a 1:1 mixture
of these two building blocks and lithium bromide to a two-
component ruthenium-tin catalyst12 in acetone at 60 °C gave
a 4:1 mixture of the Z and E bromoalkenes (only the major
(Z)-bromoalkene depicted). Despite little precedent for
Barbier reactions mediated by chromous chloride-nickel
chloride with ketones,13,14 this intramolecular reaction pro-
ceeded very well with ketones under standard conditions to
give the desired cyclopentenol 2. PDC-promoted allylic
rearrangement simultaneous with oxidation7 produced the
desired cyclopentenone as its ester, the hydrolysis of which
gave the target 1.
a (a) 10% CpRu(CH3CN)3PF6, 15% SnBr4, LiBr, CH3COCH3,
60 °C; (b) CrCl2, NiCl2, DMF, room temperature; (c) PDC, CH2Cl2,
0 °C; (d) LiOH, H2O, dioxane, 60 °C.
alcohols.7 A Barbier type reaction of Z-vinyl bromide 3
constitutes a ring-forming appraoch to the requisite allyl
alcohol 2. On the basis of a new ruthenium-catalyzed three-
component coupling under development in these laborato-
ries,8 the alkyne 4 and the enone 5 become the starting
materials.
The facility of the sequence led us to develop this strategy
for a synthesis of rosaprostol (8), an antiulcer drug marketed
as the sodium salt under the name Rosal. It displays gastric
antisecretory activity devoid of many side effects of other
prostanoids.5 Scheme 2 illustrates the retrosynthetic analysis.
Since cyclopentanone 9 is a known precursor,6 the corre-
sponding cyclopentenone 10 represents a reasonable inter-
mediate. Following the logic as outlined for tetrahydro-
dicranenone B, alkyne 13 and vinyl ketone 14 become the
basic building blocks. Alkyne 13 is available by simple
Fischer esterification of the corresponding commercially
available 8-nonynoic acid. Known vinyl ketone 1415 is
available from heptanoic acid via the Stille cross-coupling
in identical fashion to the synthesis of vinyl ketone 5 (eq 3).
As shown in Scheme 2, the ruthenium-catalyzed three-
component coupling proceeded in a fashion similar to that
used previously to give a 70% yield of a 4:1 Z:E ratio of
vinyl bromides (only the major Z-vinyl bromide 12 de-
picted.). Subjecting the mixture to the Ni-Cr-mediated
Barbier type reaction gave a 71% isolated yield of allyl
alcohol 11 whose oxidative rearrangement produced cyclo-
pentenone 10 straightforwardly. Catalytic hydrogenation
using Pd/C delivered a 3:1 trans:cis ratio of 2,3-disubstituted
cyclopentanones. However, base hydrolysis of the ester was
accompanied by equilibration to give only the E cyclopen-
tanone-carboxylic acid. Sodium borohydride reduction as
reported in the literature produced rosaprostol 8.
The known enyne 49 was derived as outlined in eq 2. The
mesylate 6b prepared from commercially available (Z)-2-
penten-1-ol (6a) (MsCl, (C2H5)3N, THF, 0 °C), underwent
copper-mediated displacement with trimethylsilylacetylene
(CuI, NaI, K2CO3, DMF, room temperature)10 to give 7 in
addition to the product of SN2′ displacement in a 3-9:1 ratio
depending upon the amount of copper iodide. Desilylation
(6) For syntheses, see: (a) Mikolajczyk, M.; Zurawinski, R. J. Org.
Chem. 1998, 63, 8894. (b) Tanimori, S.; Kainuki, T.; Nakayama, M. Biosci.
Biotech. Biochem. 1992, 56, 1807. (c) Shono, T.; Kise, N.; Fujimoto, T.;
Tominaga, N.; Morita, H. J. Org. Chem. 1992, 57, 7175. (d) Valcavi, U.;
Innocenti, S.; Bosone, E.; Farina, P.; Marotta, V.; Zabban, G. B. Eur. Pat.
Appl. EP 155392; Chem. Abstr. 1986, 104, 168263C.
(7) Dauben, W. G.; Michno, D. M. J. Org. Chem. 1977, 42, 682.
Majetich, G.; Condon, S.; Hull, K.; Ahmad, S. Tetrahedron Lett. 1989, 30,
1033.
(8) Trost, B. M.; Pinkerton, A. B. Angew. Chem., Int. Ed. 2000, 39, 360.
(9) Billington, D. C.; Bladon, P.; Helps, I. M.; Pauson, P. L.; Thomson,
W.; Willison, D. J. Chem. Res. 1988, 10, 2601.
(10) Jeffery, T.; Gueugnot, S.; Linstrumelle, G. Tetrahedron Lett. 1992,
33, 5757. Lapitskaya, M. A.; Vasiljeva, L. L.; Pivnitsky, K. K. Synthesis
1993, 65.
(11) 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.
The chemoselectivity exhibited in the ruthenium-catalyzed
three-component coupling should make this a versatile
(12) For the ruthenium-acetonitrile complex, see: Gill, T. P.; Mann,
K.R. Organometallics 1982, 1, 485.
(15) 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.
(16) 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.
(13) For a review, see: Cintas, P. Synthesis 1992, 248.
(14) For an intramolecular example, 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. For a recent modification for reactions with
ketones, see: Chen, C. Synlett 1998, 1311.
1602
Org. Lett., Vol. 2, No. 11, 2000

Scheme 2. Retrosynthetic Analysis and Synthesis of Rosaprostol (8)a
a (a) 10% CpRu(CH3CN)3PF6, 15% SnBr4, LiBr, CH3COCH3, 60 °C; (b) CrCl2, NiCl2, DMF, room temperature; (c) PDC, CH2Cl2, 0 °C;
(d) H2, Pd/C, CH3OH, room temperature; (e) i. LiOH, H2O, dioxane, 60 °C; ii. NaBH4, CH3OH, 0 °C.
approach to cyclopentenones. The synthesis of tetrahydrodi-
cranenone B requires seven linear steps and 14% overall
yield, but the yields have not been optimized. Rosaprostol
also requires seven linear steps and proceeds in 31% overall
yield. The ease of access of vinyl ketones from carboxylic
acids11,16 and alkynes makes this strategy particularly attrac-
tive. Retrosynthetically, 2,3-disubstituted cyclopentenones
now can be envisioned to evolve as shown in eq 4.
Acknowledgment. We thank the National Institutes of
Health, General Medical Sciences, and the National Science
Foundation for their generous support of our work. A.B.P.
has received an ACS Organic Division fellowship sponsored
by Bristol Myers Squibb. Mass spectra were provided by
the Mass Spectrometry Facility, University of San Francisco,
supported by the NIH Division of Research Resources.
Supporting Information Available: Characterization
data for 1, 2, 3, 8, 9, 10, 11, and 12. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL005853A
Org. Lett., Vol. 2, No. 11, 2000
1603