The First Total Synthesis of 15-Deoxy-Δ12,14- prostaglandin J2 and the Unambiguous Assignment of the C 14 Stereochemistry

Article abstract of DOI:10.1021/ol035590v

(Matrix presented) The first total synthesis of 15-deoxy-Δ ^12,14-prostaglandin J₂ is reported. The highly unsaturated cyclopentenone prostaglandin was obtained via a silicon-tethered allenic [2 + 2 + 1] cycloaddition reaction develop

Full text of DOI:10.1021/ol035590v

ORGANIC
LETTERS
2004
Vol. 6, No. 2
149-152
The First Total Synthesis of
15-Deoxy-∆12,14-prostaglandin J2 and the
14
Unambiguous Assignment of the C
Stereochemistry
Kay M. Brummond,* Peter C. Sill, and Hongfeng Chen
UniVersity of Pittsburgh, Department of Chemistry, Pittsburgh, PennsylVania 15260
kbrummon@pitt.edu
Received August 23, 2003
ABSTRACT
The first total synthesis of 15-deoxy-∆12,14-prostaglandin J2 is reported. The highly unsaturated cyclopentenone prostaglandin was obtained
14
via a silicon-tethered allenic [2 + 2 + 1] cycloaddition reaction developed in our group. In addition, the stereochemistry at C has been
assigned unambiguously.
Cyclopentenone prostaglandins have emerged in the past
decade as uniquely different from other compounds in the
prostaglandin family.1 These highly unsaturated prostaglan-
dins have antineoplastic, antiinflammatory, and antiviral
activities and elicit a biological response, not by binding to
G-protein-coupled receptors, but instead by interacting with
cellular targets, including signaling molecules and transcrip-
tion factors.2 For example, 15-deoxy-∆12,14-PGJ2 (1) repre-
sents the highest affinity natural ligand identified to date for
PPARγ, a receptor that has been linked to type II diabetes,
obesity, hypertension, and atherschlerosis.2 New insights into
the biological activity and cellular targets of cyclopentenone
prostaglandins and the prostaglandin-like clavulones3 have
led to an increased need for synthetic approaches to these
compounds.3,4 Since cyclopentenone prostaglandins are
produced in vivo on a need only basis, in very small
quantities (<1 mg), their chemical synthesis is a requirement
for further research. Approaches to prostaglandins have been
described as early as the 1960s, and the literature abounds
with syntheses of the various prostaglandins and their
analogues.5 However, the total synthesis of cyclopentenone
prostaglandins requires a different approach than has clas-
sically been used for their more saturated counterparts since
they are typically obtained using dehydration protocols that
often lead to mixtures of isomers. Interestingly, it is this
mixture of isomers that has led to some ambiguity involving
the stereochemistry of 15-deoxy-∆12,14-PGJ2 (vide infra).6
A more direct strategy for the synthesis of 15-deoxy-∆12,14
-
PGJ2 (1) incorporates an allenic Pauson-Khand-type reac-
tion since access to R-alkylidene and 4-alkylidene cyclo-
pentenones via this protocol has proven to be efficient and
general.7 Thus, direct access to the R-alkylidene core of 1
might involve an intermolecular reaction between an ap-
propriately functionalized allene and acetylene gas. Unfor-
(4) For more selected synthetic approaches to cross-conjugated cyclo-
pentenones, see: Kobayashi, Y.; Murugesh, M. G.; Nakano, M. Tetrahedron
Lett. 2001, 42, 1703. Zhu, J.; Yang, J.-Y.; Klunder, A. J. H.; Liu, Z.-Y.;
Zwanenburg, B. Tetrahedron 1995, 51, 5847; Liu, Z.-Y.; Dong, H.; Chu,
X.-J. Tetrahedron 1994, 50, 12337. Hashimoto, S.; Arai, Y.; Hamanaka,
N. Tetrahedron Lett. 1985, 26, 2679.
(1) For a review, see: Straus, D. S.; Glass, C. K. Med. Res. ReV. 2001,
21, 185.
(2) Wahli, W.; Braissant, O.; Desvergne, B. Chem. Biol. 1995, 2, 261.
Forman, B. M.; Tontonoz, P.; Chen, J.; Brun, R. P.; Spiegelman, B. M.;
Evans, R. M. Cell 1995, 83, 803.
(3) (a) Ciufolini, M. A.; Zhu, S. J. Org. Chem. 1998, 63, 1668. (b) Tius,
M. A.; Busch-Petersen, J.; Yamashita, M. Tetrahedron Lett. 1998, 39, 4219.
(5) AdVances in Prostaglandin, Thromboxane, Leukotriene Research;
Raven: New York, 1983-1991; Vols. 11-21.
(6) Maxey, K. M.; Hessler, E.; MacDonald, J.; Hitchingham. L. Pros-
taglandins Other Lipid Mediators 2000, 62, 15-21.
10.1021/ol035590v CCC: $27.50 © 2004 American Chemical Society
Published on Web 12/23/2003

tunately, this process is not well-behaved and typically
mixtures of products are obtained in moderate yields favoring
the formation of the 4-alkylidene cyclopentenones.8 However,
taking advantage of a removable tether allowed the target
ring system to be obtained intramolecularly. Along these
lines, we recently reported a successful silicon-tethered
allenic Pauson-Khand reaction and felt that this protocol
Scheme 2. Syntheis of Alkynyl Allene Precursor
was ideally suited for the total synthesis of 15-deoxy-∆12,14
PGJ2.9
-
Retrosynthetically, it was envisioned that 15-deoxy-∆12,14
-
PGJ2 (1) could be obtained from cyclopentenone 2 via an
oxidation of the primary hydroxyl group, followed by a well-
precedented Wittig reaction on the resulting aldehyde
(Scheme 1). In turn, the appending hydroxyl group is the
Scheme 1. Retrosynthetic Analysis
protocol to give the enyne 7 in 88% yield (Scheme 2).10
Reaction of enyne 7 with n-BuLi and TMEDA gives the
allenol 8 in 86% yield.11 Next, allenol 8 was converted to
iodide 9 by way of the mesylate in 71% yield for the two-
step conversion. Treatment of iodide 9 with t-BuLi at -78
°C, followed by the stepwise addition of diphenyldichloro-
silane, and then ethynylmagnesium bromide afforded the
alkynyl allene 10 in 75% yield (three steps, one reaction
vessel).12
Alkynyl allene 10 was subjected to the standard molyb-
denum-mediated conditions to give enones 3E and 3Z in 38%
yield in a 1:2 ratio.13,7a Attempts were made to increase the
yield of this annulation by using other transition metals, but
with limited success.14 While this represents a lower yield
than anticipated on the basis of all of our model studies, the
bicyclic compound 3E contains nearly all of the functionality
necessary to assemble 15-deoxy-∆12,14-PGJ2. Furthermore,
we have shown that 3Z can be isomerized quantitatively
using photolysis to give a 1:1 mixture of 3Z and 3E.
Alternatively, complete isomerization of 3Z to 3E has also
been effected in 64% yield using boron trifluoride and
propanedithiol. Presumably this is a result of an acid-
catalyzed addition of the thiol to the â-carbon of the
exocyclic double bond followed by bond rotation and
elimination. Attempts were not made to optimize these
isomerization conditions. The (E)-geometry of the C14-C15
product of a selective cleavage of the vinyl silane of 3,
followed by a Tamao-Fleming oxidation of the intermediate
silanol. The bicyclic cyclopentenone 3 can in turn be
prepared using an allenic [2 + 2 + 1] cycloaddition reaction.
The advantages to this carbon-carbon bond-forming strategy
are (1) the controlled and stereoselective introduction of each
of the double bonds of 15-deoxy-∆12,14-PGJ2 and (2) the ease
in which the Pauson-Khand cyclization precursor 4 can be
assembled.
The synthesis was initiated by treating 4-pentynol (5) and
(E)-1-bromo-1-heptene (6) with the Sonogashira coupling
(7) (a) Kent, J. L.; Wan, H.; Brummond, K. M. Tetrahedron Lett. 1995,
36, 2407. (b) Brummond, K. M.; Wan, H. Tetrahedron Lett. 1998, 39, 931.
(c) Brummond, K. M.; Wan, H.; Kent, J. L. J. Org. Chem. 1998, 63, 6535.
(d) Brummond, K. M. In AdVances in Cycloaddition; Harmata, M., Eds.;
JAI Press, Inc.: Stamford, Connecticut, 1999; Vol. 6, p 211. (e) Brummond,
K. M.; Lu, J. J. Am. Chem. Soc. 1999, 121, 5087. (f) Brummond, K. M.;
Lu, J.; Petersen, J. L. J. Am. Chem. Soc. 2000, 122, 4915. (g) Xiong, H.;
Hsung, R. P.; Wei, L. L.; Berry, C. R.; Mulder, J. A.; Stockwell, B. Org.
Lett. 2000, 2, 2869. (h) Ahmar, M.; Locatelli, C.; Colombier, D.; Cazes, B.
Tetrahedron Lett. 1997, 38, 5281. (i) Perez-Serrano, L.; Casarruubios, L.;
Dominguez, G.; Perez-Castells, J. Chem. Commun. 2001, 2602. (j) Koba-
yashi, T.; Koga, Y.; Narasaka, K. J. Organomet. Chem. 2001, 624, 73. (k)
Pagenkopf, B. L.; Belanger, D. B.; O’Mahony, D. J. R.; Livinghouse, T.
Synthesis, 2000, 1009. (l) Hicks, F. A.; Kablaoui, N. M.; Buchwald, S. L.
J. Am. Chem. Soc. 1999, 121, 5881.
(8) Aumann, R.; Weidenhaupt, H.-J. Chem. Ber. 1987, 120, 23. Ahmar,
M.; Antras, F.; Cazes, B. Tetrahedron Lett. 1995, 36, 4417. Ahmar, M.;
Chabanis, O.; Gauthier, J.; Cazes, B. Tetrahedron Lett. 1997, 38, 5277.
Shibata, T.; Koga, Y.; Narasaka, K. Bull. Chem. Soc. Jpn. 1995, 68, 911.
(9) Brummond, K. M.; Sill, P.; Rickards, B.; Geib, S. J.Tetrahedron Lett.
2002, 43, 3735.
(10) Takahashi, S.; Kuyoyama, Y. Sonogashira, K.; Hagihara, N.
Synthesis 1980, 627.
(11) Enomoto, M.; Katsuki, T.; Yamaguchi, M. Tetrahedron Lett. 1986,
27, 4599.
(12) For a procedure to prepare the allenyllithium intermediate, see:
Crandall, J. K.; Ayers, T. A. J. Org. Chem. 1992, 57, 2993.
(13) Jeong, N.; Lee, S. J.; Lee, B. Y.; Chung, Y. K. Tetrahedron Lett.
1993, 34, 4027.
(14) We found that W(CO)5‚THF gave yields nearly identical to that of
Mo(CO)6. Interestingly, there was a reversal in the E:Z selectivity (2:1)
when using the tungsten mediator. It was subsequently shown that the
stereochemical result was due to an isomerization of the (Z)-isomer to the
(E)-isomer under the reaction conditions. Hoye, T. R.; Suriano, J. A.
Organometallics 1992, 11, 2044.
(15) Prostaglandin numbering system is used.
150
Org. Lett., Vol. 6, No. 2, 2004

70% yield. Silanol 12 was not purified but subjected directly
to the Tamao-Fleming oxidation protocol to afford diol 13
in 21% yield over three chemical transformations from 3E.16
Attempts to directly oxidize diol 13 to keto-aldehyde 14
provided complex mixtures of products.
Scheme 3. Allenic [2 + 2 + 1] Cycloaddition
An advanced model system was used to explore various
oxidation protocols. Treatment of diol 15 to tetra-n-propyl-
ammonium peruthenate (TPAP) led to a mixture of products
consisting of varying amounts of keto aldehyde 16, aldehyde
17, and cyclized Michael adduct 18 (eq 1). Selective
oxidation of the allylic alcohol using MnO2 gave compound
18 in 87% yield, confirming that the primary hydroxyl group
adds to initially formed enone.
double bond in 3E and 3Z was confirmed by the coupling
constants for the olefinic protons on C14 and C15 (J ) 15.0
Hz for both compounds).15 The stereochemistry of the C12-
C13 double bond was based upon the chemical shift of the
olefinic proton on C13, where 3E shows a resonance for H13
at δ 6.91 and 3Z shows a resonance for H13 at δ 6.45.
With the (E)-alkylidene cyclopentenone 3E in hand, the
next step was to cleave the silicon tether (Scheme 4). On
With this information in hand, it became apparent that it
would be necessary to selectively oxidize the primary alcohol
in the presence of the secondary alcohol, which was
accomplished using the Einhorn protocol to provide aldehyde
19 (Scheme 5).17 Aldehyde 19 was not purified but reacted
Scheme 5. Completion of Synthesis
Scheme 4. Synthesis of 15-deoxy-∆12,14-PGJ2
with (4-carboxybutyl)triphenylphosphonium bromide18 and
sodium hexamethydisilylamide (NaHMDS) in THF which
in turn, upon isolation was immediately oxidized with MnO2
to provide 15-deoxy-∆12,14-PGJ2.
At this time, we believe it necessary to confirm that this
is indeed the structure of the natural product. Nearly 20 years
after its isolation (by an albumin-catalyzed dehydration of
PGD2)19 and characterization,20 a report was published
the basis of model studies, moderation of the electrophilicity
of the endocyclic double bond of the cyclopentenone 3E was
desirable since this olefin appeared to be very reactive toward
nucleophiles. Dibal-H reduction at low temperature provided
bisallylic alcohol 11, which proved to be unstable and
typically was taken on directly to the next step but could be
chromatographed for characterization purposes by pretreating
the silica gel with triethylamine. Cleavage of the vinyl silane
11 with benzyltrimethylammonium fluoride using buffered
conditions afforded the desired ring-opened product 12 in
claiming that the stereochemistry at C14 of 15-deoxy-∆12,14
-
PGJ2 possessed the (Z)- and not the (E)-geometry as
previously reported.6 Unfortunately, only HPLC data traces
were provided as proof for the authenticity of the C14
(16) Fleming, I. ChemtractssOrg. Chem. 1996, 9, 1. Jones, G. R.;
Landais, Y. Tetrahedron 1996, 52, 7599-7662.
(17) Einhorn, J.; Einhorn, C.; Ratajczak, F.; Pierre, J. L. J. Org. Chem.
1996, 61, 7452.
(18) Maryanoff, B. E.; Duhl-Emswiler, B. A. Tetrahedron Lett. 1981,
22, 4185.
Org. Lett., Vol. 6, No. 2, 2004
151

stereochemistry.21 The proton assignment for each of the
resonances in the NMR spectrum (600 MHz) of the synthetic
sample are provided in Supporting Information. Particularly
noteworthy is the splitting value of 15.0 Hz for H14 and H15
that corresponds to the (E)-isomer. Three discrete samples
of 15-deoxy-∆12,14-PGJ2 were purchased from Cayman, Inc.,
and prepared as suggested, and the NMR spectrum was
obtained (600 MHz). The spectral data for the samples
purchased from Cayman, Inc., completely matched that of
the synthetic compound 1. Moreover, the protons were
In conclusion, we have completed the first total synthesis
of 15-deoxy-∆12,14-PGJ2 using an allenic Pauson-Khand-
type reaction to prepare the highly unsaturated R-alkylidene
cyclopentenone core. Our approach utilizes a removable
silicon tether to set the structure of the monocycle. In addi-
tion, we have unambiguously determined that the stereo-
chemistry at C14 is E, as originally reported in the literature.22
We are currently applying this synthetic strategy to the
stereoselective synthesis of both enantiomers of 15-deoxy-
∆
12,14-PGJ2 and to the synthesis of analogues.
1
assigned unambiguously via H COSY (600 MHz).
Acknowledgment. We thank the National Institutes of
Health (GM54161) for financial support of this project.
(19) Bundy, G. L.; Morton, D. R.; Peterson, D. C.; Nishizawa, E. E.;
Miller, W. L. J. Med. Chem. 1983, 26, 790.
Supporting Information Available: Characterization
data and experimental procedures are provided for com-
pounds 1, 3E, 3Z, and 7-13. This material is available free
of charge via the Internet at http://pubs.acs.org.
(20) Fitzpatrick, F. A.; Wynalda, M. A. J. Biol. Chem. 1983, 258, 11713.
In this report the stereochemistry at C14 was depicted as the (E)-isomer,
but no comment was made with regards to this assignment. Furthermore,
the NMR data was obtained on an 80 MHz instrument that showed almost
no resolution between H10, H14, and H.15 Based upon the data at hand, the
C14 stereochemistry of 15-deoxy-∆12,14-PGJ2 was most likely an assumption
supported by the albumin-catalyzed dehydration conditions used to access
this compound from PGD2.
OL035590V
(21) NMR spectral data was obtained on a 300 MHz instrument but was
not submitted as Supporting Information.
(22) Deoxy-∆12,14-PGJ2 has not been isolated from a natural source but
has been prepared by an albumin-catalyzed dehydration of PGD2.
152
Org. Lett., Vol. 6, No. 2, 2004