Diels-Alder approach to isoprostanes. Total synthesis of iPF(2α)-V

Article abstract of DOI:10.1021/ja982596k

Isoprostanes (iPs) are a group of natural products formed in vivo by a free-radical oxygenation of arachidonic acid. They are isomeric with prostaglandins; whereas enzymatically produced prostaglandins, such as PGF(2α) have the two side chains in the tran

Full text of DOI:10.1021/ja982596k

J. Am. Chem. Soc. 1998, 120, 11953-11961
11953
Diels-Alder Approach to Isoprostanes. Total Synthesis of iPF2R-V
Zubaidha Pudukulathan,† Sukumar Manna,† Seong-Woo Hwang,† Subhash P. Khanapure,†
John A. Lawson,‡ Garret A. FitzGerald,‡ and Joshua Rokach*,†
Contribution from the Claude Pepper Institute and Department of Chemistry, Florida Institute of
Technology, 150 W. UniVersity BlVd., Melbourne, Florida 32901, and The Center for Experimental
Therapeutics, UniVersity of PennsylVania, Philadelphia, PennsylVania 19104
ReceiVed July 20, 1998
Abstract: Isoprostanes (iPs) are a group of natural products formed in vivo by a free-radical oxygenation of
arachidonic acid. They are isomeric with prostaglandins; whereas enzymatically produced prostaglandins,
such as PGF2R have the two side chains in the trans stereochemistry, the side chains of the isoprostanes are
mostly in the cis configuration. A novel synthesis of iPs is described and illustrated with the synthesis of
iPF2R-V, 8. The synthetic material allowed us to identify this iP in human urine. Because of this cis relationship
between the two side chains in the structures of iPs, we selected a synthetic design based on the Diels-Alder
rection which will guarantee that the two side chains, which will be derived from the diene part, will be cis
to each other. By substituting the OH of the hydroxycyclopentenone 14 with a bulky TBDPS group, we
controlled the face selectivity of the approaching diene 17a from the less hindered top face of the five-membered
ring. We would obtain eventually the two OH groups of the isoprostanes R to the plane of the ring and the
two isoprostane side chains cis to each other and anti to the OH groups.
Introduction
These are also the representatives on which we have based our
newly proposed nomenclature for isoprostanes.13 The broader
issue we are facing in this field is to know which classes of iPs
are produced in vivo and in what proportions and what is the
biological impact of the individual iPs. For example, we already
know by using mass spectrometric determinations, that iPs
appear to be formed in much higher amounts than their isomers,
the prostaglandins,1 and that iPF2R-III2 is a potent vasoconstric-
tor,14,15 aggregates platelets, and may possibly express its
biological activity via a receptor.16 We have also shown that
8,12-iso-iPF2R-III possesses biological activity similar to that
of PGF2R.17 In addition, since AA is mainly esterified to
phospholipids, which are the main constituents of cell mem-
branes, the formation of polyhydroxylated derivatives such as
the iPs in the midst of phospholipids is bound to disturb the
hydrophobicity of the tight cell membrane, leading to cell
leakage and death. Another important application resulting from
our discovery of group VI iPs in urine is the possibility of
quantitating them and using them as a noninvasive index of
oxygen stress in diseases.18,19 For example, we have been able
to show that increased levels of iPF2R-VI are formed as a result
of the oxidation of low-density lipoprotein or LDL. The use
Isoprostanes (iPs), a newly discovered class of natural
products are isomeric with prostaglandins and are produced in
vivo by a nonenzymatic free-radical peroxidation process on
polyunsaturated fatty acids and esters.1 Arachidonic acid (AA),
a major polyunsaturated fatty acid, is the substrate for several
enzymatic systems such as the cyclooxygenases, which produce
prostaglandins, and the lipoxygenases, which make leukotrienes
and HPETEs. It has been proposed that AA, which is mostly
esterified to phospholipid membranes and lipoproteins, can also
form four groups of isoprostanes, III, IV, V, and VI, by a free-
radical oxygenation process1-6 (Scheme 1).
We have proposed two mechanisms for the formation of iPs7
based in part on some original reports.8-12 Scheme 1 also shows
the syn-anti-syn structures 6-9. These are the isoprostanes we
selected to focus on synthetically, and group V in particular.
† Florida Institute of Technology.
‡ University of Pennsylvania.
(1) Morrow, J. D.; Hill, K. E.; Burk, R. F.; Nammour, T. M.; Badr, K.
F.; Roberts, L. J., II. Proc. Natl. Acad. Sci. U.S.A. 1990, 87, 9383-9387.
(2) Hwang, S. W.; Adiyaman, M.; Khanapure, S.; Schio, L.; Rokach, J.
J. Am. Chem. Soc. 1994, 116, 10829-10830.
(3) Hwang, S. W.; Adiyaman, M.; Khanapure, S. P.; Rokach, J.
Tetrahedron Lett. 1996, 37, 779-782.
(4) Adiyaman, M.; Lawson, J. A.; Hwang, S. W.; Khanapure, S. P.;
FitzGerald, G. A.; Rokach, J. Tetrahedron Lett. 1996, 37, 4849-4852.
(5) Adiyaman, M.; Li, H.; Lawson, J. A.; Hwang, S. W.; Khanapure, S.
P.; FitzGerald, G. A.; Rokach, J. Tetrahedron Lett. 1997, 38, 3339-3342.
(6) Waugh, R. J.; Murphy, R. C. J. Am. Soc. Mass. Spectrom. 1996, 7,
490-499.
(7) Rokach, J.; Khanapure, S. P.; Hwang, S. W.; Adiyaman, M.; Lawson,
J. A.; FitzGerald, G. A. Prostaglandins 1997, 54, 823-851.
(8) O’Connor, D. E.; Mihelich, E. D.; Coleman, M. C. J. Am. Chem.
Soc. 1984, 106, 3577-3584.
(9) Pryor, W. A.; Stanley, J. P. J. Org. Chem. 1975, 40, 3615-3617.
(10) Porter, N. A.; Caldwell, S. A.; Mills, K. A. Lipids 1995, 30, 277-
290.
(11) Corey, E. J.; Wang, Z. Tetrahedron Lett. 1994, 35, 539-542.
(12) Hecker, M.; Ullrich, V.; Fischer, C.; Meese, C. O. Eur. J. Biochem.
1987, 169, 113-123.
(13) Rokach, J.; Khanapure, S. P.; Hwang, S. W.; Adiyaman, M.;
Lawson, J. A.; FitzGerald, G. A. Prostaglandins 1997, 54, 853-873.
(14) Takahashi, K.; Nammour, T. M.; Fukunaga, M.; Ebert, J.; Morrow,
J. D.; Roberts, L. J., II.; Hoover, R. L.; Badr, K. F. J. Clin. InVest. 1992,
90, 136-141.
(15) Baberheem, M.; Kang, K. H.; Morrow, J. D.; Roberts, L. J. R., II.;
Newman, J. H. In American Physiological Society; 1992; pp H660-H663.
(16) Pratico, D.; Smyth, E. M.; Violi, F.; FitzGerald, G. A. J. Biol. Chem.
1996, 271, 14916-14924.
(17) Kunapuli, P.; Lawson, J. A.; Rokach, J.; FitzGerald, G. A. J. Biol.
Chem. 1997, 272, 27147-27154.
(18) Pratico, D.; Barry, O. P.; Lawson, J. A.; Adiyaman, M.; Hwang, S.
W.; Khanapure, S. P.; Iuliano, L.; Rokach, J.; FitzGerald, G. A. Proc. Natl.
Acad. Sci. U.S.A. 1998, 95, 3449-3454.
(19) Reilly, M. P.; Delanty, N.; Roy, L.; Rokach, J.; Callaghan, P. O.;
Crean, P.; Lawson, J. A.; FitzGerald, G. A. Circulation 1997, 96, 3314-
3320.
10.1021/ja982596k CCC: $15.00 © 1998 American Chemical Society
Published on Web 11/06/1998

11954 J. Am. Chem. Soc., Vol. 120, No. 46, 1998
Pudukulathan et al.
Scheme 1
10
of vitamin E, a free-radical inhibitor, has reduced the free-radical
oxidation as judged by the lowering of iPF2R-VI to normal
levels.18 Oxidation of LDL is thought to be the initial step
leading to plaque deposition and atherosclerosis.
The availability of synthetic isoprostanes at this early juncture
is the rate-determining factor for progress in the field. We have
reported on a general method for the synthesis of iPs which we
applied to groups III, IV, and VI, the main feature of which is
a radical cyclization step to form the five-membered ring and
at the same time orient the two side chains in the desired cis
configurations.2-5,20-22 Other independent syntheses of some
of group III iPs have appeared recently.23-25
We are reporting here on a novel and general method for the
synthesis of iPs based on the Diels-Alder reaction and its use
in the first total synthesis of a group V isoprostane, namely
iPF2R-V, 8. We are also reporting, using the synthetic standard,
on the first identification of a Group V iP in human urine.
has been documented.2,8,26-28 Whereas it is possible and, in
fact, expected that some trans-isoprostanes will be formed, we
anticipate these to be minor components.7
Because of this cis relationship between the two side chains
in the structures of iPs, we selected a synthetic design based
on the Diels-Alder reaction29,30 (Scheme 2) which will
guarantee that the two side chains, which will be derived from
the diene part, will be cis to each other. Furthermore, we
thought that by controlling the face selectivity by having the
diene approaching from the less hindered face, we would obtain
eventually the two OH groups of the isoprostanes R to the plane
of the five-membered ring and the two isoprostane side chains
cis to each other and anti to the OH groups or â with respect
to the plane of the ring. To achieve this purpose we substituted
the hydroxy group with a TBDPSi group. We were encouraged
in that route by some past results in which we had been able to
control the face-selectivity in an inverse electron demand Diels-
Alder reaction. We were particularly impressed by the exclusive
control of the stereochemistry by a substituent R to the double
bond of the dienophile, resulting in an approach of the diene
from the opposite face of this substituent.31-33
Retrosynthesis
One of the important differences between the structures of
prostaglandins, e.g., PGF2R, 10, and those of the isoprostanes
is the cis relationship of the side chains in the latter, as compared
to the trans side chains in the enzymatically produced com-
pounds. This difference changes the complexion of the
chemistry one is contemplating when dealing with the isopros-
tanes. The predominance of the cis structural arrangement in
five-membered ring molecules formed by a radical cyclization
An important structural feature of the isoprostanes, which
we took into account from the outset, is the position of the
double bonds on the two side chains. As can be seen from the
(26) Beckwith, A. L. J.; Lawrence, T.; Serelis, A. K. J. Chem. Soc., Chem.
Commun. 1980, 484-485.
(27) Beckwith, A. L. J.; Schiesser, C. H. Tetrahedron 1985, 41, 3925-
3941.
(20) Rokach, J.; Khanapure, S. P.; Hwang, S. W.; Adiyaman, M.; Schio,
L.; FitzGerald, G. A. Synthesis, First Special Issue, Natural Products
Synthesis 1998, 569-580.
(21) Rondot, B.; Durand, T.; Girard, J. P.; Rossi, J. C.; Schio, L.;
Khanapure, S. P.; Rokach, J. Tetrahedron Lett. 1993, 34, 8245-8248.
(22) Adiyaman, M.; Lawson, J. A.; Khanapure, S. P.; FitzGerald, G.
A.; Rokach, J. Anal. Biochem. 1998, 262, 45-56.
(23) Larock, R. C.; Lee, N. H. J. Am. Chem. Soc. 1991, 113, 7815-
7816.
(24) Taber, D. F.; Herr, R. J.; Gleave, D. M. J. Org. Chem. 1997, 62,
194-198.
(25) Vionnet, J.-P.; Renaud, P. HelV. Chim. Acta 1994, 77, 1781-1790.
(28) Porter, N. A.; Zuraw, P. J.; Sullivan, J. A.; Gross, P. M. Tetrahedron
Lett. 1984, 25, 807-810.
(29) Fringuelli, F.; Taticchi, A. Dienes in the Diels-Alder Reaction; John
Wiley & Sons: New York, 1990; p 348.
(30) Tetrahedron Organic Chemistry Series; Carruthers, W., Ed.; Per-
gamon Press: Oxford, 1990; Vol. 8, p 373.
(31) Fitzsimmons, B. J.; Leblanc, Y.; Rokach, J. J. Am. Chem. Soc. 1987,
109, 285-286.
(32) Fitzsimmons, B. J.; Leblanc, Y.; Chan, N.; Rokach, J. J. Am. Chem.
Soc. 1988, 110, 5229-5231.
(33) Leblanc, Y.; Fitzsimmons, B. J.; Springer, J. P.; Rokach, J. J. Am.
Chem. Soc. 1989, 111, 2995-3000.

Total Synthesis of iPF2R-V
J. Am. Chem. Soc., Vol. 120, No. 46, 1998 11955
Scheme 2
Scheme 3
four groups of iPs derived from AA (Scheme 1), we have three
structural variations of the side chains. All are accessible by
the strategy proposed here, and the four groups of syn-anti-syn
isoprostanes can be prepared from intermediates such as 11a
and its enantiomer, 11b.
The selection of the electron-rich Danishefsky dienes34 was
made in order to ensure exclusive regioselectivity in the Diels-
Alder reaction and that at some point later in the synthesis we
could excise by oxidative cleavage the unnecessary carbon to
afford a two-carbon substituent for the elaboration of the top
side chain and one carbon for the elaboration of the bottom
side chain.
Another issue we considered before the start of the synthesis
was the stereocontrolled reduction of the five-membered ring
carbonyl on the Diels-Alder adducts. Here again, we were
counting on the shielding of the R face by the bulky TBDPSi
group to force the hydride attack from the top or â face in order
to afford the desired R-hydroxy derivative. A hydride reduction
not unlike the one we were considering has been described.35
However, as can be seen later, the hydride reduction did not
proceed as anticipated. In summary, our plan was to use the
asymmetric center in 14, which would correspond to carbon 6
in the final isoprostane, to control the stereocenters at 5 and 9
by the Diels-Alder reaction and the asymmetric center at 8 by
a stereocontrolled reduction. The fifth asymmetric center at
carbon 12 can be introduced by a stereoselective reduction of
an R,â-unsaturated carbonyl.
in 7% yield instead of ∼14-15% in toluene. 2,6-Di-tert-butyl-
4-methyl phenol (BHT) was added in all of the experiments to
prevent or slow the polymerization of the dienes.
The major product was the anticipated one and is probably
formed by an endo-anti attack of the less hindered face
(Scheme 4). The minor syn-anti-syn product 19a is possibly
formed by an exo-anti attack from the less hindered face. This
is also a useful product for our purposes since we intended to
cleave this ring in any event. The other way this product could
have been formed is by an endo-anti attack from the less
hindered face by the cis methoxy isomer of the diene 17a if it
were present in our original diene. We could not, however,
find NMR evidence for that. The third product of the reaction
is most likely the result of an exo-syn attack from the more
hindered face.
The identity of the products was established by NMR, COSY,
NOE, and MS studies and by chemical transformations. The
three products clearly show by NOE, decoupling studies and
by coupling constant analysis, the cis relationship of the ring
junction protons, indicating to us that those are primary Diels-
Alder products (see Experimental Section). The zero coupling
constant observed for C2-H and C1-H for the R product 19a
is an indication that the dihedral angle between the two
hydrogens is about 90°. This situation fits only the R structure
19a and is confirmed by model studies. Equally, the coupling
constant between the same two hydrogens in the major â product
Results and Discussion
The reaction between the dienophile 16a, prepared in high
enantiomeric excess (g99%),36 and the diene 17a37 was carried
out in xylene as described in Scheme 3. Three products, 18a,
19a, and 20a, were obtained in 87% yield and in a ratio of 72,
20, and 8, respectively, or in a 92:8 ratio of products resulting
from attack of the diene from the less hindered side to the
product resulting from an attack from the more hindered side.
The reaction has also been carried out in a similar fashion in
toluene at 110 °C. The reaction times are longer (∼18 h), and
the yields somewhat lower. More importantly from our
perspective is the fact that there was significantly less attack
from the hindered face, 18a and 19a were obtained in 80%
isolated yield instead of 70% in toluene, and 20a was obtained
(34) Danishefsky, S. Acc. Chem. Res. 1981, 14, 400-406.
(35) Jeroncic, L. O.; Cabal, M. P.; Danishefsky, S. J. J. Org. Chem.
1991, 56, 387-395.
(36) Khanapure, S. P.; Najafi, N.; Manna, S.; Yang, J.-J.; Rokach, J. J.
Org. Chem. 1995, 60, 7548-7551.
(37) Dowd, P.; Weber, W. J. Org. Chem. 1982, 47, 4774-4777.

11956 J. Am. Chem. Soc., Vol. 120, No. 46, 1998
Pudukulathan et al.
Scheme 4
Scheme 5
Scheme 6
Scheme 7
18a is 5.7 (benzene), indicating a dihedral angle of 40-60°.
Examination of molecular models shows that the dihedral angles
between these two hydrogens can vary from -50° to a
maximum of 40° by changing the conformation of the molecule.
This set of data fits only the â structure 18a. It is interesting
to note that MM2 calculations for the minimum energy
conformation for 19a show a dihedral angle of 88° for the R
compound and 45° for the â compound 18a, which fits quite
well with our experimental observations and model studies. NOE
studies in two different solvent systems also confirm the identity
of 18a, 18b, and 19a and 19b. The fact that 18a and 19a are
methoxy epimers was also established unambiguously by
rearranging the allylic methoxy of the two products to a single
compound, the dimethyl ketal 30a, (Scheme 6). Furthermore,
aldehyde 37 (Scheme 9) has been transformed to bicyclic lactone
45 and compared to an authentic sample.2 This transformation
is discussed later in this section. This establishes the stereo-
chemical assignment of structures 18 and 19. The structural
assignment of 20 was based on NMR evidence, NOE, MS, and
the fact that there is a zero coupling constant between hydrogens
at C2 and C1, indicating a dihedral angle of approximately 90°.
This arrangement fits only structure 20.
We have also performed the Diels-Alder reaction with 17b
R2 ) TBDMS without appreciable differences in results
(Scheme 3). The bicyclic Diels-Alder products 18, 19, and
20 are not stable in all cases and do not store well. The two
dimethoxy epimers 18a and 19a overlap on TLC and have been
purified by careful repeated chromatography for characterization
purposes. Usually the mixture is used as such for the next step
as is described later. The TBDMS products 18b and 19b are
slightly more stable and somewhat easier to separate. However,
for reasons which will become apparent later, these intermediates
have not been selected to complete the total synthesis of 8.
The next step in the planned synthesis was the reduction of
the carbonyl group in 18a and 18b, and as mentioned, we were
expecting a hydride attack from the â face, which we anticipated
to be the less crowded face, to yield the desired R-hydroxy
group. We were counting on the shielding of the R face by the
bulky TBDPS group to force the reduction from the top.
Instead, the reduction of 18a proceeded entirely the opposite
way, and 26a was obtained exclusively (Scheme 5). Under the
same conditions, the epimeric R product 19a afforded a 10:90
mixture of 28a and 29a, respectively, favoring hydride attack
from the top face.
It was becoming obvious that the â-methoxy group in the
major product 18a was interfering seriously with an approach
from the top. At this point, we turned to a plan we had
considered in our original design, that is, to remove the methoxy
group from that position. Equally, when we planned the Diels-
Alder reaction, we were not sure of the extent of the formation
of the R-methoxy isomer 19a, if any, and to take advantage of
the two products for further synthetic manipulations, we
considered transforming 18a and 19a by an allylic rearrangement
to a common gem dimethoxy derivative 30a (Scheme 6).
Alternatively, a related transformation to yield R,â-unsaturated
ketones was described in the literature,38 and we thought we
could take advantage of it. As it turned out (Scheme 7), both
reactions worked very well, in fact, quantitatively. The
transformation of 18a and 19a to the gem dimethoxy derivative
30a was effected as described in Scheme 6 in 98% yield. The
formation of the R,â-unsatured ketone 31 (Scheme 7) using
t-BuDMSOTf 38 was accomplished in quantitative yield. The
hydrolysis product 31 obtained from the gem dimethoxy
derivative 30a and the one obtained by the t-BuDMSOTf
(38) Aldrichimica Acta 1986, 19, 42.

Total Synthesis of iPF2R-V
J. Am. Chem. Soc., Vol. 120, No. 46, 1998 11957
Scheme 9a
Scheme 8
procedure in Scheme 7 are identical. We also attempted the
allylic rearrangement on the TBDMS derivative 18b with limited
success. A mixture of 30b and 30a was obtained in low yield.
We elected to proceed with 18a and 19a instead of 18b and
19b for the completion of the total synthesis. The enone 31
presented, at this point, no particular advantage since the
carbonyl in the 6-membered ring in 30a was already protected.
The reduction of 30a with NaBH4 at -78 °C afforded in 93%
yield a 5:1 mixture of 32:33 in favor of the desired â-hydride
attack (Scheme 8). Similar distribution of products is obtained
with LiBH4 and LiAlH4. The major product is easily separated
by silica gel chromatography to afford 32. Because of the
quantitative formation of the gem dimethoxy 30a from 18a and
19a, we found it convenient to carry out the reduction in the
same pot by simply cooling the reaction mixture to -78 °C
and then adding the NaBH4.
The TBDPS derivative 34 was prepared in 85% yield
(Scheme 9). The dimethyl acetal group in 34 was hydrolyzed
under mild conditions using p-TsOH to give enone 35 in 93%
yield. The osmium tetraoxide oxidation of 35 proceeded well
from the sterically less hindered convex face of the molecule
to yield the cis diol 36 in 95% yield. The stereochemistry of
the cis diol 36 was confirmed by NOE experiments (see
Experimental Section). It is also interesting to note that all of
the hydrogens except the ring junction ones in this molecule
are pointing inward from the concave face of the molecule and
NOEs between remote protons can be seen. The cleavage of
the diol 36 with sodium periodate followed by treatment of the
crude product with methyl iodide and diisopropylamine afforded
methyl ester aldehyde 37 in 73% yield. Introduction of the
lower side chain was performed by carrying out the Wittig
reaction with phosphonate 38 at -78-0 °C for 12 h to give 39
in 72% yield. The enantioselective reduction of the C12 keto
function in 39 proceeded smoothly with (S)-BINAL-H with
>95% ee2-5,39 and afforded the 12-S derivative 40a in 85%
yield. The hydroxyl group in 40a was protected as the TBDPS
derivative 40b in 90% yield and the ester function was converted
to alcohol 40c by the reduction of 40b with DIBAL-H in 92%
yield.
a Reaction conditions: (a) Acetone, 3 h, 93%; (b) t-BuOH/CH3CN
(3:1), 1 h, 95%; (c) (1) MeOH/H2O (3:1), 20 h, (2) diisopropyl amine,
rt 24 h, 72%; (d) NaN(SiMe3)2, THF, -78 °C to 0 °C, 12 h, 72%; (e)
THF, -100 °C for 3 h then -78 °C for 2 h, 85%; (f) Imd., DMF, 2 h,
90%; (g) CH2Cl2, 0 °C, 18 h, 92%; (h) 2 equiv (COCl)2, 3 equiv DMSO,
CH2Cl2, -78 °C, 15 min, then alcohol, -78 °C, 30 min, 6 equiv Et3N,
-78 °C, 95%; (i) THF, 18 h, 90%; (j) THF, reflux, 18 h, 85%; (k)
THF, 18 h, 83%; (l) dioxane/H2O (3:1), 0 °C, 10 min, 5% aqueous
KH2PO4 (pH ) 4.2), 92%.
The introduction of the upper side chain was performed by
first preparing the aldehyde 41 by Swern oxidation of 40c in
95% yield, and the two-carbon extension was performed by
carrying out the Wittig reaction to yield 42 in 90% yield. The
selective reduction of the R,â-unsaturated double bond in 42
was performed in 85% yield using sodium borohydride in THF.
Finally, after desilylation of 43 using tetrabutylammonium
fluoride, the basic hydrolysis of 44 yielded the desired iPF2R-V
8 in 91% yield.
As mentioned previously, 37 was converted to the bicyclic
six-membered ring lactone 45 and compared with an authentic
sample we prepared previously by a different methodology.2
The lactone 45 was prepared as follows. Aldehyde ester 37
was reduced with L-selectride. On acidification and solvent
evaporation, lactone 45 was obtained.
approaching the dienophile from the less hindered top face by
an endo approach and, to a lesser extent, by an exo approach.
Recently some elegant mechanistic work described the opposite
face selectivity in a Lewis acid-catalyzed Diels-Alder reaction,
with the diene approaching from the more hindered face. The
ratio of the hindered/nonhindered approach was 96:435,40
(Scheme 10). The reason for the unusual face selectivity was
explained in terms of orbital interaction between the diene and
dienophile.35,41
We were intrigued by the contrasting results we obtained as
compared to those in Scheme 10B and decided to have a closer
look at the differences between the two reactions. (1) Our
dienophile carried a TBDPS group (Scheme 3) versus the
TBDMS in Scheme 10B. (2) A dimethoxy and a silyl-
oxymethoxy diene are used in our reaction versus the unsub-
The Diels-Alder reaction described above worked as in-
tended and afforded high face selectivity, with the diene
(40) Danishefsky, S. J.; Paz Cabal, M.; Chow, K. J. Am. Chem. Soc.
1989, 111, 3456-3457.
(41) Cieplak, A. S. J. Am. Chem. Soc. 1981, 103, 4540-4552.
(39) Noyori, R.; Tomino, I.; Tanimoto, Y.; Nishizawa, M. J. Am. Chem.
Soc. 1984, 106, 6709.

11958 J. Am. Chem. Soc., Vol. 120, No. 46, 1998
Pudukulathan et al.
Scheme 10a
the more hindered side, 23, will experience the maximum steric
interference. This is probably why we did not obtain 21 in
entries 5, 6, 7, and 8. Finally, entry 8 shows that temperature
alone can influence the ratio of syn to anti, and it is the lowest
we have experienced. From the synthetic perspective, this was
the best reaction, and we are now using these conditions
routinely for the synthetic applications.
The results shown in Scheme 11 indicate that an endo-syn
approach (approach 23, Scheme 4) of the substituted dienes from
the less hindered face of a five-membered ring dienophile is
not favored. We have been unable to obtain a reaction of 16a
with dimethoxy butadiene 17a using AlCl3 as catalyst due to
polymerization of the diene.
a A: reference 40. B: reference 35.
In conclusion, the thermal reaction (entries 3-8) is influenced
by the bulk of the substituent on the five-membered ring, by
the substituent (R6) on the diene (Scheme 4, approach 23), and
by the temperature, all of which contribute synergistically and
afford a high face selectivity from the less hindered face 92:8.
stituted butadiene 17c (Scheme 10B). (3) Our Diels-Alder
reaction was done thermally, with no Lewis acid present.
We carried out the Diels-Alder reaction with dienophile 16b
and butadiene 17c, under AlCl3 conditions (Scheme 11, entry
1). We then tried, under the same conditions, the reaction
between the bulkier TBDPS derivative 16a and butadiene 17c
(entry 2). In this case, the bulkier TBDPS derivative is causing
more of the butadiene to approach from the less hindered face.
We then performed the same reaction using our conditions
(without AlCl3), entries 3 and 4, resulting in a preponderance
of the unhindered approach.
Entries 6 and 7 are the results reported in Scheme 3. Entry
5 was performed to find out if changing R1 and keeping the
substituted diene had any influence on the outcome of the
Diels-Alder reaction. As can be seen, entries 5, 6, and 7
produce identical results and ratios of syn to anti products. This
probably means that the 3-substituent on the diene has a
controlling effect, and we do not observe any difference between
the TBDMS and TBDPS on the dienophile. Looking back at
Scheme 4 shows that R1 and R2 on an endo-syn approach from
We have used the synthetic iPF2R-V to identify by LC/MS
its existence in urine (elution and coelution retention times,
11.83 min). A linear solvent gradient was used. Solvent A
was water; solvent B was acetonitrile/methanol, 95:5, both with
0.005% acetic acid, pH adjusted to 5.7 with ammonium
hydroxide, flow rate 200 µL/min. Quantitative information is
not as yet available since we have not yet prepared the
deuterated standard. This is the first proof for the existence of
group V in vivo. The discovery of IPF2R-III1 and the proposal
of four groups of iPs derived from AA by a free-radical
mechanism in vivo have previously been reported.1,2,6 Before
the present report, using our synthetic standards, we had
identified groups III, IV, and VI in human urine. The discovery
in urine of IPF2R-V, a group V iP, reported here, completes
one of our initial objectives which was to discover the individual
iPs and confirm, using synthetic standards, the existence of four
Scheme 11

Total Synthesis of iPF2R-V
J. Am. Chem. Soc., Vol. 120, No. 46, 1998 11959
δ 7.70 (m, 4 H), 7.24 (m, 6 H), 4.83 (d, J ) 4.0, 1 H), 4.57 (d, J )
4.7, 1 H), 4.26 (ddd, J ) 8.4, 8.3, 6.0 Hz, 1 H), 3.22 (s, 3 H), 3.19 (s,
3 H), 2.83 (m, 1 H), 2.54 (dd, J ) 18.2, 7.8 Hz, 1 H), 2.37 (dd, J )
18.2, 10.1, 1 H), 2.20 (d, J ) 7.0 Hz, 1 H), 2.12 (t, J ) 8.4 Hz, 2 H),
1.11 (s, 9 H). 13C NMR (C6D6) δ 209.98, 157.56, 135.63 (2 C), 135.56
(2 C), 133.74, 133.50, 129.90, 129.86, 127.83 (4 C), 92.97, 71.67, 70.48,
54.93, 53.54, 53.49, 43.05, 36.67, 26.65, 24.12, 18.97.
Procedure b. A solution of 4-tert-butyldiphenylsilyloxycyclo-
pentenone 16a (0.164 g, 0.488 mmol) and 1,3-dimethoxy-1,3-butadiene
17a (0.222 g, 1.95 mmol) in toluene (0.5 mL) containing 2,6-di-tert-
butyl-4-methyl phenol (BHT, 5 mg) was heated at 110 °C in a sealed
tube for 18 h. Evaporation of the solvent and chromatography of the
residue (silica gel, elution with 8:2 hexanes/ether) gave a mixture of
18a and 19a 0.154 g (70%) and 0.033 g (15%) of 20a. The spectral
data were identical to those described above.
groups of iPs formed in vivo by the free-radical peroxidation
of arachidonic acid.
Experimental Section
Reagents and Methods. Unless stated otherwise, all reagents and
chemicals were obtained from commercial sources and used without
further purification.
1H NMR and 13C NMR spectra were recorded on a 360 MHz
spectrometer with tetramethylsilane as an internal standard, and J values
are given in Hz.
All reactions were carried out under an inert (nitrogen or argon)
atmosphere with dry, freshly distilled solvents under anhydrous
conditions unless otherwise noted. Yields refer to chromatographically
and spectroscopically (1H NMR) homogeneous materials.
The NOEs were performed in either d6-acetone or d6-benzene, and
the results of several compounds are shown under the appropriate
headings in the Experimental Section.
4(S)-[(tert-Butyldiphenylsilyl)oxy]cyclopent-2-en-1-one (16a). A
mixture of (-)4(S)-hydroxy-cyclopentenone (14a)36 (0.70 g, 7.14
mmol), triethylamine (6 mL, 42.80 mmol), and tert-butyldiphenyl
chlorosilane (2.35 g, 8.85 mmol) in dry methylene chloride (12 mL)
containing a catalytic amount of DMAP was stirred at 0 °C for 10 min
and then at room-temperature overnight (20 h). Water (50 mL) was
added, and the product was extracted with ether (2 × 50 mL). The
combined organic phase was washed with water (50 mL) and brine
(25 mL), dried (Na2SO4), and concentrated in Vacuo. The residue was
purified by flash chromatography (silica gel, elution with 3:7 hexanes/
methylene chloride) to give 1.4 g (60%) of 4(S)-[(tert-butyldiphenyl-
silyl)oxy]cyclopentenone 16a. 1H NMR (CDCl3) δ 7.67 (m, 4 H), 7.41
(m, 6 H), 7.33 (dd, J ) 5.7, 2.2 Hz, 1 H), 6.10 (dd, J ) 5.7, 0.9 Hz,
1 H), 4.93 (m, 1 H), 2.49 (dd, J ) 18.2, 5.9 Hz, 1 H), 2.32 (dd, J )
18.2, 2.2 Hz, 1 H), 1.06 (s, 9 H). 13C NMR ((CDCl3) δ 206.23, 163.60,
135.74, 135.70 (2 C), 134.55, 133.11, 130.15 (2 C), 127.98 (2 C), 71.88,
44.82, 26.88 (2 C), 19.13.
(1S,6S,7S,9R)-4,4-Dimethoxy-7-[(tert-butyldiphenylsilyl)oxy]bicyclo-
[4.3.0.]non-3-en-9-ol (32). A solution of the cis-adducts 18a and 19a
(0.154 g, 0.342 mmol) and methyl orthoformate (0.360 mL, 3.42 mmol)
in dry methanol (4 mL) containing a catalytic amount of pyridinium
p-toluenesulfonate (PPTs) was stirred at room temperature for 2 h. The
reaction mixture was cooled to -78 °C and treated with excess sodium
borohydride with stirring maintained at -78 °C for 3 h. The solvent
was removed under reduced pressure, and the organic material was
extracted with ether (2 × 150 mL), washed with water (2 × 50 mL),
dried (Na2SO4), and concentrated in vacuo. Purification of the residue
by flash chromatography (silica gel, elution with 5:5 hexanes/ether)
gave 0.130 g (77%) of 32 and 0.024 g (14%) of 33. The two steps
have been performed individually in yields of 98% for the gem
dimethoxy derivative 30a and 93% for the sodium borohydride step.
Spectral data for 32: 1H NMR (C6D6) δ 7.81 (m, 4 H), 7.26 (m, 6
H), 5.82 (m, 2 H), 4.20 (m, 1 H), 3.89 (m, 1 H), 3.08 (s, 3 H), 3.0 (s,
3 H), 2.93 (m, 1 H), 2.77 (m, 1 H), 2.54 (d, J ) 9.1 Hz, 1 H), 1.86 (m,
2 H), 1.61 (dd, J ) 12.8, 5.8 Hz, 1 H), 1.19 (s, 9 H), 1.04 (dd, J )
12.6, 10.3 Hz, 1 H). 13C NMR (C6D6) δ 136.65, 136.56, 134.62, 134.57,
132.13, 130.40, 130.38, 129.26, 128.42, 128.41, 97.83, 80.42, 78.71,
48.76, 48.75, 48.13, 44.48, 43.42, 33.61, 27.52, 19.53. HEIMS calcd
for C22H23O3Si 363.1417 (M - t-Bu - CH3OH)+, found 363.1423.
Diels-Alder Reaction of 4-tert-Butyldiphenylsilyloxycyclo-
pentenone (16a) with 1,3-Dimethoxy-1,3-butadiene (17a). Proce-
dure a: A solution of 4-tert-butyldiphenylsilyloxycyclopentenone (16a,
0.100 g, 0.294 mmol) and 1,3-dimethoxy-1,3-butadiene (17a, 0.100 g,
0.877 mmol) in xylene (0.5 mL) containing 2,6-di-tert-butyl-4-methyl
phenol (BHT, 5 mg) was heated at 140 °C in a sealed tube for 10 h.
Evaporation of the solvent and chromatography of the residue (silica
gel, elution with 8:2 hexanes/ether) gave a mixture of 18a and 19a
0.110 g (80%) and 0.010 g (7%) of 20a.
1
Spectral data for 33: H NMR (CDCl3) δ 1.28 (s, 9 H), 1.56 (t, J
) 11.6 Hz, 1 H), 1.88 (dd, J ) 13.2, 5.0 Hz, 1 H), 2.0 (dt, J ) 13.7,
5.1 Hz, 1 H), 2.16 (ddd, J ) 12.0, 6.4, 2.7 Hz, 1 H), 2.72 (m, 2 H),
3.12 (s, 3 H), 3.20 (s, 3 H), 4.09 (m, 1 H), 4.49 (m, 1 H), 5.56 (dd, J
) 10.3, 3.2 Hz, 1 H), 6.09 (d, J ) 10.3 Hz, 1 H), 7.32 (m, 6 H), 7.87
(m, 4 H).
(1S,6S,7S,9R)-4,4-Dimethoxy-7,9-bis-[(tert-butyldiphenylsilyl)oxy]-
bicyclo[4.3.0.]non-2-en (34). To a mixture of alcohol 33 (0.130 g,
0.285 mmol) and imidazole (0.077 g, 1.14 mmol) in DMF (7 mL) was
added tert-butyldiphenylchlorosilane (0.312 g, 0.57 mmol) in DMF (7
mL), and the solution was stirred at room temperature for 2 h.
Triethylamine (0.5 mL) was added at 0 °C prior to the addition of
water (100 mL). The reaction mixture was extracted with ether (2 ×
100 mL), washed with water (2 × 50 mL) and brine (50 mL), and
concentrated in Vacuo. The residue was purified by flash chromatog-
raphy (silica gel, elution with 9:1 hexanes/ether) to afford 0.153 g of
34 (85%). 1H NMR (C6D6) δ 7.80 (m, 8 H), 7.26 (m, 12 H), 5.79 (dd,
J ) 10.5, 3.4 Hz, 1 H), 5.73 (d, J ) 10.5, 1 H), 4.00 (m, 2 H), 3.08 (s,
3 H), 3.04 (m, 1 H), 2.96 (s, 3 H), 2.74 (m, 1 H), 2.02 (m, 2 H), 1.59
(dd, J ) 12.6, 5.1 Hz, 1 H), 1.24 (s, 18 H), 0.94 (t, J ) 12.0 Hz, 1 H).
13C NMR (C6D6) δ 136.14(4C), 136.10(4C), 134.69, 134.45, 134.43,
134.31, 131.34, 129.83, 129.76, 129.67, 129.63, 128.44, 127.78 (8 C),
97.49, 78.31, 77.61, 48.19, 47.50, 47.43, 45.01, 43.78, 33.23, 27.09 (6
C), 19.25, 19.19; HEIMS calcd for C38H41O3Si2 601.2595 (M - t-Bu
-CH3OH)+, found 601.2573.
1
Spectral data for 18a and 19a: H NMR (C6D6) δ 7.75 (m, 4H),
7.22 (m, 6 H), 4.65 (m, 1 H), 4.51 (d, J ) 5.8 Hz, 1 H), 4.01 (t, J )
5.6 Hz, 1 H), 3.10 (s, 3 H), 2.87 (s, 3 H), 2.53 (dd, J ) 17.9, 7.1 Hz,
1 H), 2.48 (d, J ) 15.5 Hz, 1 H), 2.20 (dd, J ) 17.9, 7.5 Hz, 1 H),
1.19 (s, 9 H). 13C NMR (C6D6) δ 211.94, 159.51, 135.86 (2 C), 135.84
(2 C), 134.0, 133.80, 129.67 (2 C), 127.70 (4 C), 91.35, 75.58, 73.68,
53.47, 51.09, 48.36, 42.56, 27.31, 26.88 (3 C), 19.07.
The mixture of 18a and 19a is usually used as such in the next step.
To isolate 18a and 19a in the pure form, the mixture was separated by
flash column chromatography (silica gel, elution with benzene).
Spectral data for (1S,2S,6S,7S)-2,4-dimethoxy-7-[(tert-butyl-
diphenylsilyl)oxy]bicyclo[4.3.0.]non-3-en-9-one (18a): 1H NMR (d6-
acetone) δ 7.70 (m, 4H), 7.46 (m, 6 H), 4.94 (d, J ) 5.8 Hz, 1 H),
4.47 (m, 1 H), 3.98 (t, J ) 5.6 Hz, 1 H), 3.50 (s, 3 H), 2.97 (s, 3 H),
2.61 (m, 1 H), 2.47 (m, 1 H), 2.29 (m, 2 H), 2.05-2.2 (m, 2 H), 1.08
(s, 9 H). 13C NMR (C6D6) δ 211.94, 159.51, 135.86 (2 C), 135.84 (2
C) 134.0, 133.80, 129.67 (2 C), 127.70 (4 C), 91.35, 75.58, 73.68,
53.47, 51.09, 48.36, 42.56, 27.31, 26.88 (3 C), 19.07.
Spectral data for (1S,2R,6S,7S)-2,4-dimethoxy-7-[(tert-butyl-
diphenylsilyl)oxy]bicyclo[4.3.0.]non-3-en-9-one (19a): 1H NMR (C6D6)
(d6-acetone) δ 7.71 (m, 4H), 7.48 (m, 6 H), 4.81(d, J ) 4.5 Hz, 1 H),
4.33 (d, J ) 5.3 Hz, 1 H), 4.17 (d, J ) 4.7 Hz, 1 H), 3.50 (s, 3 H),
3.27 (s, 3 H), 3.03 (d, J ) 7.7 Hz, 1 H), 2.67 (m, 1 H), 2.42 (dd, J )
19.2, 5.3 Hz, 1 H), 2.27 (d, J ) 19.2 Hz, 1 H), 1.94 (dd, J ) 17.6, 8.0
Hz, 1 H), 1.08 (s, 9 H).
(1S,6S,7S,9R)-7,9-Bis-[(tert-butyldiphenylsilyl)oxy]bicyclo[4.3.0.]-
non-2-en-4-one (35). A solution of the dimethyl ketal 34 (0.153 g,
0.242 mmol) in dry acetone (18 mL) was stirred at room temperature
for 40 min in the presence of a catalytic amount of p-TsOH. The
solvent was evaporated, and the product was purified by flash
chromatography (silica gel, elution with 8:2 hexanes/ether) to yield
0.130 g (92%) of 34. 1H NMR (C6D6) δ 7.76 (m, 8 H), 7.28 (m, 12
H), 5.75 (d, J ) 10.4 Hz, 1 H), 5.65 (d, J ) 10.4 Hz, 1 H), 3.87 (m,
2 H), 2.74 (m, 2 H), 2.26 (dd, J ) 16.8, 5.0 Hz, 1H), 2.07 (dd, J )
Spectral data for (1R,2S,6R,7S)-2,4-dimethoxy-7-[(tert-butyl-
diphenylsilyl)oxy]bicyclo[4.3.0.]non-3-en-9-one (20a): 1H NMR (C6D6)

11960 J. Am. Chem. Soc., Vol. 120, No. 46, 1998
Pudukulathan et al.
16.6, 5.2 Hz, 1 H), 1.92 (m, 2 H), 1.23 (s, 18 H). 13C NMR(C6D6) δ
196.40, 147.97, 136.60, 136.52, 136.49, 134.89, 134.60, 134.50, 134.20,
130.56, 130.54, 130.47, 130.36, 129.84, 128.55, 128.47, 128.40, 78.05,
76.93, 47.98, 46.22, 45.54, 37.99, 27.56, 27.50, 19.72, 19.62. HEIMS
calcd for C37H39O3Si2 587.24387 (M - t-Bu)+, found 587.2410.
(1S,2R,3R,6S,7S,9R)-2,3-Dihydroxy-7,9-bis-[(tert-butyldiphenylsilyl)-
oxy]bicyclo[4.3.0.]non-4-one (36). A mixture of 35 (0.130 g, 0.222
mmol) and trimethylamine oxide dihydrate (0.5 g) in t-BuOH/CH3CN/
H2O (21 mL:11 mL:5 mL) was treated with a catalytic amount of
osmium tetraoxide and stirred at room temperature for 1 h. Most of
the organic solvent was evaporated, and the reaction mixture was
extracted with ether (2 × 100 mL). The combined ether extracts were
washed with water (40 mL) and brine (40 mL), dried (Na2SO4), and
concentrated in Vacuo. Chromatography of the residue (silica gel,
elution with 5:5 hexanes/ether) afforded 0.140 g (95%) of 36. 1H NMR
(C6D6) δ 7.80 (m, 8 H), 7.32 (m, 12 H), 4.45 (br s, 1 H), 4.13 (m, 1
H),), 3.81 (br s, 1 H), 3.61 (m, 1 H), 3.43 (br s, 1 H), 3.32 (m, 1 H),
2.85 (br s, 1 H), 2.80 (m, 1 H), 2.06 (m, 2 H), 1.81 (dd, J ) 14.3, 6.4
Hz, 1 H), 1.23 (s, 9 H), 1.19 (s, 9 H). 13C NMR(C6D6) δ 208.11,
136.06 (2 C), 135.94 (2 C), 135.86 (2 C), 135.79 (2 C), 134.18, 134.14,
133.70, 133.67, 130.10, 129.86, 129.84, 129.70, 127.83 (8 C), 77.10,
74.25, 73.70, 72.96, 51.32, 46.28, 44.12, 38.82, 26.95 (2 C), 26.83 (2
C), 19.05, 18.94; HEIMS calcd for C37H41O5Si2 621.2493 (M - C4H9)+,
found 621.2489 and calcd for C37H39O4Si2 603.2387 (M - t-Bu -
H2O)+, found 603.2407.
Methyl 2-{3R,5R-Bis-[(tert-butyldiphenylsilyl)oxy]-2â-(carbox-
aldehyde)-1â-cyclopentane}-acetate (37). The diol 36 (0.140 g, 0.20
mmol) in a mixture of methanol/water (42 mL:14 mL) was treated with
sodium periodate (0.526 g, 2.46 mmol) at 0 °C and was stirred at room
temperature for 20 h. After evaporation of the solvent, the organic
material was extracted with ether (2 × 100 mL). The combined ether
extracts were dried (Na2SO4) and concentrated under reduced pressure.
The residue dissolved in acetonitrile/ether (3 mL:3 mL) was treated
with excess diisopropylethylamine (1.5 mL, 8.2 mmol) and methyl
iodide (0.5 mL, 7.1 mmol) and stirred for 24 h. Water (50 mL) was
added and extracted with ether (100 mL). The ether extract was washed
with water (50 mL) and brine (50 mL), dried (Na2SO4), and concen-
trated in Vacuo. The residue was chromatographed (silica gel, elution
with 8:2 hexanes/ether) to afford 0.100 g (72%) of 37. 1H NMR (C6D6)
δ 9.31 (S, 1 H), 7.74 (m, 8 H), 7.24 (m, 12 H), 4.49 (q, J ) 6.0 Hz,
1 H), 4.0 (q, J ) 6.2, 1 H), 3.54 (m, 1 H), 3.25 (s, 3 H), 3.09 (m, 1 H),
2.29 (dd, J ) 16.0, 5.7 Hz, 1 H), 2.22 (dd, J ) 16.0, 9.6 Hz, 1 H),
1.89 (t, J ) 6.2 Hz, 2 H), 1.20 (s, 9 H), 1.19 (s, 9 H). 13C NMR
(C6D6) δ 201.83, 172.77, 136.58 (4 C), 136.53 (4 C), 134.77, 134.48,
134.32, 134.09, 130.53, 130.48, 130.38 (2 C), 128.45 (8 C), 77.31,
72.32, 61.65, 51.49, 45.99, 44.10, 33.01, 27.57 (3 C), 27.50 (3 C),
19.75, 19.64. HEIMS calcd for C37H41O5Si2 621.24933 (M - t-Bu)+,
found 621.24929.
1,5-undecadien-3-ol]-1â-cyclopentane}acetate (40a). The BINAL
reagent was prepared by treating a solution of LAH (0.48 mL of 1 M
solution in THF, 0.48 mmol) in a flame-dried flask under nitrogen with
absolute alcohol (0.48 mL of 1 M solution in THF, 0.48 mmol) and
then subsequently with bis(S)-naphthol (0.137 g, 0.48 mmol) in dry
THF (2 mL) at room temperature. The resulting milky solution was
stirred at room temperature for 20 min before 39 (0.065 g, 0.080 mmol)
in THF was injected at -100 °C dropwise. After an additional 1 h
stirring at -100 °C, the reaction mixture was maintained at -78 °C
for 4 h. The reaction mixture was quenched with methanol followed
by KHSO4 (5% in water, 5 mL) and extracted with ether (3 × 20 mL).
The combined extracts were washed with water (10 mL) and brine (20
mL), dried (Na2SO4), and concentrated in Vacuo. Flash chromatography
of the residue on silica (5:1 hexanes/ether) gave 40a (55 mg, 85%) as
a colorless oil. 1HNMR (C6D6) δ 7.74 (m, 8 H), 7.25 (m, 12 H), 5.52
(m, 1 H), 5.43 (m, 1 H), 5.36 (dd, J ) 6.2, 15.3 Hz, 1H), 5.01 (dd, J
) 15.3, 9.4 Hz, 1 H), 3.94 (m, 2 H), 3.82 (m, 1H), 3.30 (s, 3 H), 3.17
(m, 2 H), 2.31-2.12 (m, 3 H), 2.28 (dd, J ) 16.01, 5.1 Hz, 1H), 2.02
(q, J ) 7.2 Hz, 2H), 1.93 (t, J ) 6 Hz, 2 H), 1.29 (m, 8 H), 1.12 (s,
9 H), 1.19 (s, 9 H), 0.88 (t, J ) 6.19 Hz, 3 H). 13C NMR (C6D6) δ
172.87, 136.97, 136.78, 136.69, 136.66, 136.63, 135.16, 135.12, 134.86,
135.12, 133.16, 130.36, 130.28, 130.22, 128.73, 128.64, 128.27, 128.25,
77.72, 77.63, 72.48, 53.36, 51.30, 47.57, 44.40 (2 C), 36.11, 33.97,
32.66, 30.24, 28.10, 27.61 (6 C), 23.27, 19.76, 19.34, 14.68. NH3-
DCIMS calcd for C51H68O5Si2 817.25, found 834 (M + NH4+).
Methyl 2-{3R,5R-Bis-[(tert-butyldiphenylsilyl)oxy]-2â-{[(3S)-(tert-
butyldiphenylsilyl)oxy]-(E,Z)-1,5-undecadien]-1â-cyclopentane}-
acetate (40b). To a solution of imidazole (0.018 g, 0.27 mmol) and
tert-butyldiphenylsilyl chloride (0.029 g, 0.11 mmol) in anhydrous DMF
(5 mL) was added 40a (0.044 g, 0.054 mmol) in DMF (2 mL), and the
solution was stirred at room temperature for 2 h. Water (20 mL) was
added, and the product was extracted into ether (2 × 50 mL). The
combined organic extracts were washed with water (25 mL) and brine
(10 mL), dried (Na2SO4), and concentrated in Vacuo. Purification of
the product by flash chromatography on silica (with 9:1 hexanes/ether)
gave 40b (49 mg, 90%) as a viscous liquid. 1H NMR (C6D6) δ 7.0-
7.6 (m, 30 H), 5.52 (m, 1 H), 5.13 (dd, J ) 15.2, 6.5 Hz, 1H), 5.0 (m,
1 H), 4.59 (dd, J ) 15.2, 6.5 Hz, 1 H), 3.86 (q, J ) 6.3, 1 H), 3.66 (m,
2 H), 3.5 (s, 3 H), 2.83 (m, 1 H), 2.70 (m, 1 H), 2.17 (dd, J ) 16.2, 4.9
Hz, 1 H), 2.11 (m, 1 H), 1.95 (m, 1 H), 1.82 (dd, J ) 16.2, 10.4 Hz,
1 H), 1.67 (q, J ) 6.8 Hz, 2 H), 1.59 (m, 2 H), 1.15 (m, 6 H), 1.03 (s,
9 H), 1.00 (s, 9 H), 0.91 (s, 9 H), 0.81 (t, J ) 7 Hz, 3 H); 13C NMR
δ (C6D6) δ 173.79, 136.54 (3 C), 136.47 (3 C), 136.43 (3 C), 136.41
(3 C), 136.15, 135.14, 134.97, 134.74, 134.72, 134.63, 132.34, 130.20,
130.14, 130.12, 130.09, 130.04, 130.02, 128.20 (3 C), 128.19 (3 C),
128.12 (4 C), 128.01 (3 C), 127.92 (2 C), 127.76, 125.36, 53.34, 51.84,
46.66, 43.84, 36.45, 35.61, 33.72, 32.07, 29.82, 27.83, 27.60 (9 C),
23.17, 19.81 (2 C), 19.79, 14.20.
2-{3R,5R-Bis-[(tert-butyldiphenylsilyl)oxy]-2â-{[(3S)-tert-butyl-
diphenylsilyl)oxy]-(E,Z)-1,5-undecadien]-1â-cyclopentane}ethan-1-
ol (40c). A solution of 40b (0.049 g, 0.046 mmol) in toluene (3 mL)
was treated with DIBAL-H (0.140 mL of 1 M solution in toluene, 0.14
mmol) at -78 °C and stirred at the same temperature for 4 h. The
reaction mixture was quenched with 5% KHSO4 (10 mL) and extracted
with ether (3 × 20 mL). The organic layers were washed with water
(10 mL) and sodium bicarbonate (10 mL), dried (Na2SO4), and
concentrated in Vacuo. Chromatography of the residue (elution with
9:1 hexanes/ether) afforded 40c (44 mg, 92%) as an oil. 1HNMR (C6D6)
δ 7.74 (m, 12 H), 7.16 (m, 18 H), 5.37 (m, 3 H), 4.90 (dd, J ) 15.3,
9.6 Hz, 1 H), 4.12 (m, 1 H), 4.02 (m, 1 H), 3.96 (m, 1 H), 3.41 (m, 2
H), 2.79 (m, 2 H), 2.37 (m, 2 H), 2.27 (m, 1 H), 1.82 (m, 4 H), 1.51-
(hx, J ) 6.7 Hz, 1 H), 1.37 (m, 6 H), 1.25 (s, 9 H), 1.23 (s,9 H), 1.15
(s, 9 H), 0.89 (t, J ) 6.9 Hz, 3H). 13C NMR (C6D6) δ 136.59 (2 C),
136.52 (2 C), 136.48 (2 C), 136.41 (4 C), 136.39 (2 C), 135.60, 135.43,
135.16, 135.06, 134.90, 134.74, 134.70, 130.38, 130.28, 130.24, 130.17,
130.11, 130.07, 130.01 128.44, 128.35 (2 C), 128.21 (2 C), 128.20 (2
C), 128.12 (2 C), 128.02 (2 C), 127.90 (2 C), 125.40 78.946, 78.11,
74.38, 62.45, 54.01, 46.86, 43.84, 36.54, 32.61, 32.07, 29.82, 27.89 (3
C), 27.63 (3 C), 27.58 (3 C), 27.19, 23.17, 19.84 (2 C), 19.74, 14.67.
2-{3R,5R-Bis-[(tert-butyldiphenylsilyl)oxy]-2â-{[(3S)-tert-butyl-
diphenylsilyl)oxy]-(E,Z)-1,5-undecadien]-1â-cyclopentane}ethan-1-
Methyl 2-{3R,5R-Bis-[(tert-butyldiphenylsilyl)oxy]-2â-[(E,Z)-1,5-
undecadien-3-one]-1â-cyclopentane}acetate (39). To a stirred solu-
tion of the phosphonate 38 (0.078 g, 0.29 mmol) in dry THF was added
sodium hexamethyldisilazide (0.267 mL, 0.267 mmol) at -78 °C. The
solution was stirred at this temperature for 30 min, and aldehyde 37
(0.1 g, 0.15 mmol) in dry THF (2 mL) was added at -78 °C. The
reaction mixture was warmed to 0 °C and stirred at 0 °C for 12 h. The
reaction was quenched with KHSO4 (5% in water, 5 mL) and extracted
with ether (3 × 20 mL). The organic layer was washed with water
(20 mL) and brine (20 mL), dried (Na2SO4), and concentrated in Vacuo.
The residue was purified by flash chromatography on silica (benzene)
to afford 39 (103 mg, 72%) as a colorless oil. 1HNMR (C6D6) δ 7.72
(m, 8 H), 7.20 (m, 12 H), 6.39 (dd, J ) 15.6, 10.2 Hz, 1 H), 5.94 (d,
J ) 15.6 Hz,1 H), 5.70 (m, 1 H), 5.54 (m, 1 H), 3.94 (m, 2 H), 3.28
(m, 1 H), 3.24 (s, 3 H) 3.09 (m, 1 H), 3.02 (d, J ) 7.1 Hz, 2 H), 2.05
(dd, J ) 16.25, 6.06, 1 H), 1.90 (m, 5 H), 1.23 (m, 5 H), 1.18 (s, 18
H), 1.11 (m, 1 H), 0.88 (t, J ) 7 Hz, 3 H). 13C NMR (C6D6) δ 195.89,
172.50, 144.00, 136.70, 136.64 (2 C), 136.58 (2 C), 134.96, 134.73,
134.55, 134.43, 133.62, 132.27, 130.45, 130.36, 130.35, 128.91, 128.25,
122.24, 77.43, 77.04, 53.46, 51.40, 48.09, 44.32, 40.60, 33.68, 32.12,
29.74, 28.22, 27.58 (3 C), 27.54 (3 C), 23.26, 19.75, 19.65, 14.58.
NH3-DCIMS calcd for C51H66O5Si2 815.23, found 832 (M + NH4+).
Methyl 2-{3R,5R-Bis-[(tert-butyldiphenylsilyl)oxy]-2â-[(3S)-(E,Z)-

Total Synthesis of iPF2R-V
J. Am. Chem. Soc., Vol. 120, No. 46, 1998 11961
al (41). To a stirred solution of oxalyl chloride (0.172 mL of 1 M
solution in CH2Cl2, 0.172 mmol) was added dimethyl sulfoxide (0.019
g, 0.243 mmol) dropwise at -78 °C. After the reaction mixture stirred
for 20 min at -78 °C, the alcohol 40c (0.044 mg, 0.043 mmol) was
added followed by the addition of triethylamine (0.052 g, 0.51 mmol).
The reaction mixture was warmed to 0 °C and stirred at this temperature
for 4 h. Water (20 mL) was added, and the mixture was extracted
with ether (3 × 25 mL). The organic phase was washed with water
(20 mL) and brine (20 mL), dried (Na2SO4), and concentrated in Vacuo.
The residue was chromatographed on silica (elution with 9:1 hexanes/
ether) to afford product 41 (42 mg, 95%) as a viscous oil. 1HNMR
(C6D6) δ 9.41 (s, 1 H), 7.29 (m, 30 H), 5.22 (m, 1H), 5.07 (dd, J )
15.4, 6.4 Hz, 1 H), 5.02 (m, 1 H), 4.54 (dd, J ) 15.1, 10 Hz, 1 H), 3.8
(m, 1 H), 3.66 (m, 2 H), 2.81 (m, 1 H), 2.61 (m, 1 H), 2.04 (m, 3 H),
1.85 (dd, J ) 17.2, 9.2 Hz, 1 H), 1.67 (m, 2 H), 1.54 (m, 2 H), 1.16
(m, 6 H), 1.03 (s, 9 H), 0.99 (s, 9 H), 0.90 (s, 9 H), 0.81 (t, J ) 7.2
Hz, 3 H). NH3-DCIMS calcd for C66H84O4Si3 1025.63, found 1043
(M + NH4+).
Methyl 4-{3R,5R-Bis-[(tert-butyldiphenylsilyl)oxy]-2â-{[(3S)-tert-
butyldiphenylsilyl)oxy]-(E,Z)-1,5-undecadien]-1â-cyclopentane}but-
2-ene-1-oate (42). A solution of aldehyde 41 (0.042 g, 0.041 mmol)
and carbomethoxymethelene triphenyphosphorane (0.031 g, 0.092
mmol) in THF (2 mL) was refluxed for 2 days. Evaporation of the
solvent and chromatography of residue on silica (20:1 hexanes/ether)
afforded 42 (40 mg, 90%) as a viscous oil. 1HNMR (C6D6) δ 7.79
(m, 8 H), 7.72 (dd, J ) 2 Hz, 2 H), 7.63 (d, J ) 6.6 Hz, 2H), 7.25 (m,
12 H), 7.09 (m, 7 H), 5.85 (d, J ) 15.6 Hz, 1 H), 5.40 (m, 2 H), 5.32
(dd, J ) 6.4, 15.2 Hz, 1 H), 4.85 (dd, J ) 15.2, 6.4 Hz, 1 H), 4.13 (m,
1 H), 3.9 (m, 2 H), 3.4 (s, 3H), 2.86 (m, 1 H), 2.56 (m, 1 H), 2.31 (m,
2 H), 2.04 (m, 1 H), 1.88 (m, 5 H), 1.29 (m, 6 H), 1.14 (s, 9 H), 0.87
(t, J ) 7 Hz, 3 H). 13C NMR (C6D6) δ 166.72, 148.45, 136.74 (3 C),
136.66 (3 C), 136.33 (3 C), 136.59 (3 C), 136.28, 135.25, 135.13,
135.05, 134.97, 134.88, 134.85, 132.47, 131.11 (2 C), 130.40, 130.38,
130.32 (2 C), 130.27 (2 C), 128.49 (6 C), 128.25 (6 C),125.58, 122.59,
78.45, 78.40, 74.56, 53.85, 51.18, 49.99, 44.12, 36.75, 32.19, 32.09,
29.99, 28.11, 27.65 (9 C), 19.89, 19.81, 19.75, 14.64. NH3-DCIMS
calcd for C69H88O5Si3 1081.69, found 1098 (M + NH4+).
27.70 (3 C), 27.69 (3 C), 27.65 (3 C), 24.15, 23.30, 19.90, 19.86, 19.80,
14.63. NH3-DCIMS calcd for C69H90O5Si3 1083.71, found 1101 (M
+ NH4+).
Methyl 4-{3R,5R-Dihydroxy-2â-[(3S)-hydroxy]-(E,Z)-1,5-undeca-
dien]-1â-cyclopentane} butanoate (44). A solution of 43 (18 mg,
0.0166 mmol) in THF (2 mL) was treated with tetra-n-butylammonium
fluoride (1 mL of 1 M solution in THF, 1.0 mmol), and the mixture
was stirred at room temperature for 2 days. The reaction mixture was
diluted with water (10 mL) and extracted with ether (3 × 20 mL). The
combined organic layers were washed with water (10 mL) and brine
(10 mL), dried (Na2SO4), and concentrated in Vacuo. The residue was
purified by flash chromatography (elution with 1:9 hexanes/ethyl
acetate) to give 44 (5 mg, 83%) as an oil. 1H NMR (CDCl3) δ 5.63
(dd, J ) 15.4, 6.2 Hz, 1 H), 5.56 (m, 1 H), 5.43 (dd, J ) 15.3, 9.7 Hz,
1 H), 5.37 (m, 1 H), 4.13 (q, J ) 6.2 Hz, 1 H), 4.0 (m, 2 H), 3.67 (s,
3 H), 2.76 (m, 1 H), 2.42 (m, 1 H), 2.35 (m, 1 H), 2.32 (t, J ) 7.3 Hz,
2 H), 2.28 (m, 1 H), 2.05 (q, J ) 7.1 Hz, 2 H), 1.79 (bs, 1 H), 1.67(m,
3 H), 1.30 (m, 9 H), 0.89 (t, J ) 6.9 Hz, 3 H). 13C NMR (CDCl3) δ
174.43, 135.63, 133.75, 125.01, 124.56, 77.67, 77.15, 72.57, 54.33,
52.14, 50.76, 43.30, 35.99, 34.62, 32.12, 29.89, 29.55, 28.06, 24.05,
23.15, 14.62. NH3-DCIMS calcd for C21H36O5 368.50, found 386 (M
+ NH4+).
4-{3R,5R-Dihydroxy-2â-[(3S)-hydroxy]-(E,Z)-1,5-undecadien]-1â-
cyclopentane}butanoic acid (8). Potassium hydroxide (0.5 mL of 1
M in water, 0.5 mmol) was added to a solution of 44 (5 mg, 0.0135
mmol) in dioxane/water (3:2, 1 mL) at 0 °C, and the mixture was stirred
at this temperature for 1 h. The reaction mixture was acidified with
KH2PO4 (5% in water, 20 mL) and extracted with ethyl acetate (3 ×
25 mL). The combined organic extracts were washed with water (10
mL) and brine (10 mL), dried (Na2SO4), and concentrated in Vacuo.
The residue was purified by flash chromatography (elution with 20:1
ethyl acetate/methanol) to give 8 (4.5 mg, 92%) as an oil. 1H NMR
(CD3COCD3) δ 5.54 (dd, J ) 15.3, 6.2 Hz, 1 H), 5.42 (m, 3 H), 4.03
(q, J ) 6.4 Hz, 1 H), 3.90 (m, 1 H), 3.8 (m, 1 H), 2.63 (td, J ) 8.22,
3.36 Hz, 1 H), 2.38 (m, 1 H), 2.04 (m, 4 H), 2.26 (t, J ) 7.4 Hz, 2 H),
2.26 (m, 2 H), 2.04 (m, 4 H), 1.64 (m, 2 H), 1.53 (m, 1 H), 1.38 (m,
8 H), 0.88 (t, J ) 6.88 Hz, 3 H). 13C NMR (CD3COCD3) δ 175.83,
136.95, 132.59, 130.39, 127.43, 77.21, 76.91, 73.42, 54.88, 50.81, 44.72,
37.07, 35.17, 32.85, 30.55, 29.70, 28.65, 24.96, 23.81, 14.92. Elec-
trospray MS m/z 353.2 (M - H)+. HRMS (CI - CH4) m/z calcd for
C20H31O3 [(M + 1) - 2H2O]+ 319.2274, found 319.2286.
Methyl 4-{3R,5R-Bis-[(tert-butyldiphenylsilyl)oxy]-2â-{[(3S)-tert-
butyldiphenylsilyl)oxy]-(E,Z)-1,5-undecadien]-1â-cyclopentane}-
butanoate (43). Sodium borohydride (0.1 g, 2.7 mmol) was added in
one portion to a solution of 42 (40 mg, 0.37 mmol) in dry THF (2 mL)
and refluxed for 2 days. The reaction mixture was concentrated, diluted
with water, and extracted with ether (2 × 20 mL). Drying of the
organic extracts (Na2SO4) and concentration gave an oil which was
purified by flash chromatography (elution with 20:1 hexanes/ether) to
obtain 43 (35 mg, 85%) as a viscous oil. 1HNMR (C6D6) δ 7.82 (m,
8 H), 7.73 (d, J ) 5.6 Hz, 2 H), 7.65 (d, J ) 6.7 Hz, 2H), 7.26 (m, 18
H), 5.38 (m, 2 H), 5.33 (dd, J ) 15.2, 6.8 Hz, 1 H), 4.83 (dd, J )
15.2, 9.9 Hz, 1 H), 4.11 (m, 1 H), 3.98 (m, 2 H), 3.37 (s, 3 H), 2.81
(m, 1 H), 2.66 (m, 1 H), 2.26 (m, 1 H), 2.39 (m, 1 H), 2.14 (t, J ) 7.6
Hz, 2 H), 1.87 (m, 4 H), 1.58 (m, 2 H), 1.38 (m, 2 H), 1.26 (s, 9 H),
Acknowledgment. We acknowledge the NIH for support
under Grants DK-44730 (J.R.), HL 54500, MO1RR0040, and
HL 57847 (G.A.F.) and the NSF for an AMX-360 NMR
instrument (Grant CHE-90-13145). Dr. FitzGerald is the Robi-
nette Professor of Cardiovascular Medicine. We thank Nahid
Najafi for excellent assistance at the early phase of the project.
We thank Dr. G. Goodloe, Auburn University, for performing
mass spectral analysis.
1.24 (s, 9 H), 1.26 (m, 8 H), 1.15 (s, 9 H), 0.89 (t, J ) 7 Hz, 3 H). 13
C
Supporting Information Available: Forty-five pages of
Supporting data and information (45 pages, print/PDF). See
any current masthead page for ordering information and Web
access instructions.
NMR (C6D6) δ 173.47, 136.79, 136.75 (2 C), 136.63 (8 C), 135.78,
135.52, 135.31, 135.18, 135.15, 135.11, 134.89, 132.32, 130.34, 130.28,
130.27, 130.23, 130.22 (2 C), 128.76 (3 C), 128.45 (3 C), 128.49 (3
C), 128.23 (3 C), 125.70, 79.02, 78.70, 74.80, 53.92, 51.24, 50.26,
44.34, 36.87, 34.71, 32.18, 36.83, 34.71, 32.17, 29.99, 28.86, 28.09,
JA982596K