parichehr
15th November 2010, 08:24 PM
CHAPTER 1
PROSTAGLANDINS, PEPTIDOMIMETIC
COMPOUNDS, AND RETINOIDS
1.1. PROSTAGLANDINS
It is highly likely that those not themselves involved in scientific research perceive
the development of new knowledge within a given area of science as a linear
process. The popular view is that the understanding of the specific details of
any complex system depends on prior knowledge of the system as a whole. This
knowledge is in turn believed to derive from the systematic stepwise study of
the particular system in question. The piecemeal, almost haphazard, way in
which the details of the existence and later the detailed exposition of the arachidonic
acid cascade were put together is much more akin to the assembly of a
very complex jigsaw puzzle. This particular puzzle includes the added complication
of incorporating many pieces that did not in fact fit the picture that
was finally revealed; the pieces that would in the end fit were also found at very
different times.
The puzzle had its inception with the independent observation in the early 1930s
by Kurzok and Lieb [1] and later von Euler [2] that seminal fluid contained a substance
that caused the contraction of isolated guinea pig muscle strips. The latter
named this putative compound prostaglandin in the belief that it originated in the
prostate gland; the ubiquity of those substances was only uncovered several
Strategies for Organic Drug Synthesis and Design, Second Edition. By Daniel Lednicer
Copyright # 2009 John Wiley & Sons, Inc.
1
decades later. The discovery remained an isolated oddity until the mid-1960s, by
which time methods for chromatographic separation of complex mixtures of polar
compounds and spectroscopic methods for structure determination were sufficiently
advanced for the characterization of humoral substances that occur at very low levels.
The isolation and structural assignment of the first two natural prostaglandins, PGE1
and PGF2, were accomplished by Bergstrom and his colleagues at the Karolinska
Institute [3]. (The letter that follows PG probably initially referred to the order in
which the compounds were isolated: E refers to 9-keto-11-hydroxy compounds
and F refers to 9,11-diols; the subscripts refer to the number of double bonds.) The
carbon atoms of the hypothetical, fully saturated, but otherwise unsubstituted
carbon skeleton, prostanoic acid, are numbered sequentially starting with the carboxylic
acid as 1, and then running around the ring and resuming along the other
side chain.
The identification of these two prostaglandins in combination with their very high
potency in isolated muscle preparations suggested that they might be the first of a
large class of new hormonal agents. Extensive research in the laboratories of the
pharmaceutical industry had successfully developed a large group of new steroidbased
drugs from earlier similar leads in that class of hormones; this encouraged
the belief that the prostaglandins provided an avenue that would lead to a broad
new class of drugs. As in the case of the steroids, exploration of the pharmacology
of the prostaglandins was initially constrained by the scarcity of supplies. The low
levels at which the compounds were present, as well as their limited stability,
forced the pace toward developing synthetic methods for those compounds. The
anticipated need for analogues served as an additional incentive for elaborating
routes for their synthesis.
Further work on the isolation of related compounds from mammalian sources,
which spanned several decades, led to the identification of a large group of structurally
related substances. Investigations on their biosynthesis made it evident that all
eventually arise from the oxidation of the endogenous substance, arachidonic acid.
The individual products induce a variety of very potent biological responses, with
inflammation predominating. Arachidonic acid, once freed from lipids by the
enzyme phospholipase A2, can enter one of two branches of the arachidonic acid
2 PROSTAGLANDINS, PEPTIDOMIMETIC COMPOUNDS, AND RETINOIDS
cascade [4] (Scheme 1.1). The first pathway to be identified starts with the addition of
two molecules of oxygen by a reaction catalyzed by the enzyme cyclooxygenase to
give PGG2. That enzyme, now known to occur in two and possibly three forms, is
currently identified by the acronym COX; it is sometimes called prostaglandin
synthetase. The reaction comprises the addition of one oxygen across the 9,11 positions
to give a cyclic peroxide while the other adds to the 14 position in a reaction
reminiscent of that of singlet oxygen to give a hydroperoxide at 14, with the resulting
shift of the olefin to the 12 position and with concomitant isomerization to the trans
configuration. The initial hydroperoxide is readily reduced to an alcohol to give the
key intermediate PGH2. The reductive ring opening of the bridging oxide leads to the
PGF series while an internal rearrangement leads to the very potent inflammatory
thromboxanes. It was found later that aspirin and indeed virtually all nonsteroid antiinflammatory
drugs (NSAIDs) owe their efficacy to the inhibition of the cylcooxygenase
enzymes.
Scheme 1.1. Arachidonic Acid Cascade.
1.1. PROSTAGLANDINS 3
The reaction of arachidonic acid with the enzyme lypoxygenase (LOX), on the
other hand, leads to an attack at the 5 position and rearrangement of the double
bonds to the 7,9-trans-11-cis array typical of leukotrienes; the initial product
closes to an epoxide, thus yielding leukotriene A4. The reactive oxirane in that
compound in turn reacts with endogenous glutathione to give leukotriene C4. This
compound and some of its metabolites, it turned out, constitute the previously
well-known “slow reacting substance of anaphylaxis” (srs-A), involved in allergic
reactions and asthma.
Much of the early work on this class of compounds focused on developing routes
for producing the agents in quantities sufficient for biological investigations. There
was some attention paid to elaborating flexible routes as it was expected that there
might be some demand for analogues not found in nature. This work was hindered
by the relative dearth of methods for elaborating highly substituted five-membered
rings that also allowed control of stereochemistry. The unexpected finding of a compound
with the prostanoic acid skeleton in a soft coral, the sea whip plexura homomalla
[5], offered an interim source of product. The group at Upjohn, in fact,
developed a scheme for converting that compound to the prostagland, which they
were investigating in detail [6]. The subsequent development of practical total syntheses
in combination with ecological considerations led to the eventual replacement of
that marine starting material.
The methodology developed by E. J. Corey and his associates at Harvard provides
the most widely used starting material for prostaglandin syntheses. This key intermediate,
dubbed the “Corey lactone,” depends on rigid bicyclic precursors for
controlling stereochemistry at each of the four functionalized positions of the
cyclopentane ring. Alkylation of the anion from cyclopentadiene with chloromethylmethyl
ether under conditions designed to avoid isomerization to the thermodynamically
more stable isomer gives the diene (3-1). In one approach, this is then allowed
to react with a-chloroacrylonitrile to give the Diels–Alder adduct (3-2) as a mixture
of isomers. Treatment with an aqueous base affords the bicyclic ketone (3-3),
possibly by way of the cyanohydrin derived from the displacement of halogen by
hydroxide. Bayer–Villiger oxidation of the carbonyl group with peracid gives the
lactone (3-4); the net outcome of this reaction establishes the cis relationship of
the hydroxyl that will occupy the 11 position in the product and the side chain
that will be at 9 in the final product. Simple saponification then gives hydroxyacid
(3-5). The presence of the carboxyl group provides the means by which this can be
resolved by conventional salt formation with chiral bases. Reaction of the last intermediate
with base in the presence of iodine results in the formation of iodolactone;
the reaction may be rationalized by positing the formation of a cyclic iodonium salt
on the open face of the molecule; attack by the carboxylate anion will give
the lactone with the observed stereochemistry. Acetylation of the hydroxyl gives
(3-6); halogen is then removed by reduction with tributyltin hydride (3-7).
The methyl ether on the substituent at the future 11 position is then removed by
treatment with boron tribromide. Oxidation of the primary hydroxyl by means of
the chromium trioxide : pyridine complex (Collins reagent) gives Corey lactone
(3-9) as its acetate [7].
4 PROSTAGLANDINS, PEPTIDOMIMETIC COMPOUNDS, AND RETINOIDS
A somewhat more direct route to the Corey lactone, developed later, depends on a
radical photoaddition/rearrangement reaction as the key step. The scheme starts with
the Diels–Alder addition of a-acetoxyacrylonitrile to furan to give the bridged furan
(4-1) as a mixture of isomers. Hydrolysis by means of aqueous hydroxide gives the
ketone (4-2); this reaction may also proceed through the intermediate cyanohydrin.
This cyanohydrin is in fact produced directly by treatment of the mixture of
isomers with sodium methoxide in a scheme for producing the ketone in chiral
form. The crude intermediate is treated with brucine. Acid hydrolysis of the solid
“complex” that separates affords quite pure dextrorotary ketone (4-2) [8]; this
complex may consist of a ternary imminium salt formed by a sequential reaction
1.1. PROSTAGLANDINS 5
with the cyanohydrin function. Irradiation of the ketone in the presence of phenylselenylmalonate
leads to the rearranged product (4-5) in quite good yield. The structure
can be rationalized by postulating the homolytic cleavage of the C-Se bond in
the malonate to give intermediate (4-3) as the first step; the resulting malonate
radical would then add to the olefin. Acyl migration would then give the rearranged
carbon skeleton of (4-4). Addition of the phenylselenyl radical to that intermediate
will then give the observed product. Reduction of the carbonyl group by means
of sodium borohydride gives the product of approach of hydride from the more
open exo face (4-6). Decarboxylation serves to remove the superfluous carboxyl
group to afford (4-7); treatment with tertiary-butyldimethylsilyl chloride in the
presence of imidazole gives the protected intermediate (4-8) that contains all
the elements of the Corey lactone with the future aldehyde, however, in the wrong
a configuration. Saponification of the ester followed by acid hydrolysis, in fact,
gives the all cis version of the lactone [9]. The desired trans isomer (4-9) can be
obtained by oxidizing the selenide with hydrogen peroxide in the presence of
sodium carbonate [10].
Biological investigations, once supplies of prostaglandins were available,
revealed the manifold activities of this class of agents. The very potent effect of
6 PROSTAGLANDINS, PEPTIDOMIMETIC COMPOUNDS, AND RETINOIDS
PGF2a on reproductive function was particularly notable. Ovulation in most mammalian
species is marked by the formation on the ovary of a corpus luteum that
produces high levels of progesterone if a fertile ovum has implanted in the
uterus. Administration of even low doses of PGF2a was found to have a luteolytic
effect, with loss of the implanted ovum due to the withdrawal of progestin. This
prostaglandin was in fact one of the first compounds in this class to reach the
clinic under the United States Adopted Name (USAN) name dinoprost. The development
of drugs for use in domestic animals tends to be faster and much less
expensive than those that are to be used in humans. This is particularly true if
the animals are not used as food, since this dispenses with the need to study
tissue residues. It is of interest, consequently, that one of the early prostaglandins
that reached the market is fluprostenol (5-8). This compound differs from
PGF2a in that the terminal carbon atoms in the lower side chain are replaced by
the trifluromethylphenoxy group; this modification markedly enhances potency as
well as stability. This drug is marketed under the name Equimatew for controlling
fertility in racing mares, a species in which costs are probably of little consequence.
Reaction of the anion from phosphonate (5-1) with ethyl meta-triflurophenoxymethylacetate
results in acylation of the phosphonate by the displacement of
ethoxide and the formation of (5-3). Condensation of the ylide from this intermediate
with the biphenyl ester at position 11 of Corey lactone (5-4) leads to the enone
(5-5) with the usual formation of a trans olefin expected for this reaction. The very
1.1. PROSTAGLANDINS 7
bulky biphenyl ester comes into play in the next step. Reduction of the side chain
ketone by means of zinc borohydride proceeds to give largely the 15a alcohol as
a result of the presence of that bulky group. The ester is then removed by
saponification, and the two hydroxyl groups are protected as their tetrahydropyranyl
ethers (5-6). The next step in the sequence involves the conversion of the lactone
to a lactol; the carbon chain is thus prepared for attachment of the remaining
side chain while revealing potential hydroxyl at the 9 position. This transform
is affected by treating (5-6) with diisobutylaluminum hydride at 2788C;
over-reduction to a diol occurs at higher temperatures. Wittig reactions can be
made to yield cis olefins when carried out under carefully defined, “salt-free”
conditions [11]. Condensation of the lactol (5-7) with the ylide from 5-triphenylphosphoniumpentanoic
acid under those conditions gives the desired olefin.
Treatment with mild aqueous acid serves to remove the protecting groups, thus
forming fluprostenol (5-8) [12].
Prostaglandins have been called hormones of injury since their release is often
associated with tissue insult. Most of these agents consequently exhibit activities
characteristic of tissue damage. Many prostaglandins cause vasoconstriction and a
consequent increase in blood pressure as well as the platelet aggregation that precedes
blood clot formation. Thromboxane A2 is, in fact, one of the most potent known
platelet aggregating substances. Prostacyclin, PGI2, one of the last cyclooxygenase
products to be discovered, constitutes an exception; the compound causes vasodilation
and inhibits platelet aggregation. This agent may be viewed formally as the
cyclic enol ether of a prostaglandin that bears a carbonyl group at the 6 position of
the upper side chain. This very labile functionality contributes to the short half-life
of PGI2. The fact that the lifetime of this compound is measured in single-digit
minutes precludes the use of this agent as a vasodilator or as an inhibitor of platelet
aggregation.
8 PROSTAGLANDINS, PEPTIDOMIMETIC COMPOUNDS, AND RETINOIDS
The analogue in which carbon replaces oxygen in the enol ring should of course
avoid the stability problem. The synthesis of this compound initially follows a
scheme similar to that pioneered by the Corey group. Thus, acylation of the ester
(7-2) with the anion from trimethyl phosphonate yields the activated phosphonate
(7-3). Reaction of the ylide from that intermediate with the lactone (7-4) leads to a
compound (7-5) that incorporates the lower side chain of natural prostaglandins.
This is then taken on to lactone (7-6) by sequential reduction by means of zinc
borohydride, removal of the biphenyl ester by saponification, and protection of the
hydroxyl groups as tetrahydropyranyl ethers.
The first step in building the carbocyclic ring consists, in effect, of a second acylation
on trimethyl phosphonate. Thus, the addition of the anion from that reagent to the
lactone carbonyl in (7-6) leads to the product as its cyclic hemiketal (8-1); this last, it
should be noted, now incorporates an activated phosphonate group. Oxidation of that
compound with Jones’ reagent gives the diketone (8-2). The ylide prepared from that
compound by means of potassium carbonate in aprotic media adds internally to the
ring carbonyl group to give fused cylopentenone (8-3). Conjugate addition of a
methyl group to the enone by means of the cuprate reagent from methyl lithium
occurs predominantly on the open b face of the molecule to afford (8-4). The counterpart
of the upper side chain is then added to the molecule by condensation with the
ylide from triphenylphosphoniumpentanoic acid bromide. The product (8-5) is
obtained as a mixture of E and Z isomers about the new olefin due to the absence
of directing groups. Removal of the tetrahydropyran protecting groups with mild
aqueous acid completes the synthesis of ciprostene (8-6) [13]. This compound has
the same platelet aggregation inhibitory activity as PGI2, though with greatly
reduced potency.
1.1. PROSTAGLANDINS 9
An analogue in which a fused tetralin moiety replaces the furan and part of the side
chain in prostacyclin is approved for use as a vasodilator for patients with pulmonary
hypertension. The lengthy, complex synthesis starts with the protection of the
hydroxyl group in benzyl alcohol (9-1) by reaction with tert-butyl dimethyl siliyl
chloride (9-2). Alkylation of the anion from (9-2) (butyl lithium) with allyl
bromide affords (9-3). The protecting group is then removed and the benzylic
hydroxyl oxidized with oxalyl chloride in the presence of triethyl amine to give
the benzaldehyde (9-4). The carbonyl group is then condensed with the organomagnesium
derivative from treatment of chiral acetylene (9-5) with ethyl Grignard to
afford (9-6) (the triple bond is not depicted in true linear form to simplify the
scheme). The next few steps adjust the stereochemistry of the newly formed
10 PROSTAGLANDINS, PEPTIDOMIMETIC COMPOUNDS, AND RETINOIDS
alcohol in (9-6). This group is first oxidized back to a ketone with pyridinium
chlorochromate. Reduction with diborane in the presence of chiral 2-(hydroxydiphenylmethyl)
pyrolidine affords the alcohol as a single enantiomer. This is then
again protected as its tBDMS ether (9-7). Heating this compound with cobalt
carbonyl leads to the formation of the tricyclic ring system. Mechanistic considerations
aside, the overall sequence to the product (9-8) involves eletrocylic formation
of the six-membered ring from the olefin and the acetylenic bond as well as insertion
of the elements of carbon monoxide to form the five-membered ring. Catalytic hydrogenation
of that product (9-8) leads to a reduction of the double bond in the enone as
well as hydrogenolyis of the benzylic tBDMS ether on the six-membered ring (9-9).
Reduction of the ketone then leads to the alcohol, apparently as a single enantiomer.
Acid hydrolysis leads to the loss of the tetrahydropyrany protecting group to afford
intermediate (9-10). The presence of labile groups in this compound precludes the
usual methods such as hydrogen bromide or boron tribromide for cleaving the
1.1. PROSTAGLANDINS 11
methyl ether. Instead, in an unusual sequence, phenol (9-11) is obtained by treatment
of (9-10) with butyl lithium and diphenyl phosphine. The product is then alkylated
with 2-chloroacetonitrile. Hydrolysis of the cyano group to an acid finally affords
the vasodilator treprostinil (9-12) [14–16].
Dinoprost (PGF2a) was the first prostaglandin to be approved for clinical use. The
specific indication comprised induction of labor. It has received some publicity
recently as a result of its use as an adjunct in RU-486 (mifepristone; see Chapter
4) induced abortions. Though initial supplies of PGF2a were obtained by partial
synthesis from soft coral–derived starting materials, this was supplanted by a totalsynthesis
product. The reported synthesis, like those noted above, relies on a rigid
fused bicyclic starting material for determining the relative configuration of the substituents
on the cyclopentane ring.
The sequence starts by epoxidation of bicycloheptadiene (10-1) with peracid, a
reaction that had been found earlier to proceed to aldehyde (10-3) rather than
stopping at the epoxide. This rearrangement, which will control stereochemistry at
positions 11, 12, and 15 in one fell swoop, is related conceptually to the i-steroid
rearrangement discovered at least a decade earlier. The reaction relies in effect on
the mobile equilibrium between a cyclopropylcarbinyl carbocation and its homoallyl
partner: This rearrangement can be visualized as starting with the protonation of the
initially formed epoxide to (10-2). This could then first ring open to an alcohol. The
observed product (10-3) would be obtained by Wagner–Meerwin rearrangement of
the resulting carbocation. The same product would be formed by the concerted reaction
shown in the scheme below. The aldehyde is then protected as its acetal (10-4) with 2,2-
dimethylpropylene glycol. The two carbon atoms that will form the upper side chain
are then incorporated by electrocyclic addition of dichloroketene; the chlorine atoms
are removed by reduction with zinc to give (10-5). Delaying the all-important
resolution until a late step in the synthesis of chiral compounds invokes the penalty
12 PROSTAGLANDINS, PEPTIDOMIMETIC COMPOUNDS, AND RETINOIDS
of carrying the useless inactive enantiomer through a large number of transformations.
Efficient syntheses either incorporate the separation early or, better yet, start with chiral
compounds. An unusual method is used to affect the resolution in the case at hand.
Thus, condensation of fused cyclobutanone (10-5) with l-ephedrine affords a pair of
diastereomeric oxazolidines (10-6); the higher melting of the pair providentially
corresponds to the desired isomer. Separation followed by hydrolysis over silica
gives (10-5) with the prostaglandin stereochemistry.
The cyclobutanone is then lactonized by means of Bayer–Villiger oxidation;
treatment with dilute acid then serves to remove the acetal group to afford lactone-aldehyde
(11-2). The next step comprises incorporating the remaining carbon atoms required
for the lower side chain, Thus,Wittig condensation of the aldehyde with the ylide from
triphenylphosphoniumhexyl bromide under salt-free conditions affords the cis olefin
(11-3), which is converted to epoxide (11-4) by means of peracid. Solvolysis of this
last intermediate in formic acid gives compound (11-5) accompanied by significant
amounts of glycols; the mixture is recycled to give (11-5) in modest yield.
This rearrangement, which is in effect the reverse of that used to form the
cyclopropyl ring in (10-2), can be visualized as starting with protonated epoxide
(12-1); this can then go on to rearrange via a homoallyl ion (12-2); the observed
stereoselective formation of the 11-hydroxyl argues for a concerted reaction.
Solvolysis of the diol byproduct (12-3) may also go through carbocation (12-2) or
through a more concerted transition state. The product (12-4) is finally taken on to
PGF2a by a sequence very similar to that used to first add the lower side chain to
(7-6), and after suitable protection of the hydroxyls elaboration of the upper side
chain [17,18]..
1.1. PROSTAGLANDINS 13
It has been known for some time that a mucus layer secreted by gastric cells protects
the lining of the stomach from noxious agents, including its own digestive
agents. Studies on the pharmacology of the prostaglandins revealed that these compounds
had a cytoprotective effect on the gastric mucosa by maintaining the
mucus layer. The recognition that aspirin and the pharmacologically related
NSAIDs owed their action to the inhibition of cyclooxygenase, at the time thought
to consist of a single enzyme, offered an explanation for their well-recognized injurious
effect on gastric mucosa. Inhibition of that enzyme leads to a decrease in prostaglandin
synthesis and a consequent increased vulnerability to irritants, including
normal stomach acid. This prostaglandin deficit is difficult to remedy due to the manifold
activity of most congeners, their very short biological half-life, and poor oral
bioavailabilty. The finding that biological activity is retained when the side chain
hydroxyl is moved from the prime site of metabolism, 15, to the 16 position eventually
resulted in the development of misoprostol (14-5), a drug approved for the prevention
of NSAID-induced ulcers.
The synthesis of this compound represents a notable departure from those
discussed above. The presence of the carbonyl group at the 9 position of the cyclopentane
ring, which classifies this compound as a PGE, removes one asymmetric
center and thus somewhat reduces the stereochemical complexity of the synthesis.
More importantly, this introduces the possibility of attaching the lower side chain
by means of a 1,4-addition reaction; the trans relationship of the two side
chains should be favored by thermodynamic considerations. The very unusual
functionality of the required Michael acceptor, that of a cyclopent-2-en-4-ol-1-one,
leads to a rather lengthy albeit straightforward synthesis for the requisite intermediate.
14 PROSTAGLANDINS, PEPTIDOMIMETIC COMPOUNDS, AND RETINOIDS
The scheme starts by activation of monomethylazeleiate (13-1) as its imidazole
amide by means of thionyl bisimidazole. Condensation of that product with the
bis anion from reaction lithium salt of monomethyl malonate gives acetoacetate
(13-2); the first-formed tricarbonyl compound decarboxylates on workup. The
two terminal methyl ester groups are then saponified to the corresponding acids;
that b to the carbonyl group decarboxylates to a methyl ketone on acidification to
afford (13-3). Acylation of this last intermediate with dimethyl oxalate leads to the
addition of an oxalyl group to each carbon flanking the ketone to give an intermediate
such as (13-4). (Both this and (13-5) are depicted as their unlikely all-ketone
tautomers in the interest of clarity.) That intermediate cyclizes to the triketocyclopentane
(13-5) under reaction conditions. Treatment with acid leads to a scission
of the superfluous pendant oxalyl group. The product (13-6) probably exists as a
mixture of the two possible enolates. Hydrogenation in the presence of palladium
on charcoal interestingly leads to a reduction of the single carbonyl group not
involved in that tautomerism to give the future prostaglandin 11 hydroxyl.
Reaction of the product with acetone dimethyl acetal in the presence of acid leads
initially to the formation of enol ethers; these can be forced to (13-7) because of
its lower solubility in ether. Reduction of that (13-7) with lithium aluminum
hydride or Vitride at 2608C leads on workup to the enone (13-8).
1.1. PROSTAGLANDINS 15
Preparation of the reagent required for adding the lower side chain involves a
series of metal interchanges carried out as a one-pot reaction. The sequence starts
by stereospecific stannylation of acetylene (14-1) by means of tributlytin hydride.
Reaction of that with butyl lithium gives the corresponding vinyl lithio reagent,
where the tin is replaced with retention of configuration. The lithium is then replaced
by organocopper moiety by reaction with copper pentyne to give the cuprate reagent
(14-3). The addition of (14-3) to the cyclopentenone as its silyl ether (14-4) gives the
Michael product. Removal of the silyl protecting group affords misoprostol (14-5) as
a mixture of enantiomers [19,20].
Among their many other activities, prostaglandins have a direct effect on the
gastrointestional (GI) tract. PGE2, for example, regulates many physiological functions
of the gut including mucosal protection, gastrointestinal secretion, and motility.
A PGE-related compound, lubiprostone (15-11), for example, increases both intestinal
fluid secretion and motility. This compound has been recently approved for the
treatment of chronic constipation and is being investigated as a treatment of constipation-
predominant irritable bowel syndrome. It has been ascertained that the drug
interacts with specific ion channels in the GI tract, causing increased fluid output
into the lumen. The starting material for the synthesis (15-1) comprises a variant
16 PROSTAGLANDINS, PEPTIDOMIMETIC COMPOUNDS, AND RETINOIDS
on the Corey lactone. Condensation of this aldehyde with the ylide from the difluorinated
phosphonate (15-2) leads to the addition product (15-3). The double bond in
the olefin has the expected trans geometry, though the next step, hydrogenation,
makes this point moot. Sodium borohydride then reduces the side chain ketone function
to give (15-5) as a mixture of isomers. The lactone is next reduced to the key
lactol in the usual fashion, by means of diisobutyl aluminum hydride (15-6). The
product is then condensed with the ylide obtained from the reaction of the zwitterion
4-triphenylphosphoniumbutyrate to give the chain extended olefin (15-7). The carboxylic
acid in this intermediate is next protected as the benzyl ester by alkylation
of its salt with benzyl chloride (15-8). Oxidation of the ring alcohol by means of
chromium trioxide followed by exposure to mild acid to remove the tetrahydropyranyl
group establishes the keto-alcohol PGE-like function in the five-membered ring
(15-9). Catalytic hydrogenation of this last intermediate at the same time reduces
the remaining double bond and removes the benzyl protecting group on the acid to
give the open chain version (15-10) of the product. The electron-withdrawing
power of the fluorine atoms adjacent to the side chain ketone causes the carbonyl
carbon to become a reasonable electrophile. The electron-rich oxygen on the ring
alcohol thus adds to this to give a cyclic hemiacetal. This form (15-11) greatly
predominates in the product lubiprostone [21].
1.1. PROSTAGLANDINS 17
As noted previously, NSAIDs inhibit the inflammatory and, to some extent, the
platelet-aggregating activities of products from the arachidonic cascade by inhibiting
the enzyme, cylooxygenase, that catalyzes their formation. One of the few nitrogencontaining
prostaglandin analogues, vapiprost (16-9), is reported to be an inhibitor
of thromboxane A2-induced platelet aggregation. This congener is potentially a more
specific inhibitor of platelet aggregation, the prelude to thrombus formation, than
NSAIDs in that it blocks thromboxane A2 at the receptor site. Treatment of
the chiral adduct (16-1) from ketene and cyclopentadiene with bromodimethylhydantoin
in acetic acid results in the formation of bromoacetate (16-2), which results from
the formal addition of hydrobromous acid. The stereochemistry of the product
probably results from the formation of the initial bromonium ion on the more open
face of the molecule. Treatment with piperidine leads to a rearrangement to a
2,2,1-bibycloheptane with the incorporation of nitrogen on the new one-carbon
bridge. The structure of the product can be rationalized by postulating an intermediate,
or transition, species such as (16-3) along the reaction pathway. Saponification
of the initially formed product gives keto-alcohol (16-4). This is acylated to (16-5)
by means of para-biphenylacetyl halide, a bulky group used in other prostaglandin
syntheses for directing the stereochemistry of reductions. Bayer–Villiger oxidation
with peracid gives a bridged version (16-6) of a Corey lactone; reduction with
diisobutylaluminum hydride in the cold leads to hydroxyaldehyde (16-7), here
18 PROSTAGLANDINS, PEPTIDOMIMETIC COMPOUNDS, AND RETINOIDS
isolated in open form. The aldehyde is then first homologated by reaction with
methoxymethyl phosphorane to give (16-8). A second Wittig condensation, with the
ylide from triphenylphosphonium butyrate, completes the construction of the side
chain that differs from that in natural prostaglandins in that the olefin is moved one
atom closer to the terminal acid. The next two steps consist of inverting the stereochemistry of the 11 hydroxyl group to the unnatural b configuration. Thus, Swern oxidation of the initial product followed by reduction with diisobutylaluminum hydride gives vapiprost (16-9) [22]. The stereochemistry of the reduction is probably guided by the very bulky para-phenylbenzoyl group at the 9 position
i will send the synthesis as soon as i can[tafakor]
THANKS FOR YOUR ATTENTION[golrooz]
PROSTAGLANDINS, PEPTIDOMIMETIC
COMPOUNDS, AND RETINOIDS
1.1. PROSTAGLANDINS
It is highly likely that those not themselves involved in scientific research perceive
the development of new knowledge within a given area of science as a linear
process. The popular view is that the understanding of the specific details of
any complex system depends on prior knowledge of the system as a whole. This
knowledge is in turn believed to derive from the systematic stepwise study of
the particular system in question. The piecemeal, almost haphazard, way in
which the details of the existence and later the detailed exposition of the arachidonic
acid cascade were put together is much more akin to the assembly of a
very complex jigsaw puzzle. This particular puzzle includes the added complication
of incorporating many pieces that did not in fact fit the picture that
was finally revealed; the pieces that would in the end fit were also found at very
different times.
The puzzle had its inception with the independent observation in the early 1930s
by Kurzok and Lieb [1] and later von Euler [2] that seminal fluid contained a substance
that caused the contraction of isolated guinea pig muscle strips. The latter
named this putative compound prostaglandin in the belief that it originated in the
prostate gland; the ubiquity of those substances was only uncovered several
Strategies for Organic Drug Synthesis and Design, Second Edition. By Daniel Lednicer
Copyright # 2009 John Wiley & Sons, Inc.
1
decades later. The discovery remained an isolated oddity until the mid-1960s, by
which time methods for chromatographic separation of complex mixtures of polar
compounds and spectroscopic methods for structure determination were sufficiently
advanced for the characterization of humoral substances that occur at very low levels.
The isolation and structural assignment of the first two natural prostaglandins, PGE1
and PGF2, were accomplished by Bergstrom and his colleagues at the Karolinska
Institute [3]. (The letter that follows PG probably initially referred to the order in
which the compounds were isolated: E refers to 9-keto-11-hydroxy compounds
and F refers to 9,11-diols; the subscripts refer to the number of double bonds.) The
carbon atoms of the hypothetical, fully saturated, but otherwise unsubstituted
carbon skeleton, prostanoic acid, are numbered sequentially starting with the carboxylic
acid as 1, and then running around the ring and resuming along the other
side chain.
The identification of these two prostaglandins in combination with their very high
potency in isolated muscle preparations suggested that they might be the first of a
large class of new hormonal agents. Extensive research in the laboratories of the
pharmaceutical industry had successfully developed a large group of new steroidbased
drugs from earlier similar leads in that class of hormones; this encouraged
the belief that the prostaglandins provided an avenue that would lead to a broad
new class of drugs. As in the case of the steroids, exploration of the pharmacology
of the prostaglandins was initially constrained by the scarcity of supplies. The low
levels at which the compounds were present, as well as their limited stability,
forced the pace toward developing synthetic methods for those compounds. The
anticipated need for analogues served as an additional incentive for elaborating
routes for their synthesis.
Further work on the isolation of related compounds from mammalian sources,
which spanned several decades, led to the identification of a large group of structurally
related substances. Investigations on their biosynthesis made it evident that all
eventually arise from the oxidation of the endogenous substance, arachidonic acid.
The individual products induce a variety of very potent biological responses, with
inflammation predominating. Arachidonic acid, once freed from lipids by the
enzyme phospholipase A2, can enter one of two branches of the arachidonic acid
2 PROSTAGLANDINS, PEPTIDOMIMETIC COMPOUNDS, AND RETINOIDS
cascade [4] (Scheme 1.1). The first pathway to be identified starts with the addition of
two molecules of oxygen by a reaction catalyzed by the enzyme cyclooxygenase to
give PGG2. That enzyme, now known to occur in two and possibly three forms, is
currently identified by the acronym COX; it is sometimes called prostaglandin
synthetase. The reaction comprises the addition of one oxygen across the 9,11 positions
to give a cyclic peroxide while the other adds to the 14 position in a reaction
reminiscent of that of singlet oxygen to give a hydroperoxide at 14, with the resulting
shift of the olefin to the 12 position and with concomitant isomerization to the trans
configuration. The initial hydroperoxide is readily reduced to an alcohol to give the
key intermediate PGH2. The reductive ring opening of the bridging oxide leads to the
PGF series while an internal rearrangement leads to the very potent inflammatory
thromboxanes. It was found later that aspirin and indeed virtually all nonsteroid antiinflammatory
drugs (NSAIDs) owe their efficacy to the inhibition of the cylcooxygenase
enzymes.
Scheme 1.1. Arachidonic Acid Cascade.
1.1. PROSTAGLANDINS 3
The reaction of arachidonic acid with the enzyme lypoxygenase (LOX), on the
other hand, leads to an attack at the 5 position and rearrangement of the double
bonds to the 7,9-trans-11-cis array typical of leukotrienes; the initial product
closes to an epoxide, thus yielding leukotriene A4. The reactive oxirane in that
compound in turn reacts with endogenous glutathione to give leukotriene C4. This
compound and some of its metabolites, it turned out, constitute the previously
well-known “slow reacting substance of anaphylaxis” (srs-A), involved in allergic
reactions and asthma.
Much of the early work on this class of compounds focused on developing routes
for producing the agents in quantities sufficient for biological investigations. There
was some attention paid to elaborating flexible routes as it was expected that there
might be some demand for analogues not found in nature. This work was hindered
by the relative dearth of methods for elaborating highly substituted five-membered
rings that also allowed control of stereochemistry. The unexpected finding of a compound
with the prostanoic acid skeleton in a soft coral, the sea whip plexura homomalla
[5], offered an interim source of product. The group at Upjohn, in fact,
developed a scheme for converting that compound to the prostagland, which they
were investigating in detail [6]. The subsequent development of practical total syntheses
in combination with ecological considerations led to the eventual replacement of
that marine starting material.
The methodology developed by E. J. Corey and his associates at Harvard provides
the most widely used starting material for prostaglandin syntheses. This key intermediate,
dubbed the “Corey lactone,” depends on rigid bicyclic precursors for
controlling stereochemistry at each of the four functionalized positions of the
cyclopentane ring. Alkylation of the anion from cyclopentadiene with chloromethylmethyl
ether under conditions designed to avoid isomerization to the thermodynamically
more stable isomer gives the diene (3-1). In one approach, this is then allowed
to react with a-chloroacrylonitrile to give the Diels–Alder adduct (3-2) as a mixture
of isomers. Treatment with an aqueous base affords the bicyclic ketone (3-3),
possibly by way of the cyanohydrin derived from the displacement of halogen by
hydroxide. Bayer–Villiger oxidation of the carbonyl group with peracid gives the
lactone (3-4); the net outcome of this reaction establishes the cis relationship of
the hydroxyl that will occupy the 11 position in the product and the side chain
that will be at 9 in the final product. Simple saponification then gives hydroxyacid
(3-5). The presence of the carboxyl group provides the means by which this can be
resolved by conventional salt formation with chiral bases. Reaction of the last intermediate
with base in the presence of iodine results in the formation of iodolactone;
the reaction may be rationalized by positing the formation of a cyclic iodonium salt
on the open face of the molecule; attack by the carboxylate anion will give
the lactone with the observed stereochemistry. Acetylation of the hydroxyl gives
(3-6); halogen is then removed by reduction with tributyltin hydride (3-7).
The methyl ether on the substituent at the future 11 position is then removed by
treatment with boron tribromide. Oxidation of the primary hydroxyl by means of
the chromium trioxide : pyridine complex (Collins reagent) gives Corey lactone
(3-9) as its acetate [7].
4 PROSTAGLANDINS, PEPTIDOMIMETIC COMPOUNDS, AND RETINOIDS
A somewhat more direct route to the Corey lactone, developed later, depends on a
radical photoaddition/rearrangement reaction as the key step. The scheme starts with
the Diels–Alder addition of a-acetoxyacrylonitrile to furan to give the bridged furan
(4-1) as a mixture of isomers. Hydrolysis by means of aqueous hydroxide gives the
ketone (4-2); this reaction may also proceed through the intermediate cyanohydrin.
This cyanohydrin is in fact produced directly by treatment of the mixture of
isomers with sodium methoxide in a scheme for producing the ketone in chiral
form. The crude intermediate is treated with brucine. Acid hydrolysis of the solid
“complex” that separates affords quite pure dextrorotary ketone (4-2) [8]; this
complex may consist of a ternary imminium salt formed by a sequential reaction
1.1. PROSTAGLANDINS 5
with the cyanohydrin function. Irradiation of the ketone in the presence of phenylselenylmalonate
leads to the rearranged product (4-5) in quite good yield. The structure
can be rationalized by postulating the homolytic cleavage of the C-Se bond in
the malonate to give intermediate (4-3) as the first step; the resulting malonate
radical would then add to the olefin. Acyl migration would then give the rearranged
carbon skeleton of (4-4). Addition of the phenylselenyl radical to that intermediate
will then give the observed product. Reduction of the carbonyl group by means
of sodium borohydride gives the product of approach of hydride from the more
open exo face (4-6). Decarboxylation serves to remove the superfluous carboxyl
group to afford (4-7); treatment with tertiary-butyldimethylsilyl chloride in the
presence of imidazole gives the protected intermediate (4-8) that contains all
the elements of the Corey lactone with the future aldehyde, however, in the wrong
a configuration. Saponification of the ester followed by acid hydrolysis, in fact,
gives the all cis version of the lactone [9]. The desired trans isomer (4-9) can be
obtained by oxidizing the selenide with hydrogen peroxide in the presence of
sodium carbonate [10].
Biological investigations, once supplies of prostaglandins were available,
revealed the manifold activities of this class of agents. The very potent effect of
6 PROSTAGLANDINS, PEPTIDOMIMETIC COMPOUNDS, AND RETINOIDS
PGF2a on reproductive function was particularly notable. Ovulation in most mammalian
species is marked by the formation on the ovary of a corpus luteum that
produces high levels of progesterone if a fertile ovum has implanted in the
uterus. Administration of even low doses of PGF2a was found to have a luteolytic
effect, with loss of the implanted ovum due to the withdrawal of progestin. This
prostaglandin was in fact one of the first compounds in this class to reach the
clinic under the United States Adopted Name (USAN) name dinoprost. The development
of drugs for use in domestic animals tends to be faster and much less
expensive than those that are to be used in humans. This is particularly true if
the animals are not used as food, since this dispenses with the need to study
tissue residues. It is of interest, consequently, that one of the early prostaglandins
that reached the market is fluprostenol (5-8). This compound differs from
PGF2a in that the terminal carbon atoms in the lower side chain are replaced by
the trifluromethylphenoxy group; this modification markedly enhances potency as
well as stability. This drug is marketed under the name Equimatew for controlling
fertility in racing mares, a species in which costs are probably of little consequence.
Reaction of the anion from phosphonate (5-1) with ethyl meta-triflurophenoxymethylacetate
results in acylation of the phosphonate by the displacement of
ethoxide and the formation of (5-3). Condensation of the ylide from this intermediate
with the biphenyl ester at position 11 of Corey lactone (5-4) leads to the enone
(5-5) with the usual formation of a trans olefin expected for this reaction. The very
1.1. PROSTAGLANDINS 7
bulky biphenyl ester comes into play in the next step. Reduction of the side chain
ketone by means of zinc borohydride proceeds to give largely the 15a alcohol as
a result of the presence of that bulky group. The ester is then removed by
saponification, and the two hydroxyl groups are protected as their tetrahydropyranyl
ethers (5-6). The next step in the sequence involves the conversion of the lactone
to a lactol; the carbon chain is thus prepared for attachment of the remaining
side chain while revealing potential hydroxyl at the 9 position. This transform
is affected by treating (5-6) with diisobutylaluminum hydride at 2788C;
over-reduction to a diol occurs at higher temperatures. Wittig reactions can be
made to yield cis olefins when carried out under carefully defined, “salt-free”
conditions [11]. Condensation of the lactol (5-7) with the ylide from 5-triphenylphosphoniumpentanoic
acid under those conditions gives the desired olefin.
Treatment with mild aqueous acid serves to remove the protecting groups, thus
forming fluprostenol (5-8) [12].
Prostaglandins have been called hormones of injury since their release is often
associated with tissue insult. Most of these agents consequently exhibit activities
characteristic of tissue damage. Many prostaglandins cause vasoconstriction and a
consequent increase in blood pressure as well as the platelet aggregation that precedes
blood clot formation. Thromboxane A2 is, in fact, one of the most potent known
platelet aggregating substances. Prostacyclin, PGI2, one of the last cyclooxygenase
products to be discovered, constitutes an exception; the compound causes vasodilation
and inhibits platelet aggregation. This agent may be viewed formally as the
cyclic enol ether of a prostaglandin that bears a carbonyl group at the 6 position of
the upper side chain. This very labile functionality contributes to the short half-life
of PGI2. The fact that the lifetime of this compound is measured in single-digit
minutes precludes the use of this agent as a vasodilator or as an inhibitor of platelet
aggregation.
8 PROSTAGLANDINS, PEPTIDOMIMETIC COMPOUNDS, AND RETINOIDS
The analogue in which carbon replaces oxygen in the enol ring should of course
avoid the stability problem. The synthesis of this compound initially follows a
scheme similar to that pioneered by the Corey group. Thus, acylation of the ester
(7-2) with the anion from trimethyl phosphonate yields the activated phosphonate
(7-3). Reaction of the ylide from that intermediate with the lactone (7-4) leads to a
compound (7-5) that incorporates the lower side chain of natural prostaglandins.
This is then taken on to lactone (7-6) by sequential reduction by means of zinc
borohydride, removal of the biphenyl ester by saponification, and protection of the
hydroxyl groups as tetrahydropyranyl ethers.
The first step in building the carbocyclic ring consists, in effect, of a second acylation
on trimethyl phosphonate. Thus, the addition of the anion from that reagent to the
lactone carbonyl in (7-6) leads to the product as its cyclic hemiketal (8-1); this last, it
should be noted, now incorporates an activated phosphonate group. Oxidation of that
compound with Jones’ reagent gives the diketone (8-2). The ylide prepared from that
compound by means of potassium carbonate in aprotic media adds internally to the
ring carbonyl group to give fused cylopentenone (8-3). Conjugate addition of a
methyl group to the enone by means of the cuprate reagent from methyl lithium
occurs predominantly on the open b face of the molecule to afford (8-4). The counterpart
of the upper side chain is then added to the molecule by condensation with the
ylide from triphenylphosphoniumpentanoic acid bromide. The product (8-5) is
obtained as a mixture of E and Z isomers about the new olefin due to the absence
of directing groups. Removal of the tetrahydropyran protecting groups with mild
aqueous acid completes the synthesis of ciprostene (8-6) [13]. This compound has
the same platelet aggregation inhibitory activity as PGI2, though with greatly
reduced potency.
1.1. PROSTAGLANDINS 9
An analogue in which a fused tetralin moiety replaces the furan and part of the side
chain in prostacyclin is approved for use as a vasodilator for patients with pulmonary
hypertension. The lengthy, complex synthesis starts with the protection of the
hydroxyl group in benzyl alcohol (9-1) by reaction with tert-butyl dimethyl siliyl
chloride (9-2). Alkylation of the anion from (9-2) (butyl lithium) with allyl
bromide affords (9-3). The protecting group is then removed and the benzylic
hydroxyl oxidized with oxalyl chloride in the presence of triethyl amine to give
the benzaldehyde (9-4). The carbonyl group is then condensed with the organomagnesium
derivative from treatment of chiral acetylene (9-5) with ethyl Grignard to
afford (9-6) (the triple bond is not depicted in true linear form to simplify the
scheme). The next few steps adjust the stereochemistry of the newly formed
10 PROSTAGLANDINS, PEPTIDOMIMETIC COMPOUNDS, AND RETINOIDS
alcohol in (9-6). This group is first oxidized back to a ketone with pyridinium
chlorochromate. Reduction with diborane in the presence of chiral 2-(hydroxydiphenylmethyl)
pyrolidine affords the alcohol as a single enantiomer. This is then
again protected as its tBDMS ether (9-7). Heating this compound with cobalt
carbonyl leads to the formation of the tricyclic ring system. Mechanistic considerations
aside, the overall sequence to the product (9-8) involves eletrocylic formation
of the six-membered ring from the olefin and the acetylenic bond as well as insertion
of the elements of carbon monoxide to form the five-membered ring. Catalytic hydrogenation
of that product (9-8) leads to a reduction of the double bond in the enone as
well as hydrogenolyis of the benzylic tBDMS ether on the six-membered ring (9-9).
Reduction of the ketone then leads to the alcohol, apparently as a single enantiomer.
Acid hydrolysis leads to the loss of the tetrahydropyrany protecting group to afford
intermediate (9-10). The presence of labile groups in this compound precludes the
usual methods such as hydrogen bromide or boron tribromide for cleaving the
1.1. PROSTAGLANDINS 11
methyl ether. Instead, in an unusual sequence, phenol (9-11) is obtained by treatment
of (9-10) with butyl lithium and diphenyl phosphine. The product is then alkylated
with 2-chloroacetonitrile. Hydrolysis of the cyano group to an acid finally affords
the vasodilator treprostinil (9-12) [14–16].
Dinoprost (PGF2a) was the first prostaglandin to be approved for clinical use. The
specific indication comprised induction of labor. It has received some publicity
recently as a result of its use as an adjunct in RU-486 (mifepristone; see Chapter
4) induced abortions. Though initial supplies of PGF2a were obtained by partial
synthesis from soft coral–derived starting materials, this was supplanted by a totalsynthesis
product. The reported synthesis, like those noted above, relies on a rigid
fused bicyclic starting material for determining the relative configuration of the substituents
on the cyclopentane ring.
The sequence starts by epoxidation of bicycloheptadiene (10-1) with peracid, a
reaction that had been found earlier to proceed to aldehyde (10-3) rather than
stopping at the epoxide. This rearrangement, which will control stereochemistry at
positions 11, 12, and 15 in one fell swoop, is related conceptually to the i-steroid
rearrangement discovered at least a decade earlier. The reaction relies in effect on
the mobile equilibrium between a cyclopropylcarbinyl carbocation and its homoallyl
partner: This rearrangement can be visualized as starting with the protonation of the
initially formed epoxide to (10-2). This could then first ring open to an alcohol. The
observed product (10-3) would be obtained by Wagner–Meerwin rearrangement of
the resulting carbocation. The same product would be formed by the concerted reaction
shown in the scheme below. The aldehyde is then protected as its acetal (10-4) with 2,2-
dimethylpropylene glycol. The two carbon atoms that will form the upper side chain
are then incorporated by electrocyclic addition of dichloroketene; the chlorine atoms
are removed by reduction with zinc to give (10-5). Delaying the all-important
resolution until a late step in the synthesis of chiral compounds invokes the penalty
12 PROSTAGLANDINS, PEPTIDOMIMETIC COMPOUNDS, AND RETINOIDS
of carrying the useless inactive enantiomer through a large number of transformations.
Efficient syntheses either incorporate the separation early or, better yet, start with chiral
compounds. An unusual method is used to affect the resolution in the case at hand.
Thus, condensation of fused cyclobutanone (10-5) with l-ephedrine affords a pair of
diastereomeric oxazolidines (10-6); the higher melting of the pair providentially
corresponds to the desired isomer. Separation followed by hydrolysis over silica
gives (10-5) with the prostaglandin stereochemistry.
The cyclobutanone is then lactonized by means of Bayer–Villiger oxidation;
treatment with dilute acid then serves to remove the acetal group to afford lactone-aldehyde
(11-2). The next step comprises incorporating the remaining carbon atoms required
for the lower side chain, Thus,Wittig condensation of the aldehyde with the ylide from
triphenylphosphoniumhexyl bromide under salt-free conditions affords the cis olefin
(11-3), which is converted to epoxide (11-4) by means of peracid. Solvolysis of this
last intermediate in formic acid gives compound (11-5) accompanied by significant
amounts of glycols; the mixture is recycled to give (11-5) in modest yield.
This rearrangement, which is in effect the reverse of that used to form the
cyclopropyl ring in (10-2), can be visualized as starting with protonated epoxide
(12-1); this can then go on to rearrange via a homoallyl ion (12-2); the observed
stereoselective formation of the 11-hydroxyl argues for a concerted reaction.
Solvolysis of the diol byproduct (12-3) may also go through carbocation (12-2) or
through a more concerted transition state. The product (12-4) is finally taken on to
PGF2a by a sequence very similar to that used to first add the lower side chain to
(7-6), and after suitable protection of the hydroxyls elaboration of the upper side
chain [17,18]..
1.1. PROSTAGLANDINS 13
It has been known for some time that a mucus layer secreted by gastric cells protects
the lining of the stomach from noxious agents, including its own digestive
agents. Studies on the pharmacology of the prostaglandins revealed that these compounds
had a cytoprotective effect on the gastric mucosa by maintaining the
mucus layer. The recognition that aspirin and the pharmacologically related
NSAIDs owed their action to the inhibition of cyclooxygenase, at the time thought
to consist of a single enzyme, offered an explanation for their well-recognized injurious
effect on gastric mucosa. Inhibition of that enzyme leads to a decrease in prostaglandin
synthesis and a consequent increased vulnerability to irritants, including
normal stomach acid. This prostaglandin deficit is difficult to remedy due to the manifold
activity of most congeners, their very short biological half-life, and poor oral
bioavailabilty. The finding that biological activity is retained when the side chain
hydroxyl is moved from the prime site of metabolism, 15, to the 16 position eventually
resulted in the development of misoprostol (14-5), a drug approved for the prevention
of NSAID-induced ulcers.
The synthesis of this compound represents a notable departure from those
discussed above. The presence of the carbonyl group at the 9 position of the cyclopentane
ring, which classifies this compound as a PGE, removes one asymmetric
center and thus somewhat reduces the stereochemical complexity of the synthesis.
More importantly, this introduces the possibility of attaching the lower side chain
by means of a 1,4-addition reaction; the trans relationship of the two side
chains should be favored by thermodynamic considerations. The very unusual
functionality of the required Michael acceptor, that of a cyclopent-2-en-4-ol-1-one,
leads to a rather lengthy albeit straightforward synthesis for the requisite intermediate.
14 PROSTAGLANDINS, PEPTIDOMIMETIC COMPOUNDS, AND RETINOIDS
The scheme starts by activation of monomethylazeleiate (13-1) as its imidazole
amide by means of thionyl bisimidazole. Condensation of that product with the
bis anion from reaction lithium salt of monomethyl malonate gives acetoacetate
(13-2); the first-formed tricarbonyl compound decarboxylates on workup. The
two terminal methyl ester groups are then saponified to the corresponding acids;
that b to the carbonyl group decarboxylates to a methyl ketone on acidification to
afford (13-3). Acylation of this last intermediate with dimethyl oxalate leads to the
addition of an oxalyl group to each carbon flanking the ketone to give an intermediate
such as (13-4). (Both this and (13-5) are depicted as their unlikely all-ketone
tautomers in the interest of clarity.) That intermediate cyclizes to the triketocyclopentane
(13-5) under reaction conditions. Treatment with acid leads to a scission
of the superfluous pendant oxalyl group. The product (13-6) probably exists as a
mixture of the two possible enolates. Hydrogenation in the presence of palladium
on charcoal interestingly leads to a reduction of the single carbonyl group not
involved in that tautomerism to give the future prostaglandin 11 hydroxyl.
Reaction of the product with acetone dimethyl acetal in the presence of acid leads
initially to the formation of enol ethers; these can be forced to (13-7) because of
its lower solubility in ether. Reduction of that (13-7) with lithium aluminum
hydride or Vitride at 2608C leads on workup to the enone (13-8).
1.1. PROSTAGLANDINS 15
Preparation of the reagent required for adding the lower side chain involves a
series of metal interchanges carried out as a one-pot reaction. The sequence starts
by stereospecific stannylation of acetylene (14-1) by means of tributlytin hydride.
Reaction of that with butyl lithium gives the corresponding vinyl lithio reagent,
where the tin is replaced with retention of configuration. The lithium is then replaced
by organocopper moiety by reaction with copper pentyne to give the cuprate reagent
(14-3). The addition of (14-3) to the cyclopentenone as its silyl ether (14-4) gives the
Michael product. Removal of the silyl protecting group affords misoprostol (14-5) as
a mixture of enantiomers [19,20].
Among their many other activities, prostaglandins have a direct effect on the
gastrointestional (GI) tract. PGE2, for example, regulates many physiological functions
of the gut including mucosal protection, gastrointestinal secretion, and motility.
A PGE-related compound, lubiprostone (15-11), for example, increases both intestinal
fluid secretion and motility. This compound has been recently approved for the
treatment of chronic constipation and is being investigated as a treatment of constipation-
predominant irritable bowel syndrome. It has been ascertained that the drug
interacts with specific ion channels in the GI tract, causing increased fluid output
into the lumen. The starting material for the synthesis (15-1) comprises a variant
16 PROSTAGLANDINS, PEPTIDOMIMETIC COMPOUNDS, AND RETINOIDS
on the Corey lactone. Condensation of this aldehyde with the ylide from the difluorinated
phosphonate (15-2) leads to the addition product (15-3). The double bond in
the olefin has the expected trans geometry, though the next step, hydrogenation,
makes this point moot. Sodium borohydride then reduces the side chain ketone function
to give (15-5) as a mixture of isomers. The lactone is next reduced to the key
lactol in the usual fashion, by means of diisobutyl aluminum hydride (15-6). The
product is then condensed with the ylide obtained from the reaction of the zwitterion
4-triphenylphosphoniumbutyrate to give the chain extended olefin (15-7). The carboxylic
acid in this intermediate is next protected as the benzyl ester by alkylation
of its salt with benzyl chloride (15-8). Oxidation of the ring alcohol by means of
chromium trioxide followed by exposure to mild acid to remove the tetrahydropyranyl
group establishes the keto-alcohol PGE-like function in the five-membered ring
(15-9). Catalytic hydrogenation of this last intermediate at the same time reduces
the remaining double bond and removes the benzyl protecting group on the acid to
give the open chain version (15-10) of the product. The electron-withdrawing
power of the fluorine atoms adjacent to the side chain ketone causes the carbonyl
carbon to become a reasonable electrophile. The electron-rich oxygen on the ring
alcohol thus adds to this to give a cyclic hemiacetal. This form (15-11) greatly
predominates in the product lubiprostone [21].
1.1. PROSTAGLANDINS 17
As noted previously, NSAIDs inhibit the inflammatory and, to some extent, the
platelet-aggregating activities of products from the arachidonic cascade by inhibiting
the enzyme, cylooxygenase, that catalyzes their formation. One of the few nitrogencontaining
prostaglandin analogues, vapiprost (16-9), is reported to be an inhibitor
of thromboxane A2-induced platelet aggregation. This congener is potentially a more
specific inhibitor of platelet aggregation, the prelude to thrombus formation, than
NSAIDs in that it blocks thromboxane A2 at the receptor site. Treatment of
the chiral adduct (16-1) from ketene and cyclopentadiene with bromodimethylhydantoin
in acetic acid results in the formation of bromoacetate (16-2), which results from
the formal addition of hydrobromous acid. The stereochemistry of the product
probably results from the formation of the initial bromonium ion on the more open
face of the molecule. Treatment with piperidine leads to a rearrangement to a
2,2,1-bibycloheptane with the incorporation of nitrogen on the new one-carbon
bridge. The structure of the product can be rationalized by postulating an intermediate,
or transition, species such as (16-3) along the reaction pathway. Saponification
of the initially formed product gives keto-alcohol (16-4). This is acylated to (16-5)
by means of para-biphenylacetyl halide, a bulky group used in other prostaglandin
syntheses for directing the stereochemistry of reductions. Bayer–Villiger oxidation
with peracid gives a bridged version (16-6) of a Corey lactone; reduction with
diisobutylaluminum hydride in the cold leads to hydroxyaldehyde (16-7), here
18 PROSTAGLANDINS, PEPTIDOMIMETIC COMPOUNDS, AND RETINOIDS
isolated in open form. The aldehyde is then first homologated by reaction with
methoxymethyl phosphorane to give (16-8). A second Wittig condensation, with the
ylide from triphenylphosphonium butyrate, completes the construction of the side
chain that differs from that in natural prostaglandins in that the olefin is moved one
atom closer to the terminal acid. The next two steps consist of inverting the stereochemistry of the 11 hydroxyl group to the unnatural b configuration. Thus, Swern oxidation of the initial product followed by reduction with diisobutylaluminum hydride gives vapiprost (16-9) [22]. The stereochemistry of the reduction is probably guided by the very bulky para-phenylbenzoyl group at the 9 position
i will send the synthesis as soon as i can[tafakor]
THANKS FOR YOUR ATTENTION[golrooz]