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WO2012078608A1 - Préparation de phantasmidine et de ses analogues - Google Patents

Préparation de phantasmidine et de ses analogues Download PDF

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WO2012078608A1
WO2012078608A1 PCT/US2011/063502 US2011063502W WO2012078608A1 WO 2012078608 A1 WO2012078608 A1 WO 2012078608A1 US 2011063502 W US2011063502 W US 2011063502W WO 2012078608 A1 WO2012078608 A1 WO 2012078608A1
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product
temperature
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solvent
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Barry Snider
Quan Zhou
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Brandeis University
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Brandeis University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/14—Ortho-condensed systems
    • C07D491/147—Ortho-condensed systems the condensed system containing one ring with oxygen as ring hetero atom and two rings with nitrogen as ring hetero atom

Definitions

  • Amphibians in general, and poison frogs, in particular, have been a source of many biologically active natural products.
  • a number of frog-skin alkaloids have been shown to have activity at nicotinic acetylcholine receptors (nAChRs).
  • nAChRs nicotinic acetylcholine receptors
  • the ability of poison frogs to sequester alkaloids from their diet results in a unique complexity, and to date over 800 alkaloids in more than 20 structural classes have been characterized.
  • Nicotinic acetylcholine receptors are broadly distributed in both the peripheral and central nervous systems; activation of these receptors in the brain results in enhanced release of various key neurotransmitters. Dysfunction of these receptors is associated with a variety of neurological diseases, including nicotine and alcohol addiction. Nicotinic agonists enhance action at nicotinic acetylcholine receptors and have been shown to possess potential clinical utility in many of these diseases, although development is hindered by the existence of a large number of receptor subtypes with highly variable properties. Nicotinic agonists may ultimately play a role in the treatment of Alzheimer's disease, attention deficit hyperactivity disorder (ADHD), or schizophrenia.
  • ADHD attention deficit hyperactivity disorder
  • phantasmidine may serve as a useful pharmacological probe and potential lead compound for the development of selective nicotinic receptor therapeutics.
  • phantasmidine was obtained in only microgram amounts, insufficient for full pharmacological characterization. Consequently, there exists a need for an efficient synthesis of phantasmidine and analogs thereof.
  • the invention relates to a method of preparing a product, comprising the step depicted in Scheme I:
  • A represents an optionally-substituted aromatic ring
  • R 1 represents H or lower alkyl
  • Y represents C(R 1 ) 2 , O or NR 1 ;
  • n 1, 2, 3, or 4.
  • the invention relates to a method of preparing a product, comprising the step depicted in Scheme II:
  • the invention relates to a method of preparing a product, comprising the steps depicted in Scheme III:
  • A represents an optionally-substituted aromatic ring
  • R 1 represents H or lower alkyl
  • Y represents O or NR 1 ;
  • n 1, 2, 3, or 4;
  • Step a comprises a first reagent, a first acid, and a first solvent, at a first temperature, for a first period of time;
  • Step b comprises a base, and a second solvent, at a second temperature, for a second period of time;
  • Step c comprises a second reagent, and a third solvent, at a third temperature, for a third period of time;
  • Step d comprises a third reagent, at a fourth temperature
  • Step e comprises a fourth reagent, and a fourth solvent, at a fifth temperature, for a fourth time.
  • the invention relates to a method of preparing a product, comprising the steps depicted in Scheme IV:
  • Figure 1 depicts a retrosynthetic analysis of ⁇ -phantasmidine (1), and the structure of epibatidine (2)
  • Figure 2 depicts a synthetic scheme that failed to produce ⁇ -phantasmidine (1).
  • Figure 3 depicts a synthetic scheme that produced ⁇ -phantasmidine (1).
  • Figure 4 depicts the x-ray structure of lactam 3.
  • Figure 5 depicts the circular dichroism (CD) spectra of the purified enantiomers of phantasmidine.
  • Figure 6 depicts the structures and observed ratios of various conformers of derivatives of phantasmidine.
  • phantasmidine (1) could be prepared by reduction of lactam 3 ( Figure 1).
  • Figure 1 In the key step of the proposed synthesis we planned to prepare lactam 3 from keto amide 5 by a novel, tandem intramolecular aldol reaction-intramolecular nucleophilic aromatic substitution sequence. Addition of the amide enolate of 5 to the cyclobutanone carbonyl group would provide alkoxide 4, which would undergo a nucleophilic aromatic substitution reaction at the activated 2-halopyridine to form the furan ring of 3. Although two stereoisomeric aldol products could be formed, the alkoxide can only displace the halide in 4.
  • Keto amide 5 was expected to be readily available by the reaction of primary amide 6 with l,2-bis(trimethylsilyloxy)cyclobutene (7), the readily available acyloin formed from succinate esters.
  • dichloro amide 6a Schlosser has shown that nucleophilic substitution of a 2-fluoropyridine is -320 times faster than substitution of a 2-chloropyridine.
  • fluoro chloro amide 6b therefore, offered an attractive alternative if nucleophilic aromatic substitution of dichloropyridine 4a failed to form the furan ring of 3a.
  • the increased reactivity of the fluoride of keto amide 5b was sufficient to facilitate formation of the furan ring of lactam 3.
  • Treatment of a degassed solution of 5b in t-BuOH with degassed 2 M aqueous KOH resulted in aldol cyclization to give alkoxide 4b, which underwent the desired nucleophilic aromatic substitution reaction to form furan 3 in 46%o yield.
  • the structure of 3 was readily assigned by analysis of the NMR spectra and was confirmed by X-ray crystal structure determination.
  • the 1H and 13 C NMR spectra of 17 are identical to those reported for the acetamide of phantasmidine.
  • the GC retention times of synthetic and natural phantasmidine are identical, as are the mass spectra of synthetic and natural phantasmidine and phantasmidine acetamide. Therefore, the remarkable synthesis of 1 validates the structure of phantasmidine assigned based on incomplete data obtained from the limited amount ( ⁇ 20 ⁇ g) of natural material available.
  • starting materials for the processes described in the present patent application are known or can be prepared by known processes from commercially available materials.
  • the products of the reactions described herein are isolated by conventional means such as extraction, crystallization, distillation, chromatography, and the like.
  • the invention relates to a short, efficient synthesis (8 steps, 8% overall yield) of racemic phantasmidine that confirms the structure assigned from the limited amount of available natural material.
  • the invention relates to a method of producing phantasmidine for further biological evaluation.
  • the key step a novel tandem intramolecular aldol reaction-intramolecular nucleophilic aromatic substitution, should be broadly useful for making phantasmidine analogues.
  • Racemic forms can be resolved into the optical antipodes by known methods, for example, by separation of diastereomeric salts thereof with an optically active acid, and liberating the optically active amine compound by treatment with a base. Another method for resolving racemates into optical antipodes is based upon chromatography on an optically active matrix. Racemic compounds of the present invention can thus be resolved into their optical antipodes, e.g., by fractional crystallization of D- or L-(tartrate, mandelate, or camphorsulphonate) salts, for example.
  • the compounds of the present invention may also be resolved by the formation of diastereomeric amides by reaction of the compounds of the present invention with an optically active activated carboxylic acid such as that derived from (+) or (-) phenylalanine, (+) or (-) phenylglycine, (+) or (-) camphanic acid or by the formation of diastereomeric carbamates by reaction of the compounds of the present invention with an optically active chloroformate or the like.
  • an optically active activated carboxylic acid such as that derived from (+) or (-) phenylalanine, (+) or (-) phenylglycine, (+) or (-) camphanic acid
  • HPLC high-performance liquid chromatography
  • stereoisomers of compounds 5b, 3, or 1 may be resolved.
  • stereoisomers of compound 3 are resolved.
  • stereoisomers of compound 1 are resolved.
  • Optically active compounds can also be prepared from optically active starting materials.
  • Drugs of abuse have differing mechanisms of action, but share a common pathway toward physical dependency.
  • the mesolimbic dopamine pathway is widely accepted as a central pathway in producing the rewarding effects of addictive drugs.
  • This pathway includes the dopaminergic neurons in the ventral tegmental area (VTA) of the midbrain and their targets in the limbic forebrain, especially the nucleus accumbens (NAc). All drugs of abuse, regardless of their mechanisms of actions, converge on the VTA-NAc pathway.
  • Acute exposure to addictive drugs results in the elevation of dopamine levels, a reward signaling event, which promotes repeated drug intake.
  • Addiction is then reinforced by the drugs producing a negative emotional symptom when the drug is removed, developing a period of sensitization, and associative learning toward drug-related environmental cues.
  • nAChRs may be an important target for the treatment of multiple addictions, not just nicotine addiction. Activation of the central nAChRs has also been shown to mediate the reinforcing effects of other drugs of abuse, including alcohol and cocaine. Behavior sensitization induced by nicotine, amphetamine, or cocaine was shown to be associated with an increase in electrically evoked release of [ 3 H] dopamine in nucleus accumbens slices, suggesting a related pathway for these three different drugs.
  • the nAChR ⁇ 4 ⁇ 2 subtype is implicated in the addictive effects of nicotine.
  • the nAChRs are integral membrane proteins of approximately 290 kDa and members of the Cys-loop superfamily of receptor-coupled ion channels. These receptors are ligand-gated ion channels that are permeable to cations, particularly Na+, K+, and Ca++.
  • the neuronal nAChRs are pentameric membrane proteins composed of five subunits. To date, nine a subunits (a2 - a 10) and three ⁇ subunits ( ⁇ 2 - ⁇ 4) have been found in vertebrates. Different combinations of these a and ⁇ subunits define the various nAChR subtypes.
  • nAChR subtypes Although the theoretical number of subtypes is very large, a much smaller number of native nAChR subtypes represents the majority of neuronal nAChRs, including two heteromeric subtypes, ⁇ 4 ⁇ 2 and ⁇ 3 ⁇ 4, and one homomeric subtype, a7. In most areas of mammalian brain subtype ⁇ 4 ⁇ 2 represents the predominant population of nAChRs.
  • the nAChRs are allosteric proteins that respond to the action of ACh at the binding site by changing the status of the channel gate to carry out the function of the nAChR.
  • the receptors have at least three discrete conformational states: a resting state (closed), an open state (opened) and a desensitized state (closed).
  • a particular nicotinic ligand, such as ACh has a certain affinity for each of the three states. In the absence of bound ligand, nAChRs fluctuate among all three conformational states, but most of the time they are in the resting state. The binding of a ligand to a certain state of the receptor increases the probability of the receptor to be in that state.
  • an agonist binds with a reasonably high affinity to the open state of a receptor, and thus increases the probability of it being in the open (active) conformational state.
  • the overall initial effect of an agonist is to shift a certain subpopulation of receptors from the resting state to the open state. In the open state, cations flow through the channel.
  • agonists have an even higher affinity for the desensitized state of the receptor; therefore, the eventual effect of an agonist is to "drive" the receptor population from the resting and open states to the desensitized state, in which receptors remain closed.
  • the kinetic rates for transitions between states vary greatly among different nACfiR subtypes, which contributes to the great functional diversity of neuronal nACfiRs.
  • Nicotinic ligands belong to the following four major classes, defined classically, according to their actions.
  • Agonists Nicotinic agonists, such as ACh or nicotine, activate nACfiRs leading to the opening of their channels, which allows cations to cross the membrane; but prolonged presence of agonists desensitizes the receptors.
  • the actions can be explained by the three-state model described above.
  • Agonists have low binding affinity to the resting state of nACfiRs, higher affinity to the open state, and highest binding affinity to the desensitized state. After an agonist binds, the transition from the resting state to the open state is fast, but the transition from open state to desensitized state is slow. Therefore, agonists can activate receptors to open their channels initially, but if present for an extended period agonists desensitize receptors to close the channels.
  • a competitive antagonist such as dihydro- ⁇ - erythroidine ( ⁇ ) does not activate nACfiRs but prevents agonists from activating the receptor by occupying the ACh binding site.
  • a possible mechanism is that competitive antagonists have higher binding affinity at the resting state of receptors than at the open state; therefore, they do not increase the probability of the open state but can prevent agonists from binding to the ACh site.
  • Noncompetitive Antagonists A noncompetitive antagonist, such as mecamylamine, does not activate nACfiRs but prevents an agonist from activating nACfiRs by binding to a site different from the ACh site.
  • the binding site for mecamylamine is in the central pore of the receptors, and so it blocks the pathway for ions, preventing the functional activity of an agonist.
  • Allosteric Modulators An allosteric modulator, such as progesterone, does not bind to the acetylcholine binding site (orthosteric site) but modulates nAChR signaling through its binding to an allosteric site. There are positive and negative allosteric modulators of nAChRs and some of them show selectivity among nAChR subtypes.
  • the ⁇ 4 ⁇ 2 subtype stands out not only because of its prevalence in most of the brain, but also because its expression is increased by chronic administration of nicotine in rats and mice. Moreover, recent in vivo studies of imaged brain ⁇ 4 ⁇ 2 nAChRs in human smokers indicate that these receptors are virtually saturated by the nicotine taken in during the smoking of a single cigarette. Therefore, it is likely that most of the ⁇ 4 ⁇ 2 nAChRs in a smoker's brain are in a state of desensitization during the time the addicted individual is awake and smoking at a typical rate.
  • the resumption of endogenous acetylcholine signaling through even a relatively small percentage of these receptors may provide the critical neurophysiological cues for the individual to smoke his/her next cigarette, silencing those cues by once again desensitizing the receptors.
  • Cytisine has been used extensively as a probe for 4 ⁇ 2 receptors in natural and radiolabeled forms for in vitro pharmacology, as well as clinically as a smoking cessation agent, where the drug varenicline is an analogue of cytisine.
  • Norchloroepibatidine and UB-165 display only a modest (3-10-fold) ⁇ 4 preference over ⁇ 2, while AR-R17779 is more selective (>20-fold), though the latter is considered a selective l agonist.
  • Mice in which the ?4-subunit has been knocked out are resistant to nicotine- induced seizures and exhibited reduced nicotine withdrawal relative to their wild-type counterparts.
  • Preliminary studies showed that phantasmidine was a ?4-selective agonist. If phantasmidine is, indeed, a ?4-selective agonist, it may provide a useful tool for probing subtype-selectivity in this receptor class, especially due to its highly rigid structure.
  • phantasmidine may serve as useful pharmacologic probes for / ⁇ -containing nicotinic receptors, much as the semirigid laburnum alkaloid cytisine and pyridohomotropane (a derivative of the dinoflagellate alkaloid anatoxin) have for /?2-containing receptors. Phantasmidine and its analogs also have the potential to be active at a7 and/or 5-HT3 receptors given its structural similarity to pyridofurans.
  • compounds made by methods of the present invention may be useful as agonists of nicotinic acetylcholine receptors. In certain embodiments, compounds made by methods of the present invention may be useful as agonists of ⁇ 2- containing nicotinic acetylcholine receptors. In certain embodiments, compounds made by methods of the present invention may be useful as agonists of / ⁇ -containing nicotinic acetylcholine receptors.
  • Phantasmidine may fill a new niche for characterization of ⁇ 2- or / ⁇ -containing nicotinic receptors.
  • the invention relates to a method of preparing a product, comprising the step depicted in Scheme I:
  • A represents an optionally-substituted aromatic
  • R 1 represents H or lower alkyl
  • Y represents C(R 1 ) 2 , O or NR 1 ;
  • n 1, 2, 3, or 4.
  • the invention relates to any one of the aforementioned methods, wherein A is an optionally-substituted aromatic ring selected from the group consisting of benzene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine, pyrimidine, naphthalene, indole, quinoline, isoquinoline, benzothiophene, benzofuran, benzimidazole, benzothiazole, benzoxazole, and quinazoline.
  • A is an optionally-substituted aromatic ring selected from the group consisting of benzene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine, pyrimidine, n
  • the invention relates to any one of the aforementioned methods, wherein A is an optionally-substituted aromatic ring selected from the group consisting of benzene, pyridine, pyrazine, pyridazine, pyrimidine, naphthalene, indole, quinoline, isoquinoline, benzothiophene, and benzofuran.
  • A is an optionally-substituted aromatic ring selected from the group consisting of benzene, pyridine, pyrazine, pyridazine, pyrimidine, naphthalene, indole, quinoline, isoquinoline, benzothiophene, and benzofuran.
  • the invention relates to any one of the aforementioned methods, wherein A is an optionally- substituted aromatic ring selected from the group consisting of pyridine, pyrazine, pyridazine, pyrimidine, indole, quinoline, isoquinoline, benzothiophene, and benzofuran.
  • A is an optionally- substituted aromatic ring selected from the group consisting of pyridine, pyrazine, pyridazine, pyrimidine, indole, quinoline, isoquinoline, benzothiophene, and benzofuran.
  • the invention relates to any one of the aforementioned methods, wherein R 1 is H, methyl, or ethyl.
  • the invention relates to any one of the aforementioned methods, wherein R 1 is H.
  • the invention relates to any one of the aforementioned methods, wherein Y is O or NR 1 .
  • the invention relates to any one of the aforementioned methods, wherein Y is NR 1 .
  • the invention relates to any one of the aforementioned methods, wherein n is 1 or 2.
  • the invention relates to any one of the aforementioned methods, wherein n is 1.
  • the invention relates to any one of the aforementioned methods, wherein the base is a carbonate, phosphate, oxide, hydroxide, alkoxide, aryloxide, or metal amide.
  • the invention relates to any one of the aforementioned methods, wherein the base is sodium tert-butoxide, potassium hydroxide, cesium hydroxide, calcium hydroxide, or sodium hydroxide.
  • the invention relates to any one of the aforementioned methods, wherein the period of time is about 3 minutes to about 60 minutes. In certain embodiments, the invention relates to any one of the aforementioned methods, wherein the period of time is about 5 minutes, about 10 minutes, about 15 minutes, or about 20 minutes.
  • the invention relates to any one of the aforementioned methods, wherein the temperature is about 10 °C to about 40 °C.
  • the invention relates to any one of the aforementioned methods, wherein the temperature is about 15 °C, about 20 °C, about 25 °C, about 30 °C, or about 35 °C.
  • the invention relates to any one of the aforementioned methods, further comprising the step of resolving the product, thereby producing a substantially enantiomerically pure product.
  • the invention relates to any one of the aforementioned methods, wherein the product is substantially enantiomerically pure.
  • the invention relates to a method of preparing a product, comprising the step depicted in Scheme II:
  • the invention relates to any one of the aforementioned methods, wherein the product is substantially enantiomerically pure.
  • the invention relates to any one of the aforementioned methods, further comprising the step of resolving the product, thereby producing a substantially enantiomerically pure product.
  • the invention relates to a method of preparing a product, comprising the steps depicted in Scheme III:
  • A represents an optionally-substituted aromatic ring
  • R 1 represents H or lower alkyl
  • Y represents O or NR 1 ;
  • n 1, 2, 3, or 4;
  • Step a comprises a first reagent, a first acid, and a first solvent, at a first temperature, for a first period of time;
  • Step b comprises a base, and a second solvent, at a second temperature, for a second period of time;
  • Step c comprises a second reagent, and a third solvent, at a third temperature, for a third period of time;
  • Step d comprises a third reagent, at a fourth temperature
  • Step e comprises a fourth reagent, and a fourth solvent, at a fifth temperature, for a fourth time.
  • the invention relates to any one of the aforementioned methods, wherein A is an optionally- substituted aromatic ring selected from the group consisting of benzene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine, pyrimidine, naphthalene, indole, quinoline, isoquinoline, benzothiophene, benzofuran, benzimidazole, benzothiazole, benzoxazole, and quinazoline.
  • A is an optionally- substituted aromatic ring selected from the group consisting of benzene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine, pyrimidine, naphthalene, in
  • the invention relates to any one of the aforementioned methods, wherein A is an optionally-substituted aromatic ring selected from the group consisting of benzene, pyridine, pyrazine, pyridazine, pyrimidine, naphthalene, indole, quinoline, isoquinoline, benzothiophene, and benzofuran.
  • A is an optionally-substituted aromatic ring selected from the group consisting of benzene, pyridine, pyrazine, pyridazine, pyrimidine, naphthalene, indole, quinoline, isoquinoline, benzothiophene, and benzofuran.
  • the invention relates to any one of the aforementioned methods, wherein A is an optionally-substituted aromatic ring selected from the group consisting of pyridine, pyrazine, pyridazine, pyrimidine, indole, quinoline, isoquinoline, benzothiophene, and benzofuran.
  • A is an optionally-substituted aromatic ring selected from the group consisting of pyridine, pyrazine, pyridazine, pyrimidine, indole, quinoline, isoquinoline, benzothiophene, and benzofuran.
  • the invention relates to any one of the aforementioned methods, wherein R 1 is H, methyl, or ethyl.
  • the invention relates to any one of the aforementioned methods, wherein R 1 is H.
  • the invention relates to any one of the aforementioned methods, wherein Y is NR 1 .
  • the invention relates to any one of the aforementioned methods, wherein n is 1 or 2.
  • the invention relates to any one of the aforementioned methods, wherein n is 1.
  • the invention relates to any one of the aforementioned
  • the invention relates to any one of the aforementioned methods, wherein the first acid is HI, HBr, HC10 4 , HC1, H 2 S0 4 , HN0 3 , or HC10 3 .
  • the invention relates to any one of the aforementioned methods, wherein the first solvent is hexane, cyclohexane, toluene, 1,4-dioxane, chloroform, tetrahydrofuran, or diethyl ether.
  • the invention relates to any one of the aforementioned methods, wherein the first solvent is diethyl ether.
  • the invention relates to any one of the aforementioned methods, wherein the first temperature is about 60 °C to about 100 °C.
  • the invention relates to any one of the aforementioned methods, wherein the first temperature is about 65 °C, about 70 °C, about 75 °C, about 80 °C, about 85 °C, about 90 °C, or about 95 °C. In certain embodiments, the invention relates to any one of the aforementioned methods, wherein the first period of time is about 20 min to about 5 h.
  • the invention relates to any one of the aforementioned methods, wherein the first period of time is about 45 min, about 1 h, about 1.5 h, about 2 h, about 2.5 h, or about 3 h.
  • the invention relates to any one of the aforementioned methods, further comprising the step of purifying the product of "Step a.”
  • the invention relates to any one of the aforementioned methods, wherein the base is a carbonate, phosphate, oxide, hydroxide, alkoxide, aryloxide, or metal amide.
  • the invention relates to any one of the aforementioned methods, wherein the base is sodium tert-butoxide, potassium hydroxide, cesium hydroxide, calcium hydroxide, or sodium hydroxide.
  • the invention relates to any one of the aforementioned methods, wherein the second solvent is water.
  • the invention relates to any one of the aforementioned methods, wherein the second temperature is about 10 °C to about 40 °C.
  • the invention relates to any one of the aforementioned methods, wherein the second temperature is about 15 °C, about 20 °C, about 25 °C, about 30 °C, or about 35 °C.
  • the invention relates to any one of the aforementioned methods, wherein the second period of time is about 3 minutes to about 60 minutes.
  • the invention relates to any one of the aforementioned methods, wherein the second period of time is about 5 minutes, about 10 minutes, about 15 minutes, or about 20 minutes.
  • the invention relates to any one of the aforementioned methods, further comprising the step of purifying the product of "Step b.”
  • the invention relates to any one of the aforementioned methods, further comprising the step of resolving the product of "Step b.”
  • the invention relates to any one of the aforementioned methods, wherein the second reagent is BH 3 .
  • the invention relates to any one of the aforementioned methods, wherein the third solvent is tetrahydrofuran or diethyl ether. In certain embodiments, the invention relates to any one of the aforementioned methods, wherein the third temperature is about 0 °C to about 40 °C.
  • the invention relates to any one of the aforementioned methods, wherein the third period of time is about 10 h to about 50 h.
  • the invention relates to any one of the aforementioned methods, wherein the third period of time is about 15 h, about 20 h, about 25 h, about 30 h, about 35 h, or about 40 h.
  • the invention relates to any one of the aforementioned methods, wherein the third reagent is methanol.
  • the invention relates to any one of the aforementioned methods, wherein the fourth temperature is about 0 °C to about 40 °C.
  • the invention relates to any one of the aforementioned methods, wherein the fourth reagent is piperazine.
  • the invention relates to any one of the aforementioned methods, wherein the fourth solvent is methanol, ethanol, water, or ethyl acetate.
  • the invention relates to any one of the aforementioned methods, wherein the fourth solvent is methanol.
  • the invention relates to any one of the aforementioned methods, wherein the fifth temperature is the refiux temperature of the fourth solvent.
  • the invention relates to any one of the aforementioned methods, wherein the fourth period of time is about 1 h to about 5 h.
  • the invention relates to any one of the aforementioned methods, wherein the fourth period of time is about 2 h, about 2.5 h, about 3 h, about 3.5 h, or about 4 h.
  • the invention relates to any one of the aforementioned methods, further comprising the step of purifying the product of "Step e.”
  • the invention relates to any one of the aforementioned methods, wherein the product of "Step e" is substantially enantiomerically pure.
  • the invention relates to any one of the aforementioned methods, further comprising the step of resolving the product of "Step e", thereby producing a substantially enantiomerically pure product.
  • the invention relates to a method of preparing a product, comprising the steps depicted in Scheme IV:
  • nucleophile is recognized in the art, and as used herein means a chemical moiety having a reactive pair of electrons.
  • nucleophiles include uncharged compounds such as water, amines, mercaptans and alcohols, and charged moieties such as alkoxides, thiolates, carbanions, and a variety of organic and inorganic anions.
  • Illustrative anionic nucleophiles include simple anions such as hydroxide, azide, cyanide, thiocyanate, acetate, formate or chloroformate, and bisulfite.
  • Organometallic reagents such as organocuprates, organozincs, organolithiums, Grignard reagents, enolates, acetylides, and the like may, under appropriate reaction conditions, be suitable nucleophiles. Hydride may also be a suitable nucleophile when reduction of the substrate is desired.
  • Electrophiles useful in the method of the present invention include cyclic compounds such as epoxides, aziridines, episulfides, cyclic sulfates, carbonates, lactones, lactams and the like.
  • Non-cyclic electrophiles include sulfates, sulfonates (e.g., tosylates), chlorides, bromides, iodides, and the like
  • electrophilic atom refers to the atom of the substrate which is attacked by, and forms a new bond to, the nucleophile. In most (but not all) cases, this will also be the atom from which the leaving group departs.
  • electron-withdrawing group is recognized in the art and as used herein means a functionality which draws electrons to itself more than a hydrogen atom would at the same position.
  • Exemplary electron-withdrawing groups include nitro, ketone, aldehyde, sulfonyl, trifluoromethyl, -CN, chloride, and the like.
  • electron-donating group means a functionality which draws electrons to itself less than a hydrogen atom would at the same position.
  • Exemplary electron-donating groups include amino, methoxy, and the like.
  • meso compound is recognized in the art and means a chemical compound which has at least two chiral centers but is achiral due to an internal plane or point of symmetry.
  • chiral refers to molecules which have the property of non- superimposability on their mirror image partner, while the term “achiral” refers to molecules which are superimposable on their mirror image partner.
  • a "prochiral molecule” is an achiral molecule which has the potential to be converted to a chiral molecule in a particular process.
  • stereoisomers refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of their atoms or groups in space.
  • enantiomers refers to two stereoisomers of a compound which are non-superimposable mirror images of one another.
  • diastereomers refers to the relationship between a pair of stereoisomers that comprise two or more asymmetric centers and are not mirror images of one another.
  • a “stereoselective process” is one which produces a particular stereoisomer of a reaction product in preference to other possible stereoisomers of that product.
  • An “enantioselective process” is one which favors production of one of the two possible enantiomers of a reaction product.
  • the subject method is said to produce a "stereoselectively-enriched" product (e.g., enantioselectively-enriched or diastereoselectively-enriched) when the yield of a particular stereoisomer of the product is greater by a statistically significant amount relative to the yield of that stereoisomer resulting from the same reaction run in the absence of a chiral catalyst.
  • an enantioselective reaction catalyzed by one of the subject chiral catalysts will yield an e.e. for a particular enantiomer that is larger than the e.e. of the reaction lacking the chiral catalyst.
  • regioisomers refers to compounds which have the same molecular formula but differ in the connectivity of the atoms. Accordingly, a “regioselective process" is one which favors the production of a particular regioisomer over others, e.g., the reaction produces a statistically significant preponderence of a certain regioisomer.
  • reaction product means a compound which results from the reaction of a nucleophile and a substrate.
  • reaction product will be used herein to refer to a stable, isolable compound, and not to unstable intermediates or transition states.
  • substrate is intended to mean a chemical compound which can react with a nucleophile, or with a ring-expansion reagent, according to the present invention, to yield at least one product having a stereogenic center.
  • catalytic amount is recognized in the art and means a substoichiometric amount relative to a reactant.
  • the reactions contemplated in the present invention include reactions which are enantioselective, diastereoselective, and/or regioselective.
  • An enantioselective reaction is a reaction which converts an achiral reactant to a chiral product enriched in one enantiomer. Enantioselectivity is generally quantified as "enantiomeric excess" (ee) defined as follows:
  • % Enantiomeric Excess A (ee) (% Enantiomer A) - (% Enantiomer B) where A and B are the enantiomers formed. Additional terms that are used in conjunction with enatioselectivity include "optical purity" or "optical activity".
  • An enantioselective reaction yields a product with an e.e. greater than zero.
  • Preferred enantioselective reactions yield a product with an e.e. greater than 20%, more preferably greater than 50%, even more preferably greater than 70%, and most preferably greater than 80%.
  • a diastereoselective reaction converts a chiral reactant (which may be racemic or enantiomerically pure) to a product enriched in one diastereomer. If the chiral reactant is racemic, in the presence of a chiral non-racemic reagent or catalyst, one reactant enantiomer may react more slowly than the other. This class of reaction is termed a kinetic resolution, wherein the reactant enantiomers are resolved by differential reaction rate to yield both enantiomerically-enriched product and enantimerically-enriched unreacted substrate.
  • Kinetic resolution is usually achieved by the use of sufficient reagent to react with only one reactant enantiomer (i.e., one-half mole of reagent per mole of racemic substrate).
  • Examples of catalytic reactions which have been used for kinetic resolution of racemic reactants include the Sharpless epoxidation and the Noyori hydrogenation.
  • a regioselective reaction is a reaction which occurs preferentially at one reactive center rather than another non-identical reactive center.
  • a regioselective reaction of an unsymmetrically substituted epoxide substrate would involve preferential reaction at one of the two epoxide ring carbons.
  • non-racemic with respect to the chiral catalyst, means a preparation of catalyst having greater than 50% of a given enantiomer, more preferably at least 75%.
  • substantially non-racemic refers to preparations of the catalyst which have greater than 90% ee for a given enantiomer of the catalyst, more preferably greater than 95% ee.
  • alkyl refers to the radical of saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups.
  • a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C 1 -C30 for straight chain, C3-C30 for branched chain), and more preferably 20 of fewer.
  • preferred cycloalkyls have from 4-10 carbon atoms in their ring structure, and more preferably have 5, 6 or 7 carbons in the ring structure.
  • lower alkyl as used herein means an alkyl group, as defined above, but having from one to ten carbons, more preferably from one to six carbon atoms in its backbone structure. Likewise, “lower alkenyl” and “lower alkynyl” have similar chain lengths.
  • alkenyl and alkynyl refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one double or triple carbon-carbon bond, respectively.
  • amine and “amino” are art-recognized and refer to both unsubstituted and substituted amines, e.g., a moiet that can be represented by the general formula: wherein R9, Ri g and R' lO each independently represent a group permitted by the rules of valence.
  • acylamino is art-recognized and refers to a moiety that can be represented by the general formula:
  • R 9 is as defined above, and R'i j represents a hydrogen, an alkyl, an alkenyl or -(CH2) m -R8, where m and Rg are as defined above.
  • amino is art recognized as an amino-substituted carbonyl and includes a moiety that can be represented by the general formula:
  • R9, Rj Q are as defined above.
  • Preferred embodiments of the amide will not include imides which may be unstable.
  • alkylthio refers to an alkyl group, as defined above, having a sulfur radical attached thereto.
  • the "alkylthio" moiety is represented by one of -S-alkyl, -S-alkenyl, -S-alkynyl, and -S-(CH2) m -Rg, wherein m and Rg are defined above.
  • Representative alkylthio groups include methylthio, ethyl thio, and the like.
  • carbonyl is art recognized and includes such moieties as can be represented by the general formula:
  • X is a bond or represents an oxygen or a sulfur
  • R ⁇ ⁇ represents a hydrogen, an alkyl, an alkenyl, -(CH2) m -Rg or a pharmaceutically acceptable salt
  • R'j ⁇ represents a hydrogen, an alkyl, an alkenyl or -(CH2) m -Rg, where m and Rg are as defined above.
  • X is an oxygen and R j ⁇ or R' j ⁇ is not hydrogen
  • the formula represents an "ester”.
  • X is an oxygen, and Rj ⁇ is as defined above, the moiety is referred to herein as a carboxyl group, and particularly when Ri j is a hydrogen, the formula represents a "carboxylic acid".
  • alkoxyl or "alkoxy” as used herein refers to an alkyl group, as defined above, having an oxygen radical attached thereto.
  • Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy and the like.
  • An "ether” is two hydrocarbons covalently linked by an oxygen. Accordingly, the substituent of an alkyl that renders that alkyl an ether is or resembles an alkoxyl, such as can be represented by one of -O-alkyl, -O- alkenyl, -O-alkynyl, -0-(CH2) m -Rg, where m and Rg are described above.
  • R4 ⁇ is an electron pair, hydrogen, alkyl, cycloalkyl, or aryl.
  • sulfonyl refers to a moiety that can be represented by the general formula: O
  • R44 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.
  • sulfoxido refers to a moiety that can be represented by the general formula:
  • R44 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aralkyl, or aryl.
  • sulfate means a sulfonyl group, as defined above, attached to two hydroxy or alkoxy groups.
  • a sulfate has the structure:
  • R40 and R41 are independently absent, a hydrogen, an alkyl, or an aryl.
  • R40 and R4 taken together with the sulfonyl group and the oxygen atoms to which they are attached, may form a ring structure having from 5 to 10 members.
  • Analogous substitutions can be made to alkenyl and alkynyl groups to produce, for example, alkenylamines, alkynylamines, alkenylamides, alkynylamides, alkenylimines, alkynylimines, thioalkenyls, thioalkynyls, carbonyl-substituted alkenyls or alkynyls, alkenoxyls, alkynoxyls, metalloalkenyls and metalloalkynyls.
  • aryl or “aromatic” as used herein includes 4-, 5-, 6- and 7-membered single-ring aromatic groups or multiple-ring aromatic groups, which may include from zero to four heteroatoms, for example, benzene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like. Those aryl groups having heteroatoms in the ring structure may also be referred to as "aryl heterocycle".
  • the aromatic ring can be substituted at one or more ring positions with such substituents as described above, as for example, halogens, alkyls, alkenyls, alkynyls, hydroxyl, amino, nitro, thiol amines, imines, amides, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, or - (CH 2 ) m -R7, -CF 3 , -CN, or the like.
  • substituents as described above, as for example, halogens, alkyls, alkenyls, alkynyls, hydroxyl, amino, nitro, thiol amines, imines, amides, phosphonates, phosphines, carbonyls, carboxyls, silyl
  • heterocycle or “heterocyclic group” refer to 4 to 10-membered ring structures, more preferably 5 to 7 membered rings, which ring structures include one to four heteroatoms.
  • Heterocyclic groups include pyrrolidine, oxolane, thiolane, imidazole, oxazole, piperidine, piperazine, morpholine.
  • the heterocyclic ring can be substituted at one or more positions with such substituents as described above, as for example, halogens, alkyls, alkenyls, alkynyls, hydroxyl, amino, nitro, thiol, amines, imines, amides, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, or -(CH2) m -Ry, -CF3, -CN, or the like.
  • substituents as described above, as for example, halogens, alkyls, alkenyls, alkynyls, hydroxyl, amino, nitro, thiol, amines, imines, amides, phosphonates, phosphines, carbonyls, carboxyls, silyls,
  • polycycle or “polycyclic group” refer to two or more cyclic rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocycles) in which two or more carbons are common to two adjoining rings, e.g., the rings are "fused rings". Rings that are joined through non-adjacent atoms are termed "bridged" rings.
  • Each of the rings of the polycycle can be substituted with such substituents as described above, as for example, halogens, alkyls, alkenyls, alkynyls, hydroxyl, amino, nitro, thiol, amines, imines, amides, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, or -(CH2) m -R7, -CF3, -CN, or the like.
  • substituents as described above, as for example, halogens, alkyls, alkenyls, alkynyls, hydroxyl, amino, nitro, thiol, amines, imines, amides, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers
  • heteroatom as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, sulfur, phosphorus and selenium.
  • triflyl, tosyl, mesyl, and nonaflyl are art-recognized and refer to trifluoromethanesulfonyl, /?-toluenesulfonyl, methanesulfonyl, and nonafluorobutanesulfonyl groups, respectively.
  • triflate, tosylate, mesylate, and nonaflate are art-recognized and refer to trifluoromethanesulfonate ester, /?-toluenesulfonate ester, methanesulfonate ester, and nonafluorobutanesulfonate ester functional groups and molecules that contain said groups, respectively.
  • Me, Et, Ph, Tf, Nf, Ts, Ms represent methyl, ethyl, phenyl, trifluoromethanesulfonyl, nonafluorobutanesulfonyl, /?-toluenesulfonyl and methanesulfonyl, respectively.
  • a more comprehensive list of the abbreviations utilized by organic chemists of ordinary skill in the art appears in the first issue of each volume of the Journal of Organic Chemistry; this list is typically presented in a table entitled Standard List of Abbreviations. The abbreviations contained in said list, and all abbreviations utilized by organic chemists of ordinary skill in the art are hereby incorporated by reference.
  • ortho, meta and para apply to 1,2-, 1,3- and 1 ,4-disubstituted benzenes, respectively.
  • the names 1 ,2-dimethylbenzene and ortAo-dimethylbenzene are synonymous.
  • protecting group means temporary substituents which protect a potentially reactive functional group from undesired chemical transformations.
  • protecting groups include esters of carboxylic acids, silyl ethers of alcohols, and acetals and ketals of aldehydes and ketones, respectively.
  • the field of protecting group chemistry has been reviewed (Greene, T.W.; Wuts, P.G.M. Protective Groups in Organic Synthesis, 2 nd ed.; Wiley: New York, 1991).
  • the term "substituted" is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds.
  • Illustrative substituents include, for example, those described hereinabove.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valencies of the heteroatoms. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds.
  • Reactions were conducted in flame- or oven-dried glassware under a nitrogen atmosphere and were stirred magnetically.
  • concentration refers to removal of solvents by means of a rotary evaporator attached to a diaphragm pump (15-60 Torr) followed by removal of residual solvents at ⁇ 1 Torr with a vacuum pump.
  • Flash chromatography was performed on silica gel 60 (230-400 mesh).
  • Analytical thin layer chromatography (TLC) was performed using silica gel 60 F-254 pre-coated glass plates (0.25 mm).
  • TLC Plates were analyzed by short wave UV illumination, or by dipping in vanillin stain (27 g of vanillin in 380 mL of EtOH, 50 mL of water and 20 mL of concentrated sulfuric acid) and heating on a hot plate or by spray with permanganate spray (5 g of KMn0 4 in 495 mL of water).
  • THF and ether were dried and purified by distillation from sodium/benzophenone. DIPEA, Et 3 N, MeOH, and benzene were distilled from Ca3 ⁇ 4. 1H and 13 C NMR spectra were obtained on a 400 MHz spectrometer in CDCI 3 with tetramethylsilane as internal standard unless otherwise indicated.
  • 2,6-Dichloropyridine-3-pyridinemethanol (9a).
  • a solution of diisopropylamine (5.80 mL, 41.5 mmol) in anhydrous THF (100 mL) was treated with n- BuLi (2.1 M in hexanes, 18.0 mL, 37.8 mmol) at -78 °C.
  • the cold bath was removed and the resulting solution was stirred at 0 °C for 30 min.
  • the light yellow solution was re- cooled to -78 °C and 2-chloro-6-fluoropyridine (15, 3.80 g, 29.0 mmol) in anhydrous THF (20 mL) was added dropwise.
  • Powdered NaCN (1.10 g, 22.4 mmol) was added to 20 mL of DMSO. The mixture was stirred at 25 °C for 20 min. A solution of crude 10b in 5 mL of DMSO was added to the NaCN suspension dropwise over 10 min. The NaCN fully dissolved after addition. The resulting solution was stirred for 1 h at 25 °C and cooled to 0 °C. Water (100 mL) was added slowly to the reaction and the mixture was extracted with CH 2 CI 2 (50 mL x 3). The combined organic layers were washed with H 2 0 and brine, dried (Na 2 S0 4 ), and concentrated to give 1.50 g of crude lib.
  • 6-Chloro-2-fluoro-3-pyridineacetamide (6b).
  • a mixture of lib (300 mg, 1.76 mmol) and alumina (570 mg, 5.59 mmol) in MsOH (5 mL) was heated at 120 °C for 15 min.
  • the reaction was cooled and H 2 0 (30 mL) was added.
  • the mixture was extracted with CH 2 C1 2 (30 mL x 5).
  • the combined CH 2 C1 2 layers were washed with brine (30 mL), dried (MgS0 4 ), and concentrated to give 285 mg of 6b as a white solid.
  • Crude 6b was dissolved in the minimum amount of MeOH at 60 °C and the solution was cooled and hexanes were added to facilitate recrystallization.
  • the two isomers also show the appropriate CD spectra ( Figure 5).
  • MMX calculations by PCMODEL revealed that in the major conformations (more stable by 1 kcal/mol) of phantasmidine Mosher amides 18ma and 19ma (see Figure 6) the large Ph(OMe)CF 3 C group is adjacent to the cyclobutane-substituted methine carbon rather than the methylene carbon as in 2-methylpyrrolidine Mosher amides.
  • the methyl group of phantasmidine acetamide (17) also prefers to be adjacent to the cyclobutane-substituted methine carbon (see 17ma) by 1 kcal/mol.
  • Racemic Phantasmidine (S)-(-)-MPTA Amide A mixture of (5)-(-)-MPTA-OH (8.5 mg, 36 ⁇ ) in 1 mL of hexanes was treated with 2 ⁇ ⁇ of DMF and then 10 (14.8 mg, 1 16 ⁇ ) of oxalyl chloride at 25 °C. The reaction was kept at 25 °C for 30 min and filtered. The filtrate was concentrated to give crude (R)-(-)-MPTA-Cl as colorless oil, which was used directly without further purification.

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Abstract

La présente invention a pour objet des procédés de synthèse de la phantasmidine et de ses analogues à partir de matières premières disponibles dans le commerce. Les composés sont utiles en tant que sondes pharmacologiques et têtes de série potentielles pour le développement de produits thérapeutiques de type récepteurs nicotiniques sélectifs.
PCT/US2011/063502 2010-12-10 2011-12-06 Préparation de phantasmidine et de ses analogues Ceased WO2012078608A1 (fr)

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Publication number Priority date Publication date Assignee Title
WO2011111628A1 (fr) * 2010-03-09 2011-09-15 旭硝子株式会社 Phosphate, électrode positive pour pile secondaire et méthode de production d'une pile secondaire

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011111628A1 (fr) * 2010-03-09 2011-09-15 旭硝子株式会社 Phosphate, électrode positive pour pile secondaire et méthode de production d'une pile secondaire

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
FITCH ET AL.: "Phantasmidine: An Epibatidine Congener from the Ecuadorian Poison Frog Epipedobates anthonyi", JOURNAL OF NATURAL PRODUCTS, vol. 73, 26 March 2010 (2010-03-26), pages 331 - 337 *
ZHOU ET AL.: "Synthesis of Phantasmidine.", ORGANIC LETTERS., vol. 13, no. 3, 22 December 2010 (2010-12-22), pages 526 - 529 *

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