WO2014124651A1 - Pyrrolidine-2-carboxylic acid derivatives as iglur antagonists - Google Patents

Abstract

The present invention relates to compounds of Formula (I), combinations and use thereof for disease therapy, or pharmaceutically acceptable salt or solvate thereof, including all tautomers, stereoismers and polymorphs thereof, which are iGlu R inhibitors, and hence are useful in the treatment of psychiatric diseases or neurological disorders or a disease or disorder associated with abnormal activities of iGluR receptors.

Description

Pyrrolidine-2-carboxylic acid derivatives as iGluR antagonists Field of the invention

The present invention relates to a class of substituted pyrrolidine-2- carboxylic acid derivatives as iGluR antagonist, their salt and solvates, phar- maceutical compositions comprising them, their use as medicament and in therapy, and preparation thereof. In particular, the invention relates to a class of substituted pyrrolidine-2-carboxylic acid derivatives as iGluR antagonists, which is useful in the treatment of psychiatric diseases or neurological disorders or a disease or disorder associated with abnormal activities of iGluR receptors.

Background

In the mammalian central nervous system (CNS), (S)-glutamate (Glu) functions as the major excitatory neurotransmitter.¹ The glutamatergic neurotransmitter system is involved in a vast number of basic neuro- physiological processes such as memory, cognition, as well as neuronal plasticity and development.^2"9 Thus, psychiatric diseases or neurological disorders such as depression,^10"12 anxiety,^13"15 addiction,¹⁶ migraine,¹⁷ and schizophrenia^18"22 may be directly related to disordered glutamatergic neurotransmis- sion. Moreover, elevated synaptic Glu levels or excessive Glu signaling is neurotoxic and will ultimately cause neuronal death.^23"26 Thus, it is believed that neurodegenerative diseases such as Alzheimer's,^27"31 Huntington's,³² amyotrophic lateral sclerosis (ALS),³³ cerebral stroke,³⁴ and epilepsy³⁵ may indeed be the result of a malfunctioning glutamatergic neurotransmitter system which may be reversed by action of small molecule Glu ligands.¹

Once released from the pre-synaptic neuron into the synapse, Glu activates a number of pre- and post-synaptic Glu receptors. On the basis of the pharmacological profile and ligand selectivity, the Glu receptors have been grouped in two main classes: the fast acting ionotropic Glu receptors (iGluRs) comprising the three groups AMPA receptors (subunits GluAl-4), kainate (KA) receptors (subunits GluKl-5), and NMDA receptors (subunits GluNl, GluN2A-D and GluN3A-C),³⁶ and the G-protein coupled metabotropic Glu receptors (mGluRs, subunits mGluRl-8),³⁷ which produce a slower signal transduction through second messenger systems. For example, disturbances of expression of KA receptors and function of KA receptors has been suggested to be linked to severe neurological- and psychiatric diseases.³⁸ Abnormal expression of KA subunit composition (GluK3 and GluK5) in the prefrontal cortex has been observed in schizophrenic sub- jects,³⁹ but also decreased expression of GluK2 and GluK3 from the medial dorsal thalamus to the dorsolateral prefrontal cortex and other cortical regions may be important to the pathophysiology of schizophrenia.⁴⁰ Furthermore, two population studies have suggested altered GluK3 expression (GRIK3 gene) as a risk factor,^41,42 whereas GluK2 (GRIK2 gene) in one Japa- nese study came out short.⁴³ In bipolar disorder the GluK3 receptor is suggested to play a role,⁴⁴ but also intervention of GluK2 may constitute a therapeutic target.⁴⁵ In an rodent (rat) model of pain, trigeminal caudal nucleus nerve terminals mainly express GluK2/GluK3 subunits, which evidence that differentiated expression of KA receptor subtypes plays a role at the various stages of pain transmission.⁴⁶

To this date only selective antagonists for the GluKl subtype has been reported.⁴⁷

(S)-Glutamate 1 LY466195 UBP310

(Glu) (CNG-10100)

Chemical structures of (S)-Glu, rationally designed iGluR anta- gonist 1 (CNG-10100) and examples of selective high-affinity GluKl antagonists LY466195⁴⁸ and UBP310.

Hence, there is a strong need present for novel selective antagonists for iGluR or its subtypes such as GluAl-4, GluKl-5, or GluNl-3, such as GluN2A, GluN2B, GluN2C or GluN2D, which can be used to elucidate the role and function of iGluR receptors under both physiological and pathological conditions. Thus, new antagonists having high affinity and/or high specificity to one and more of the iGluR receptors such as GluAl-4, GluKl-5, or GluNl- 3, such as GluN2A, GluN2B, GluN2C or GluN2D, would therefore be useful in the treatment of disorders and diseases associated with these receptors.

Summary of the invention With this background, it is an object of the present invention in a first embodiment to provide a compound of Formula (I)

and pharmaceutically acceptable derivatives, as well as all tautomers and stereoisomers of compound of Formula (I), wherein

Q represents compounds of Formula (la) or (lb);

— in each case may represent if appropriate the presence of at least one double bond between T₂ and (Z₂ or Z₃), or between Z₂ and (Zi or Z₃), or between Zi and Ti, or between Ti and Z_4; or between Z₄ and T₂; or

Ti is C, or CH,

T₂ is C, or CH,

Zi is CR₂, C(R₂)₂, N, S, O, or NR₃,

Z₂ is CR₂, C(R₂)₂, N, S, O, or NR₃,

Z₃ is CR₂, C(R₂)₂, N, S, O, or NR₃,

Z₄ is CR₂, C(R₂)₂, N, S, O, or NR₃,

wherein the residues Zi, Z₂, and Z₃ cannot represent adjacent O or S;

Ri may together with Zi or Z₄, or

Z₂ may together with Zi or Z₃,

form a saturated or unsaturated C₅- or C₆-cycloalkyl, or a saturated or unsaturated heterocyclyl containing 5 or 6 ring atoms, wherein the satu- rated or unsaturated C₅- or C₆-cycloalkyl, or the saturated or unsaturated heterocyclyl containing 5 or 6 ring atoms, may be substituted with one or more substituents selected from the group comprising OR₄ or R₄,

Ri is H, OR₄, Ci-Ce-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, COOR₄, N(OH)H, or NHR₄,

R₂ is independently selected among R₄, O, OR₄, halogen, N(OH)H, N(OH)R₄, NHR₄, COR₄, CONHR₄, CN, CF₃, CCI₃, SH, or S0₂NHR₄,

R₃ is independently selected among R₄, O, OR₄, or halogen,

R₄ is independently selected among H, OH, Ci-C₆-alkyl, C₂-C₆- alkenyl, C₂-C₆-alkynyl, phenyl, Ci-C₆-alkylphenyl, or saturated or unsaturated C₅- or C₆-cycloalkyl, or saturated or unsaturated Ci-C₆-alkyl C₅- or C₆- heterocyclyl, wherein Ci-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, phenyl, Ci-C₆- alkylphenyl, or saturated or unsaturated C₅- or C₆-cycloalkyl, or saturated or unsaturated Ci-C₆-alkyl C₅- or C₆- heterocyclyl may be substituted with one or more substituents selected from the group comprising d-C₆-alkyl, Ci-C₆- alkoxy, aryl, halogen, and amine,

halogen represents CI, Br, or I, and

with the proviso that Zi, Z₂, Z₃ and Z₄ are not all CH, and Ti and T₂ are not both C, when Ri is OH.

In one particular embodiment of the present invention, the compounds of Formula (I) as previously described are stereoisomeric and contain at least two isomeric centers. Thus, depending on the orientation of the stereoisomers, presence of four different diastereomers is possible. Thus, compounds of Formula (II) according to Formula (I), wherein

(II),

wherein

^Q represents compounds of Formula (Ia l) or (Ib2);

, are also part of the invention.

In one particular embodiment of the present invention, Q represents a saturated ring.

Thus, compounds according to Formula (I), wherein

Q represents

.T₂

z₄- ^z₃

/

wherein

Ti is C,

T₂ is C,

Zi is CR₂, N, S, O, or NR₃,

Z₂ is CR₂, or N, Z₃ is CR₂, or N,

Z₄ is CR₂, or N,

wherein the residues Zi, Z₂, and Z₃ cannot represent adjacent O or

S;

Ri may together with Zi or Z₄, or

Z₂ may together with Zi or Z₃,

form a saturated or unsaturated C₅- or C₆-cycloalkyl, or a saturated or unsaturated heterocyclyl containing 5 or 6 ring atoms, wherein the saturated or unsaturated C₅- or C₆-cycloalkyl, or the saturated or unsaturated heterocyclyl containing 5 or 6 ring atoms, may be substituted with one or more substituents selected from the group comprising OR₄ or R₄;

Ri is H, OR₄, Ci-Ce-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, COOR₄, N(OH)H, or NHR₄,

R₂ is R₄, O, OR₄, halogen, N(OH)H, N(OH)R₄, NHR₄, COR₄, CONHR₄, or S0₂NHR₄,

R₃ is R₄, O, OR₄, or halogen,

R₄ is H, Ci-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, phenyl, Ci-C₆- alkylphenyl, or saturated or unsaturated C₅- or C₆-cycloalkyl, or saturated or unsaturated Ci-C₆-alkyl C₅- or C₆-heterocyclyl, wherein Ci-C₆-alkyl, C₂-C₆- alkenyl, C₂-C₆-alkynyl, phenyl, Ci-C₆-alkylphenyl, or saturated or unsaturated C₅- or C₆-cycloalkyl, or saturated or unsaturated Ci-C₆-alkyl C₅- or C₆- heterocyclyl may be substituted with one or more substituents selected from the group comprising Ci-C₆-alkyl, Ci-C₆-alkoxy, aryl, halogen, and amine, halogen represents CI, Br, or I, and

with the proviso that Zi, Z₂, Z₃ and Z₄ are not all CH, and Ti and T₂ are not both C when Ri is OH,

are also part of the invention.

In a second embodiment of the present invention, the compound of Formula (I) as previously described can comprise additional ringforming structures wherein

Ri may together with Zi or Z₄, or

Z₂ may together with Zi or Z₃,

form a saturated or unsaturated C₅- or C₆-cycloalkyl, or a saturated or unsaturated heterocyclyl containing 5 or 6 ring atoms, wherein the satu- rated or unsaturated C₅- or C₆-cycloalkyl, or the saturated or unsaturated heterocyclyl containing 5 or 6 ring atoms, may be substituted with one or more substituents selected from the group comprising OR₄ or R₄.

In particular, in yet a further embodiment, compounds of Formula (I) as previously described, which are selected from the group consisting of

(IV),

wherein

Z₅ is CR₂, C(R₂)₂, N, S, O, or NR₃,

wherein the residues Zi, Z₂, Z₃ and Z₅ cannot represent adjacent O

wherein

Z₅ is CR₂, C(R₂)₂, N, S, O, or NR₃,

Z₆ is CR₂, C(R₂)₂, N, S, O, or NR₃,

Z₇ is CR₂, C(R₂)₂, N, S, O, or NR₃,

wherein the residues Zi, Z₂, Z₃, Z₅, Z₆, Z₇ cannot represent adjacent

O or S,

— , Ti, T₂, Zi, Z₂, Z₃, Z₄, R₂, R₂, R₃, R₄ have the same meaning as given above,

are also part of the invention.

In another embodiment of the present invention, the compounds Formula (I) as previously described, which is selected from the group consisting of

wherein

R₄ has the same meaning as given above, are also part of the invention.

In one particular embodiment of the invention, compounds of Formula (I) are selected from the group wherein R₄ is alkyl, benzyl, alkylbiphenyl, preferably propyl, benzyl, or 3-methyl[l,l'-biphenyl].

Each of the described embodiments of the present invention is to be construed as disclosing the present invention either individually or in combination with the other embodiments.

Detailed description of the invention

In the following the present invention is described in more detail. All individual features and details can be individually applied to each embodiment and aspect of the compounds of Formula (I), its preparations, its formulations, its methods and its use.

The term "Ci-₆ alkyl", unless specifically limited, denotes a straight chain or branched alkyl group with 1, 2, 3, 4, 5 or 6 carbon atoms. Suitable Ci-6 alkyl groups include, for example, methyl, ethyl, propyl (e.g. n-propyl and isopropyl), butyl (e.g n-butyl, iso-butyl, sec-butyl and tert-butyl), pentyl (e.g. n- pentyl), and hexyl (e.g. n-hexyl).

The term "Ci-6 alkenyl", unless specifically limited, may be inter- preted similarly to the term "alkyl". Alkenyl groups contain at least 1 double bond. Suitable alkenyl groups include ethenyl, propenyl, 1-butenyl, and 2- butenyl.

The term "Ci-6 alkynyl", unless specifically limited, may be interpreted similarly to the term "alkyl". Alkenyl groups contain at least 1 triple bond.

The term "saturated or unsaturated C₅- or C₆-cycloalkyl", unless specifically limited, denotes cyclic carbon rings comprising 5 or 6 carbon atoms, wherein either a single or double bond between the mutually adjacent carbon atoms exist. Suitable saturated or unsaturated C₅- or C₆-cycloalkyl groups include cyclopentane, cyclohexane, cyclopentene, cyclohexene, cyclopenta- di-ene, cyclohhexa-di-ene, and phenyl.

The term "saturated or unsaturated heterocyclyl", unless specifically limited, denotes a heterocyclic compound, such as a carbocyclyl group, phenyl group, or aryl residue, having atoms of at least two different elements as members of its ring. Suitable ring atoms in heterocyclic compound may be C, N, S, or O. Heterocyclic compounds according to the present invention may contain 3, 4, 5, 6, 7, 8 or even more rings atoms, preferably 5 or 6 ring atoms. Suitable saturated or unsaturated heterocyclic compounds may include pyrrolidine, pyrrole, tetrahydrofuran, furan, thiolane, thiophene, imida- zolidine, pyrazolidine, imidazole, pyrazole, oxazolidine, isoxazolidine, oxazole, isoxazole, thiazolidine, isothiazolidine, thiazole, isothiazole, dioxolane, dithi- olane, triazoles, furazan, oxadiazole, thiadiazole, dithiazole, tetrazole, piperi- dine, pyridine, oxane, pyran, thiane thiopyran, piperazine, diazines, morpho- line, oxazine, thiomorpholine, thiazine, dioxane, dioxine, dithiane, dithiine, triazine, trioxane, or tetrazine.

The term "halogen" comprises fluorine (F), chlorine (CI), bromine (Br) and iodine (I), more typically F, CI or Br.

All possible tautomers of the claimed compounds are included in the present invention. Tautomers are isomers of organic compounds that readily interconvert by a chemical reaction called tautomerization. This reaction commonly results in the formal migration of a hydrogen atom or proton, accompanied by a switch of a single bond and adjacent double bond.

As compounds of Formula (I) contains at least 2 two asymmetric carbons, there are up to 4 possible configurations, which cannot all be non- superimposable mirror images of each other.

The compounds of the invention have one or more asymmetric centers. Compounds with asymmetric centers give rise to enantiomers (optical isomers), diastereomers (configurational isomers) or both, and it is intended that all of the possible enantiomers and diastereomers in mixtures and as pure or partially purified compounds are included within the scope of this invention. The present invention is meant to encompass all isomeric forms of the compounds of the invention. The present invention includes all stereoisomers of compounds of Formula (I). Compounds of Formula (I) comprises although depending on the choice of T₂ at least one chiral centers, i.e. at the second position of pyrrolidine, a COOH group, and at the third position of pyrrolidine, a 5- or 6-membered ring, as indicated by the Q-group. Diastereomers differ from enantiomers in that these are pairs of stereoisomers that differ in all stereocenters. Diastereomers have different physical properties (unlike enantiomers) and different chemical reactivity. Diastereoselectivity is the preference for the formation of one or more than one diastereomer over the other in an organic reaction.

The independent syntheses of the enantiomerically or diastereomeri- cally enriched compounds, or their chromatographic separations, may be achieved as known in the art by appropriate modification of the methodology disclosed herein. Their absolute stereochemistry may be determined by the x-ray crystallography of crystalline products or crystalline intermediates that are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration. If desired, racemic mixtures of the compounds may be separated so that the individual enantiomers or diastereo- mers are isolated. The separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography. The coupling reaction is often the formation of salts using an enantiomerically pure acid or base. The diastereomeric derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue. The racemic mixture of the compounds can also be separated directly by chromatographic methods using chiral stationary phases, which methods are well known in the art.

Alternatively, any enantiomer or diastereomer of a compound may be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well known in the art.

Pyrrolidine-2-carboxylic acid derivatives according to the invention can be prepared from the various examples given further below or by con- suiting handbooks within organic chemistry. Examples of such handbook - although not intending to be limited thereto - are "Organic Chemistry, 2^nd Edition, 2000, by Maitland Jones, Jr., and Organic Chemistry, 6th Edition, Robert T. Morrison, and Robert N. Boyd. These two specifically referred handbooks are hereby incorporated by reference.

The term "pharmaceutically acceptable derivative" in present context includes pharmaceutically acceptable salts, which indicate a salt which is not harmful to the patient. Such salts include pharmaceutically acceptable basic or acid addition salts as well as pharmaceutically acceptable metal salts, ammonium salts and alkylated ammonium salts. A pharmaceutically acceptable derivative further includes hydrates, polymorphs, esters and prodrugs, or other precursors of a compound which may be biologically metabolized into the active compound, or crystal forms of a compound. Salts and solvates of the compounds of Formula (I) and physiologically functional derivatives thereof which are suitable for use in medicine are those wherein the counter-ion or associated solvent is pharmaceutically acceptable. However, salts and solvates having non-pharmaceutically acceptable counter-ions or associated solvents are within the scope of the present invention, for example, for use as intermediates in the preparation of other compounds and their pharmaceutically acceptable salts and solvates.

Pharmaceutically acceptable acid addition salts include those formed from hydrochloric, hydrobromic, sulfuric, nitric, citric, tartaric, phosphoric, lactic, pyruvic, acetic, trifluoroacetic, triphenylacetic, sulfamic, sulfanilic, succinic, oxalic, fumaric, maleic, malic, mandelic, glutamic, aspartic, oxaloacetic, methanesulfonic, ethanesulfonic, arylsulfonic (for example p-toluenesulfonic, benzenesulfonic, naphthalenesulfonic or naphthalenedisulfonic), salicylic, glu- taric, gluconic, tricarballylic, cinnamic, substituted cinnamic (for example, phenyl, methyl, methoxy or halo substituted cinnamic, including 4-methyl and 4-methoxycinnamic acid), ascorbic, oleic, naphthoic, hydroxynaphthoic (for example 1- or 3-hydroxy-2-naphthoic), naphthaleneacrylic (for example naphthalene-2-acrylic), benzoic, 4-methoxybenzoic, 2- or 4- hydroxybenzoic, 4-chlorobenzoic, 4-phenylbenzoic, benzeneacrylic (for example 1,4- benzene- diacrylic), isethionic acids, perchloric, propionic, glycolic, hydroxyethanesul- fonic, pamoic, cyclohexanesulfamic, salicylic, saccharinic and trifluoroacetic acid.

Pharmaceutically acceptable base salts include ammonium salts, alkali metal salts such as those of sodium and potassium, alkaline earth metal salts such as those of calcium and magnesium and salts with organic bases such as dicyclohexylamine and [Lambda]/-methyl-D-glucamine.

Furthermore, some of the crystalline forms of the compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (i.e. hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention. The compounds, including their salts, can also be obtained in the form of their hy- drates, or include other solvents used for their crystallization. Organic molecules can form crystals that incorporate water into the crystalline structure without modification of the organic molecule. An organic molecule can exist in different crystalline forms, each different crystalline forms may contain the same number of water molecules pr organic molecule or a different number of water molecules pr organic molecule.

The term "administering" shall encompass the treatment of the various disorders described with derivatives of the claimed compounds which convert to the active compound in vivo after administration to the subject. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bund- gaard, Elsevier, 1985.

The term "antagonist" in the present context refers to a substance that does not provoke a biological response itself upon binding to a receptor. Hence, antagonists have affinity to but no efficacy for their cognate recep- tors, and binding will disrupt the interaction and inhibit the function of e.g. an agonist.

The term "AMPA receptor" denotes a receptor family within the iG- luRs receptors. The AMPA receptor comprises subunits such as, GluAl, GluA2, GluA3, or GluA4.

The term "KA" denotes a receptor family within iGluRs receptors. The

KA receptor comprises subunits such as GluKl, GluK2, GluK3, GluK4, or GluK5.

The term "NMDA" denotes a receptor family within iGluRs receptors. The NMDA receptor comprises subunits such as GluNl, GluN2A, GluN2B, GluN2C, GluN2D, GluN3A, GluN3B, or GluN3C.

A receptor antagonist defined by the Formula (I) , is thus capable of binding to the GluKl, GluK2, GluK3, GluK4, or GluK5 receptor, respectively. The same considerations apply similarly to receptor antagonists of the AMPA receptor and NMDA receptor subunits.

The antagonist may be an antagonist of several different types of receptors, and thus capable of binding to several different types of receptors, such AMPA receptors, KA receptors, and NMDA receptors.

The antagonist can also be a selective antagonist, which only binds to and activates one type of receptor. Antagonist may bind reversible or irre- versible depending on the antagonist-receptor complex. The term "IC₅₀" is commonly used as a measure of antagonist drug potency and reflects the measure of the effectiveness of a compound in inhibiting biological or biochemical function. This quantitative measure indicates how much of a compound of Formula (I) is needed to inhibit 50% of the ac- tivity of a particular receptor. IC₅₀ can be regarded as the functional strength of the different compounds of Formula (I).

IC₅₀ is not a direct indicator of affinity although the two can be related at least for competitive agonists and antagonists by the Cheng-Prusoff equation.

The term 'V refers to the binding affinity, which describe the binding of compounds of Formula (I) to a receptor.

As used herein, the term "pharmaceutical composition" is intended to encompass a product comprising compounds of Formula (I) in the therapeutically effective amounts, as well as any product which results, directly or indi- rectly, from combinations of the claimed compounds.

The term "therapeutically effective amount" of a compound as used herein refers to an amount sufficient to cure, alleviate, prevent, reduce the risk of, or partially arrest the clinical manifestations of a given disease or disorder and its complications. An amount adequate to accomplish this is de- fined as a "therapeutically effective amount".

Compounds of Formula (I) according to the present invention may be used in pharmaceutical compositions and method for treatment of disorders, diseases in a subject, or conditions associated with the dysfunction of iGluR receptors, e.g. the AMPA receptors, KA receptors and NMDA receptors, and their corresponding subunits, GluAl-4, GluKl-5 and GluNl, GluN2A-D, and GluN3A-C. Thus, targeting iGluR or its subtypes such as GluAl-4, GluKl-5, GluNl-3 and its subtypes with antagonists according to the present invention would be helpful in the treatment of disorders and diseases associated with these receptors.

The terms "treatment" and "treating" as used herein refer to the management and care of a patient for the purpose of combating a condition, disease or disorder. The term is intended to include the full spectrum of treatments for a given condition from which the patient is suffering, such as administration of the active compound for the purpose of: alleviating or re- lieving symptoms or complications; delaying the progression of the condition, disease or disorder; curing or eliminating the condition, disease or disorder; and/or preventing the condition, disease or disorder, wherein "preventing" or "prevention" is to be understood to refer to the management and care of a patient for the purpose of hindering the development of the condition, dis- ease or disorder, and includes the administration of the active compounds to prevent or reduce the risk of the onset of symptoms or complications.

The term "subject" refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment. Treatment of animals, such as mice, rats, dogs, cats, cows, sheep and pigs, is, however, also within the scope of the present invention.

In a certain embodiment, the present invention relates to compounds of Formula (I) or pharmaceutical compositions thereof, or methods for treatment of diseases or conditions binding one or more of the GluAl, GluA2, GluA3, GluA4, GluKl, GluK2, GluK3, GluK4, GluK5, GluN2A, GluN2B, GluN2C or GluN2D receptor subunits to obtain a beneficial therapeutic effect.. Optionally, compounds of Formula (I) or pharmaceutical compositions thereof are used for treatment of diseases or conditions binding one or more of the GluAl, GluA2, GluA3, GluA4, GluKl, GluK2, GluK3, GluK4, GluK5, GluN2A, GluN2B, GluN2C or GluN2D receptor subunits to obtain a beneficial therapeu- tic effect..

In yet a certain embodiment, the present invention relates to compounds of Formula (I) or pharmaceutical compositions thereof, or methods for treatment of disorders of the central nervous system, neuro-physiological processes such as memory, cognition; as well as neuronal plasticity and de- velopment, psychiatric diseases or neurological disorders such as depression, anxiety, addiction, pain, migraine, and schizophrenia, and neurodegenerative diseases; such as Alzheimer, Huntington disease, amyotrophic lateral sclerosis (ALS), cerebral stroke, and epilepsy; and diseases including aching, ADHD, Autism, Diabetes, Huntington's disease, ischemia, multiple sclerosis, Parkinson's disease (Parkinsonism), Rasmussen's encephalitis, seizures, AIDS dementia complex, amyotrophic lateral sclerosis, combined systems disease (vitamin B12 deficiency), drug addiction, drug tolerance, drug dependency, glaucoma, hepatic encephalopathy, hydroxybutyric aminoaciduria, hyperho- mocysteinemia and homocysteinuria, hyperprolinemia, lead encephalopathy, leber's disease, MELAS syndrome, MERRF, mitochondrial abnormalities (and other inherited or acquired biochemical disorders), neuropathic pain syndromes (e.g. causalgia or painful peripheral neuropathies), nonketotic hyperglycinemia, olivopontocerebellar atrophy, essential tremor, Rett syndrome, sulfite oxidase deficiency, Wernicke's encephalopathy or cancer.

According to the present invention, the antagonist of compound of

Formula (I) is administered to subjects in need of treatment in pharmaceutically effective doses. A therapeutically effective amount of a compound according to the present invention is an amount sufficient to cure, prevent, reduce the risk of, alleviate or partially arrest the clinical manifestations of a given disease or its complications. The amount that is effective for a particular therapeutic purpose will depend on the severity and the sort of the disease as well as on the weight and general state of the subject. The antagonists of the present invention may be administered one or several times per day, such as from 1 to 4 times per day, such as from 1 to 3 times per day, such as from 1 to 2 times per day, wherein administration from 1 to 3 times per day is preferred.

In a preferred embodiment, the present invention relates to antagonist of compound of Formula (I) which is administered in doses of 0.5-1500 mg/day, preferably 0.5-200 mg/day, more preferably 0.5-60 mg/day, even more preferably 0.5-30 mg/day.

In a preferred embodiment, the present invention relates to antagonist of compound of Formula (I) suitable for oral, rectal, nasal, pulmonary, buccal, sublingual, transdermal or parenteral administration.

During any of the processes for preparation of the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Syn- thesis, John Wiley & Sons, 1991, fully incorporated herein by reference. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.

In a preferred embodiment, the present invention relates to compounds of Formula (I), such as

(1) (2S,3R)-2-Carboxy-3-(3-carboxy-4-hydroxyphenyl)pyrrolidin-l-ium- 2,2,2-trifluoroacetate,

(2) (2S,3R)-3-(3-Carboxy-5-propoxyphenyl)pyrrolidine-2-carboxylic acid hydrochloride,

(3) (2S,3R)-3-(3-(Benzyloxy)-5-carboxyphenyl)pyrrolidine-2-carboxylic acid hydrochloride,

(4) (2S,3R)-3-(3-([l,l'-Biphenyl]-3-ylmethoxy)-5- carboxyphenyl)pyrrolidine-2-carboxylic acid, (2S,3R)-2-Carboxy-3-(3- carboxy-5-hydroxyphenyl)pyrrolidin-l-ium 2,2,2-trifluoroacetate,

(5) (2S,3R)-tert-butyl 2-(((tert-butyldimethylsilyl)oxy)methyl)-3-(2,2- dimethyl-4H-benzo[d][l,3]dioxin-6-yl)-5-oxopyrrolidine-l-carboxylate,

(6) (2S,3R)-tert-Butyl 2-(((tert-butyldimethylsilyl)oxy)methyl)-3-(3- (((tert-butyldimethylsilyl)oxy)-methyl)-5-propoxyphenyl)-5-oxopyrrolidine-l- carboxylate,

(7) (2S,3R)-tert-Butyl 3-(3-(benzyloxy)-5-(((tert- butyldimethylsilyl)oxy)methyl)phenyl)-2-(((tert-butyldime- thylsilyl)oxy)methyl)-5-oxopyrrolidine-l-carboxylate,

(8) (2S,3R)-tert-Butyl 3-(3-([l,l'-biphenyl]-3-ylmethoxy)-5-(((tert- butyldimethylsilyl)oxy)methyl)phenyl)-2-(((tert- butyldimethylsilyl)oxy)methyl)-5-oxopyrrolidine-l-carboxylate,

(9) (2S,3R)-tert-Butyl 2-(((tert-butyldimethylsilyl)oxy)methyl)-3-(2,2- dimethyl-4H-benzo[d][l,3]-dioxin-6-yl)pyrrolidine-l-carboxylate,

(10) (2S,3R)-tert-Butyl- 2-(((tert-butyldimethylsilyl)oxy)methyl)-3-(3- (((tert-butyldimethylsilyl)oxy)-methyl)-5-propoxyphenyl)pyrrolidine-l- carboxylate,

(11) (2S,3R)-tert-Butyl-3-(3-(benzyloxy)-5-(((tert- butyldimethylsilyl)oxy)methyl)phenyl)-2-(((tert- butyldimethylsilyl)oxy)methyl)pyrrolidine-l-carboxylate

(12) (2S,3R)-tert-Butyl- 3-(3-([l,l'-biphenyl]-3-ylmethoxy)-5-(((tert- butyldimethylsilyl)oxy)methyl)-phenyl)-2-(((tert- butyldimethylsilyl)oxy)methyl)pyrrolidine-l-carboxylate,

(13) (2S,3R)-tert-Butyl 3-(2,2-dimethyl-4H-benzo[d][l,3]dioxin-6-yl)-2- (hydroxymethyl)-pyrrolidine-l-carboxylate,

(14) (2S,3R)-tert-Butyl 2-(hydroxymethyl)-3-(3-(hydroxymethyl)-5- propoxyphenyl)pyrrolidine-l-carboxylate,

(15) (2S,3R)-tert-Butyl 3-(3-(benzyloxy)-5-(hydroxymethyl)phenyl)-2- (hydroxymethyl)pyrrolidine- l-carboxylate,

(16) (2S,3R)-tert-Butyl 3-(3-([l,l'-biphenyl]-3-ylmethoxy)-5- (hydroxymethyl)phenyl)-2-(hydroxymethyl)-pyrrolidine-l-carboxylate,

(17) (2S,3R)-l-(tert-Butoxycarbonyl)-3-(2,2-dimethyl-4-oxo-4H- benzo[d][l,3]dioxin-6-yl)pyrrolidine-2-carboxylic acid,

(18) (2S,3R)-l-(tert-butoxycarbonyl)-3-(2,2-dimethyl-4H- benzo[d][l,3]dioxin-6-yl)pyrrolidine-2-carboxylic acid,

(19) (2S,3R)-l-(tert-Butoxycarbonyl)-3-(3-carboxy-5- propoxyphenyl)pyrrolidine-2-carboxylic acid,

(20) (2S,3R)-3-(3-(Benzyloxy)-5-carboxyphenyl)-l-(tert- butoxycarbonyl)pyrrolidine-2-carboxylic acid, and

(21) (2S,3R)-3-(3-([l,l'-Biphenyl]-3-ylmethoxy)-5-carboxyphenyl)- l-(tert-butoxycarbonyl)-pyrrolidine-2-carboxylic acid Examples

Results and discussion

Based on ligand conformational analysis and the vast structural information on the GluA2 & GluKl ligand binding domains, (2S,3£)-3-(3- carboxyphenyl)pyrrolidine-2-carboxylic acid (1, CNG-10100) was design as a broad-range iGluR antagonist.⁴⁹ Succeeding its synthesis, pharmacological characterization of 1 showed low-to-medium range micromolar binding affinity to AMPA, KA and NMDA receptors, and antagonist function in a non- desensitizing functional GluKl assay.⁴⁹ Thus 1 defined a new lead structure for the discovery of subtype selective iGluR antagonists.

From our modeling studies introduction of substituents on the phenyl ring was attractive. Introduction of a hydroxyl group in the 4'-position (compound 2a, Figure 2) would immediately enhance the ligand's ability to engage in favorable hydrogen bonding interactions with amino acid residues AAA, AAA (GluKl numbering) as well as key water molecules trapped in the receptor. However, this process could also be net-disfavored, which would then induce subtype or group selectivity rather than enhanced overall binding affinity.

Figure 2. Chemical structures of rationally design analogs 2a- e

2a (2b) 2c (2d) (2e)

(CNG-10104) (CNG-10107)

Chemistry

The synthesis commenced with double protection of commercially available optically pure (S)-glutaminol (3), to give 4 in high yield (Scheme 1). Subsequently, introduction of the double bond was carried out under standard selenylation conditions, to give enone 5. For target compound 2a, the synthesis of suitably protected phenylbromide 6a was carried out starting from commercially available phenolic alcohol 12 (Scheme 2). With enone 5 and phenyl bromide 6a in hand, the copper catalyzed conjugate addition reaction was carried out as previously described to give the desired product 7a as a single diastereomer (70% yield, Scheme 1). Reduction of the endo- cyclic carbonyl group by borane gave pyrrolidinone 8a in low-to-acceptable yield (32-46%), with the byproduct being reductive opening of isopropylidene group (determined by LC-MS). At this stage a shortcut was attempted : Full deprotection of 8a in p-TsOH/MeOH at rt gave the expected phenolic diol 13 in high yield (Scheme 3). However, oxidation to the corresponding diacid 14 was unsuccessful although several conditions were tried : RuCl3-NaI0₄, TEM- PO-NaOCI-NaCI0₂, Pd-C/O^NaBH^ PDC in DMF, and KMn0₄ in acetone (Scheme 3). Returning to the planned pathway (Scheme 1), ruthenium catalyzed oxidation of 8a gave the desired acid-lactone 10a together with acid 11, in a 1 : 2 ratio. The two products were easily separated using flash chromatography after which acid-lactone 10a was fully deprotected in TFA/H₂0 to give target compound 2a.

Scheme 1. Synthesis of 2a (CNG-10104)

9a 10a 11 2a

(CNG-10104)

Reagents and conditions, a) TBSCI, imidazole, DCM, rt, 24h, aq workup, then BOC₂0, DMAP, ACN, rt, 16h (two steps, 91%); b) LHMDS, PhSeCI, THF, -78 °C, then 30% H₂0₂, EtOAc, 0 °C to rt (two steps, 64%); c) 6a, tert- BuLi, CuCN, Et₂0, -78 to -42 °C (70%); d) BH₃, THF, reflux, 3¹/₂h, then H₂0, NaOH, H₂0₂, rt, 3¹/₂h (46%); e) TBAF, THF, rt, 2h (87%); f) NaI0₄, RuCI₃, 0 °C, l¹/₂h (10a: 22%, 11 : 40%); g) 10a only, TFA: H₂0 (1 : 1), rt, 16h (59%).

cheme thesis of bromide 6a

12 6a

Reagents and conditions, a) 2,2-dimethoxypropane, ZnCI₂, acetone, 40

Scheme 3. Attempted oxidation of phenolic diol 12

13

Reagents and conditions, a) p-TsOH, MeOH, rt, 5h (71%).

The synthesis of target structures 2b-e (Scheme 4) followed the strategy described for 2a with only few changes Firstly, suitably protected phenyl bromides 6b-d were prepared starting from commercially available acid 15 in two (three) steps (Scheme 5). Due to the bulkiness of the phenyl bromides 6b-d, conjugate addition to enone 5 was carried out by use of a mixed-cyano Gilman cuprate, as previously described by us to be advantageous for this specific enone.⁵⁰ Reduction of the endo-carbonyl group gave pyrrolidinones 8a-d in acceptable yields (51-60%), and removal of the TBS groups provided the free diols 9b-d in high yield. Subsequent ruthenium catalyzed oxidation to give diacids lOb-d was carried out at 0 °C to prevent over oxidation of the electron rich phenyl ring giving L-trans-2,3-dicarboxy-pyrrolidinone 17 (Scheme 4), which was otherwise identified as the major byproduct. Finally removal of the BOC-group under acidic water-free conditions gave target compounds 2b-d, as the HCI salts. Analog 2e which comprised a free 5'- phenol was obtained by hydrogenation over Pd/C of 2c to give the desired product in 63% after purification on HPLC.

Reagents and conditions, a) 6b-d, tert-BuLi, CuCN, ThLi, Et₂0, -78 to -

42 °C (42-62%); b) BH₃, THF, reflux, 20h, then H₂0, NaOH, H₂0₂, rt, lh (51- 60%); c) TBAF, THF, rt, (92-94%); d) NaI0₄, RuCI₃, 0 °C, 2h (66-83%); e) 2 M HCI in Et₂0, AcOH, rt, 18h (87-99%). f) 2c only, H₂ (g), Pd/C (10%), AcOH, rt, 6d (44%).

Scheme 5. Synthesis of substituted phenylbromides 6b-d

15 16 6b: R = n-Pr

6c: R = Bn

6d: R = 3-Ph-Bn Reagents and conditions, a) BH₃, THF, 0°C to rt, aq work-up, then TBSCI, imidazole, DMF, 0°C to rt (71%); b) For 6b: RBr, K₂C0₃, rt in DMF (90%); for 6c,d: RBr, K₂C0₃, reflux in acetone (92-95%). The synthesis of analogs 2f-n (Figure 3) was carried out following the general strategy described for 2a-e (Scheme 1-5). Starting from 5 and appropriately substituted aryl analog 6 analogs 2f-n were prepared in moderate yields.

Pharmacological characterization

The five new analogs 2a-e were characterized pharmacologically in radio ligand binding assays at native iGluRs (rat synaptosomes) and cloned homomeric subtypes, GluKl-3 (Table 1). 4'-Hydroxy analog 2a displayed a general higher binding affinity for the iGluRs in native tissue, and reduced iGluR class selectivity, as compared to lead structure 1. In details, a 25- and 15-fold higher affinity for AMPA and KA receptors was observed, while a 6- fold higher affinity at NMDA receptors could be demonstrated. But most interestingly, 2a displayed a 10-fold increase in binding affinity for homomeric GluK3 (0.87 μΜ), while affinity for homomeric GluKl and -GluK2 was essentially unchanged. This 5-fold preference for GluK3 over GluKl is indeed a unique binding affinity profile for a KA antagonist and encourages future SAR investigations of the 4'-position for the discovery of a fully selective GluK3 antagonist. Furthermore, as the binding affinity profile of the 5'-hydroxy ana- log 2e is essentially unchanged compared to 1, strengthen the interest in the 4'-position as a point of modification to obtain selectivity for the GuK3 subtype.

The pharmacological profiles of 5'-ethers 2b-d at native iGluRs show that affinity for AMPA receptors is increased (2 to 10 fold) with increasing steric bulk of the 5'-substituent, whereas for KA receptors only a 2-3 fold increase in observed. At the NMDA receptors the affinity was unaffected. At cloned homomeric GluKl-3 the three analogs 2b-d displayed only modest changes in affinity as compared to 1 (Table 1) : A general 4-fold increase was observed for 2b, whereas 2c only displayed a 4-fold higher affinity for GluK2,3. Analog 2d displayed slightly lower affinity for GluKl, mid micromo- lar affinity for GluK2, and similar affinity for GluK3. Together these data confirms that the 5'-sidechain is directed into the spacious compartment in the receptors located between the Dl and D2 domain. However, by targeting differences in amino acid residues in this area of the receptors, it may be possi- ble to achieve class or subtype selectivity.

The pharmacological characterization of 2f and 2g which comprise a halogen in the 4-position, showed a surprising shift in profile to selectivity for the NMDA receptors over both AMPA and KA receptors (Table 1). The pharmacological profile of analog 2j proved that a heterocycle can also be ac- commodated by the iGlu receptors (Table 1).

Table 1. Chemical structures and pharmacological characterization of 1 and 2a-e at native iGluR as well as cloned homomeric GluKl- 3 subtypes. All values in μΜ AM PA KA NMDA GluKl GluK2 GluK3 GluKl:K3

IC₅₀ IC₅₀ K| K| K| ratio l^a

51 22 6.0 4.3 > 100 8.1 0.5

2.0 1.4 1.0 4.8 10- 0.87

2a 5.5

[5.71±0.03] [5.87±0.07] [6.02±0.11] ± 1.5 100 ±0.09

25 7.2 5.0 1.7 56 2.7

2b 0.6

[20;30] [6.4;8.0] [3.9;6.4] ±0.05 ± 1.4 ± 0.3

2c 6.3 6.7 4.1 3.7 32 2.1

1.8

[5.20±0.04] [5.18±0.06] [5.41±0.10] ± 0.8 ± 2.5 ± 0.4

4.9 12 4.0 8.7 68 8.6

2d 1.0

[5.34±0.09] [4.92±0.03] [5.41±0.08] ± 1.2 ± 7.6 ± 0.6

54 34 5.4 8.3 8.5

2e > 100 1.0

[4.28±0.05] [4.52±0.11] [5.27±0.04] ± 0.2 + 1.2

59 4.6

2f > 100

[4.23 ± 0.05] [5.34 ± 0.04]

0.63 154 131

2g >100 >100 > 100

[6.22 ±0.10] ± 13 ± 13

40 20 3.8

2j

[4.40±0.05] [4.71±0.05] [5.42±0.01]

17 -10 1-10 1.2

b

a Values taken from reference 49. Agonist activity was shown in functional assays This section provides specific examples of selected targets molecules. However, it is to be understood that these examples outline the synthetic routes for other target molecules not specifically disclosed.

All reagents were obtained from commercial suppliers and used without further purification. Dry solvents were obtained differently. THF was distilled over sodium/benzophenone. Et₂0 was dried over neatly cut sodium . All solvents were tested for water content using a Carl Fisher apparatus. Water - or air sensitive reactions were conducted in flame dried glassware under n i- trogen with syringe-septum cap technique. Purification by DCVC (dry column vacuum chromatography) was performed with silica gel size 25-40μηι (Merck, Silica gel 60). For TLC was used Merck TLC Silica gel F₂5₄ with appropriate spray reagents: KMn0₄ or Molybdenum blue. ¹H NMR and ¹³C NMR spectra were obtained on a Varian Mercury Plus (300 MHz) and a Varian Gemini 2000 instrument (75 MHz), respectively. HPLC was done using Agilent Prep HPLC systems with Agilent 1100 series pump, Agilent 1200 series diode array, mu ltiple wavelength detector (G1365B), and Agilent PrepHT High Performance Preparative Cartridge Column (Zorbax, 300 SB-C18 Prep HT, 21.2 x 250 mm, 7 μηι). Preparative HPLC was performed using Spectraseries UV100 with a JASCO 880-PU HPLC pump and an XTerra®Prep MS C18 ,( ΙΟμηι, 10X300 mm) column. LC-MS was performed using an Agilent 1200 series solvent delivery system equipped with an autoinjector coupled to an Agilent 6400 series triple quadrupole mass spectrometer equipped with an electrospray ionization source. Gradients of 10% aqueous acetonitrile + 0.05% formic acid (buffer A) and 90% aqueous acetonitrile + 0.046% formic acid (buffer B) were employed or an Agilent 1200 system using a C18 reverse phase column (Zorbax 300 SB-C18, 21.1 mm - 250 mm) with a linear gradient of the binary solvent system of H₂0/CH₃CN/TFA (A: 100/0/0.1 and B: 5/95/0.1) with a flow rate of 20 mL/min. Optical rotation was measured using a Perkin-Elmer 241 spec- trometer, with Na lamp at 589 nm . Melting points were measured using an automated melting point apparatus, MPA100 OptiMelt (SRS) and are uncorrected. Compounds were dry either under high vacuum or freeze dried using a Holm & Halby, Heto LyoPro 6000 freeze drier.

(2S,3 ?)-2-Carboxy-3-(3-carboxy-4-hydroxyphenyl)pyrrolidin- l-ium-2,2,2-trifluoroacetate (2a). The carboxylic acid compound (44 mg, 0.112 mmol, 1.00 equiv) was dissolved in TFA: H₂0 (1 : 1) (4 mL) and stirred overnight at room temperature. The clear and colorless reaction mixture was evaporated in vacuo and co-evaporated with MeCN (5 x 10 mL) and then lyophilized overnight to re- move the water. The brownish viscous oil (34 mg, 83%) was trituated with a few mL of ice-cold Et₂0 by which the product precipitated. The trituation was repeated once. The product was isolated upon drying in high vacuum to an off-white solid (24 mg, 59%). MS (m/z) calcd. for Ci₂Hi₄N0₅ [M+H]⁺ 252.1, found 252.1. ^ NMR (400 MHz, DMSO-d₆) δ 7.77 (s, 1H), 7.36 (d, J = 8.1 Hz, 1H), 6.81 (d, J = 8.6 Hz, 1H), 4.10-4.04 (m, 2H), 3.42 (t, J = 8.4 Hz, 2H), 3.26-3.18 (m, 1H), 3.15-3.06 (m, 2H), 2.36-2.27 (m, 1H), 2.13-2.05 (m, 1H), 2.00- 1.91 (m, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ 171.6, 171.5, 170.0, 169.7, 160.9, 133.3, 129.4, 129.0, 116.7, 64.6, 60.0, 46.8, 45.5, 45.3, 43.1, 33.5, 26.8. [a]²⁵ _D -65.7° (c = 0.067, 10% DMSO in H₂0). Mp 172- 178 °C (decomp.).

(2S,3/?)-3-(3-Carboxy-5-propoxyphenyl)pyrrolidine-2- carboxylic acid hydrochloride (2b).

The compound 10b (180 mg, 0.46 mmol, 1.00 equiv) was dissolved in AcOH (2.5 mL) and added 2M HCI in Et₂0 (2.5 mL, 5 mmol, 10.9 equiv). The mixture was left to stir under N₂ at r.t. for 18 h. The mixture was suspended in H₂0 (10 mL), solidified by cooling on a dry ice/acetone bath and freeze dried to yield 149 mg (99%) of 2b as a slightly off white, crisp solid. H NMR (300 MHz, DMSO) : δ 0.98 (3H, t, J = 7 Hz), 1.73 (2H, m), 2.01 (1H, m), 2.36 (1H, m), 3.23 (1H, m), 3.41 (1H, m), 3.54 (1H, m), 3.96 (2H, m), 4.17 (1H, m), 7.28 (1H, m), 7.30 (1H, m), 7.51 (1H, m); ¹³C NMR (75 MHz, DMSO) : δ 10.5, 22.1, 33.6, 45.2, 47.3, 64.3, 69.2, 112.9, 118.6, 120.8, 132.2, 142.5, 158.7, 166.8, 169.6; LCMS : m/z [M + H] ⁺ : calc: 293.1, found : 294.2; HPLC: purity₂₅₄ = 99.4 % OR: [a]³⁵ _D: +42.09° (c = 0.43, abs EtOH : H₂0 (3 : 1)).

(2S,3/?)-3-(3-(Benzyloxy)-5-carboxyphenyl)pyrrolidine-2- carboxylic acid hydrochloride (2c).

The compound 10c (302 mg, 0.68 mmol, 1.00 equiv) was dissolved in AcOH (4 mL) and added 2M HCI in Et₂0 (4 mL, 8 mmol, 11.8 equiv). The mixture was left to stir under N₂ at RT for 18 h. The mixture was suspended in H₂0 (20 mL), solidified by cooling on a dry ice/acetone bath and freeze dried to yield 228 mg (88%) of 2c as a slightly off white, crisp solid. H NMR (300 MHz, DMSO) : δ 2.01 (1H, m), 2.37 (1H, m), 3.05 - 3.48 (2H, m), 3.56 (1H, q, J = 9 Hz), 4.04 (0.1H, d, J = 11 Hz), 4.19 (0.9H, d, J = 8 Hz), 5.15 (2H, s), 7.28-7.49 (7H, m), 7.56 (1H, m), 9.53 (1H, vbs); ¹³C NMR (75 MHz, DMSO) : δ 33.6, 45.3, 47.2, 64.2, 69.5, 113.3, 119.1, 121.2, 127.7, 127.8, 128.3, 132.2, 136.6, 142.5, 158.4, 166.8, 169.5; LCMS: m/z [M + H] ⁺ : calc: 341.1, found : 342.2; HPLC: purity₂₅₄ = 96.6 %; OR: [a]³⁵ _D: -11.46° (c = 0.41, abs EtOH : DMSO (3: 1)).

(2S,3 ?)-3-(3-([l,l'-Biphenyl]-3-ylmethoxy)-5- carboxyphenyl)pyrrolidine-2-carboxylic acid hydrochloride (2d).

The compound lOd (247 mg, 0.48 mmol, 1.0 equiv) was dissolved in AcOH (4 mL) and added 2M HCI in Et₂0 (4 mL, 8 mmol, 16.7 equiv). The mixture was left to stir under N₂ at r.t. for 18 h. The mixture was suspended in H₂0 (20 mL), solidified by cooling on a dry ice/acetone bath and freeze dried to yield 188 mg (87%) of 2d as a slightly off white, crisp solid. H NMR (300 MHz, DMSO): δ 1.98 (1H, m), 2.35 (1H, m), 3.22 (1H, m), 3.38 (1H, m), 3.54 (1H, q, J = 8 Hz), 4.15 (1H, d, J = 9 Hz), 5.20 (2H, s), 7.30 - 7.70 (11H, m), 7.74 (1H, s); ¹³C NMR (75 MHz, DMSO) : δ 33.5, 45.2, 47.1, 64.7, 69.4, 113.0, 119.3, 121.2, 126.1, 126.2, 126.6, 126.8, 127.5, 128.9, 129.0, 132.3, 137.3, 139.7, 140.2, 142.8, 158.3, 166.8, 169.5, 201.9; LCMS: m/z [M + H]⁺ : calc: 417.2, found : 418.2; HPLC: purity₂₅₄ = 99.9 %; OR: [a]³⁵ _D: + 37.50 (c = 0.40°, abs EtOH : DMSO (3 : 1)).

(2S,3/?)-2-Carboxy-3-(3-carboxy-5-hydroxyphenyl)pyrrolidin- 1-ium 2,2,2-trifluoroacetate (2e).

The O-benzyl analog 2c (91 mg, 0.24 mmol, 1.00 equiv) was dissolved in AcOH (7 mL) and an atmosphere of N₂ was applied. Pd/C (10 mg) was added followed by purging with H₂(g). The reaction was stirred for 6 days after which HPLC did not show further change in reaction outcome. The mixture was diluted with MeCN (50 mL), filtered through a syringe filter and eva- porated in vacuo. The residue was co-evaporated with MeCN (3 x 50 mL) and the crude product was dried in high vacuum overnight affording a pale brown glass (57 mg, 83%). The product was further purified by preparative HPLC to yield a clear, colorless oil (30 mg, 44%). ^ NMR (300 MHz, NaOD) : δ 2.10 - 2.24 (1H, m), 2.41 - 2.53 (1H, m), 3.40 - 3.51 (1H, m), 3.53 - 3.64 (2H, m), 4.25 (1H, d, J = 9 Hz), 7.04 (1H, t, J = 2 Hz), 7.29 (1H, dd, J = 1, 2 Hz), 7.47 (1H, t, J = 1 Hz); ¹³C NMR (75 MHz, NaOD) : δ 33.6, 46.4, 48.5, 66.0, 116.1, 120.4, 121.0, 132.2, 141.5, 156.6, 170.2, 172.1; LCMS : m/z [M + H]⁺ : calc: 252.1, found : 252.1; HPLC: purity₂₅₄ = 100 %; OR: [a]³⁵ _D: + 52.64° (c = 0.35, 2M NaOH).

(2S,3R)-2-carboxy-3-(3-carboxy-4-fluorophenyl)pyrrolidin-l- ium chloride (2f).

Compound (2g) was prepared following general procedure described in Scheme 1-4. The oily residue was dissolved in HCI 1M (10 mL) and the solvent was evaporated (3 times) to afford the corresponding HCI salt (42 mg). mp 196.8→dec. ^ NMR (D₂0 + dioxane, 400 MHz) δ 7.97 (dd, J = 6.9, 2.6 Hz, 1H), 7.69 (ddd, J = 8.6, 4.6, 2.5 Hz, 1H), 7.31 (dd, J = 11.0, 8.6 Hz, 1H), 4.36 (d, J = 9.7 Hz, 1H), 3.77 - 3.66 (m, 2H), 3.57 (ddd, J = 11.8, 10.2, 6.9 Hz, 1H), 2.59 (dtd, J = 13.9, 7.0, 3.3 Hz, 1H), 2.29 (dtd, J = 13.4, 10.4, 8.2 Hz, 1H). ¹³C NMR (D₂0+dioxane) δ 172.0, 168.4, 162.5, 160.8, 135.34, 135.31, 135.2, 135.1, 131.5, 119.2, 119.1, 118.2, 118.1, 67.2, 65.9, 47.8, 46.3, 33.5. MS (m/z) calcd. for Ci₂Hi₃FN0₄ [M + H]⁺ 254.1, found 254.1.

(2S,3R)-3-(3-carboxy-4-chlorophenyl)pyrrolidine-2-carboxylic acid (2g).

Compound (2g) was prepared following general procedure described in Scheme 1-4. The final crude product was recrystallized from H₂0/acetone to afford IPS-068 (89 mg, 0.291 mmol, 56% yield) as an off-white solid, mp 239.4-241.3 °C. ^ NMR (D₂0 + dioxane) δ 7.85 (d, J = 1.8 Hz, 1H), 7.68 - 7.49 (m, 2H), 4.37 (d, J = 9.7 Hz, 1H), 3.71 (ddd, J = 11.8, 9.2, 5.1 Hz, 2H), 3.62 - 3.52 (m, 1H), 2.60 (dtd, J = 13.9, 7.1, 3.4 Hz, 1H), 2.35 - 2.23 (m, 1H). ¹³C NMR (D₂0+dioxane) δ 171.9, 170.7, 138.3, 132.6, 131.9, 131.8, 131.7, 130.3, 65.7, 47.8, 46.2, 33.4. MS (m/z) calcd. for Ci₂Hi₃CIN0₄ [M + H]⁺ 270.0, found 270.0.

(2S,3R)-3-(3-carboxy-4-methylphenyl)pyrrolidine-2-carboxylic acid hydrochloride (2h)

Compound (2h) was prepared following general procedure described in Scheme 1-4. The crude reaction mixture was purified by preparative HPLC (0- 20 % B in A) to afford the title compound (21 mg, 22 % over two steps) after 3 evaporations from 1M HCI to isolate as a white HCI salt. H NMR (400 MHz, D₂0) δ: 7.78 (d, J = 2.0 Hz, 1H), 7.45 (dd, J = 7.9, 2.1 Hz, 1H), 7.29 (d, J = 7.9 Hz, 1H), 4.39 (d, J = 9.8 Hz, 1H), 3.70 - 3.61 (m, 2H), 3.51 (ddd, J = 11.7, 10.2, 6.9 Hz, 1H), 2.50 (dtd, J = 14.0, 7.1, 3.2 Hz, 1H), 2.44 (s, 3H), 2.26 - 2.17 (m, 1H) ¹³C NMR (100 MHz, D₂0) δ: 171.54, 170.63, 139.15, 135.72, 132.31, 131.28, 130.16, 129.04, 64.56, 47.25, 45.81, 32.82, 20.04. LC-MS (m/z) calcd for Ci₃Hi₆N0₄ [M + H⁺], 250.3; found, 250.1.

5-((2S,3R)-2-carboxypyrrolidin-3-yl)-2-oxo-l,2- dihydropyridine-3-carboxylic acid hydrochloride (2i)

Compound (2i) was prepared following general procedure described in Scheme 1-4. The crude reaction mixture was purified by preparative HPLC (0^20 % B in A) to afford the title compound (7.10 mg, 28 % over two steps) after 3 evaporations from 1M HCI to isolate as a white HCI salt. H NMR (400 MHz, D₂0) δ: 8.63 (d, J = 2.6 Hz, 1H), 8.00 (d, J = 2.6 Hz, 1H), 4.38 (d, J = 10.0 Hz, 1H), 3.76 - 3.65 (m, 2H), 3.55 (td, J = 11.1, 6.8 Hz, 1H), 2.59 (dtd, J = 13.8, 7.1, 3.0 Hz, 1H), 2.28 (dtd, J = 13.7, 10.6, 8.2 Hz, 1H). ¹³C NMR (100 MHz, D₂0) δ: 170.44, 167.93, 163.99, 146.40, 140.48, 119.94, 116.61, 63.97, 45.48, 43.83, 31.76. LC-MS (m/z) calcd for CiiHi₃N₂0₅ [M + H⁺], 253.2; found, 253.1.

(2S,3R)-3-(3-carboxy-5-(pyridin-4-yl)phenyl)pyrrolidine-2- carboxylic acid hydrochloride (2j)

Compound (2j) was prepared following general procedure described in Scheme 1-4. The crude reaction mixture was purified by preparative HPLC (0^20 % B in A) to afford the title compound (18.0 mg, 9 % over two steps) after 3 evaporations from 1M HCI to isolate as a white HCI salt. H NMR (400 MHz, D₂0) δ: 8.84 (d, J = 7.0 Hz, 2H), 8.36 (t, J = 1.7 Hz, 1H), 8.34 (d, J = 7.0 Hz, 2H), 8.24 (t, J = 1.4 Hz, 1H), 8.18 (t, J = 1.9 Hz, 1H), 4.58 (d, J = 10.1 Hz, 1H), 3.95 - 3.85 (m, 1H), 3.77 (ddd, J = 11.6, 8.2, 3.1 Hz, 1H), 3.61 (td, J = 11.8, 7.0 Hz, 1H), 2.67 (dtd, J = 13.9, 7.0, 3.2 Hz, 1H), 2.45 - 2.29 (m, 1H). ¹³C NMR (100 MHz, D₂0) δ: 170.65, 168.79, 156.56, 141.32, 140.63, 135.63, 132.22, 131.88, 131.46, 131.43, 128.54, 124.79, 64.71, 47.53, 45.77, 32.95. ; LC-MS (m/z) calcd for Ci₇Hi₇N₂0₄ [M + H⁺], 313.3; found, 313.2.

(2S,3R)-3-(3-carboxy-5-(pyridin-3-yl)phenyl)pyrrolidine-2- carboxylic acid hydrochloride (2k) Compound (2k) was prepared following general procedure described in Scheme 1-4. The crude reaction mixture was purified by preparative HPLC (0^20 % B in A) to afford the title compound (18.0 mg, 9 % over two steps) after 3 evaporations from 1M HCI to isolate as a white HCI salt. H NMR (400 MHz, D₂0) δ: 9.11 (d, J = 2.1 Hz, 1H), 8.89 (dt, J = 8.3, 1.7 Hz, 1H), 8.83 (d, J = 5.8 Hz, 1H), 8.28 (t, J = 1.6 Hz, 1H), 8.21 - 8.17 (m, 2H), 8.04 (t, J = 1.6 Hz, 1H), 4.56 (d, J = 10.0 Hz, 1H), 3.88 (td, J = 10.3, 7.4 Hz, 1H), 3.76 (ddd, J = 11.6, 8.3, 3.2 Hz, 1H), 3.60 (ddd, J = 11.9, 10.2, 6.9 Hz, 1H), 2.66 (dtd, J = 14.0, 7.1, 3.2 Hz, 1H), 2.42 - 2.32 (m, 1H). ¹³C NMR (100 MHz, D₂0) δ: 170.68, 169.06, 145.03, 140.52, 140.02, 139.38, 139.05,

134.73, 131.81, 131.74, 129.91, 128.00, 127.60, 64.76, 47.56, 45.78, 32.97. LC-MS (m/z) calcd for Ci₇Hi₇N₂0₄ [M + H⁺], 313.3; found, 313.2.

(2S,3R)-3-(3-carboxy-5-(pyridin-2-yl)phenyl)pyrrolidine-2- carboxylic acid hydrochloride (21)

Compound (21) was prepared following general procedure described in

Scheme 1-4, (30.6 mg, 48 % over two steps) as a white HCI salt. H NMR (400 MHz, D₂0) δ: 8.84 (ddd, J = 6.0, 1.6, 0.7 Hz, 1H), 8.70 (td, J = 8.0, 1.6 Hz, 1H), 8.41 (t, J = 1.6 Hz, 1H), 8.35 (dd, J = 8.1, 1.0 Hz, 1H), 8.32 (t, J =

I.6 Hz, 1H), 8.17 (t, J = 1.8 Hz, 1H), 8.09 (ddd, J = 7.4, 5.9, 1.2 Hz, 1H), 4.55 (d, J = 10.0 Hz, 1H), 3.91 (td, J = 10.3, 7.4 Hz, 1H), 3.77 (ddd, J =

I I.6, 8.2, 3.2 Hz, 1H), 3.61 (ddd, J = 11.8, 10.2, 6.9 Hz, 1H), 2.68 (dtd, J = 13.9, 7.0, 3.2 Hz, 1H), 2.44 - 2.33 (m, 1H). ¹³C NMR (100 MHz, D₂0) δ: 170.68, 169.06, 145.03, 140.52, 140.02, 139.38, 139.05, 134.73, 131.81,

131.74, 129.91, 128.00, 127.60, 64.76, 47.56, 45.78, 32.97. LC-MS (m/z) calcd for Ci₇Hi₇N₂0₄ [M + H⁺], 313.3; found, 313.2.

(2S,3R)-3-(3-carboxy-5-(pyrimidin-5-yl)phenyl)pyrrolidine-2- carboxylic acid hydrochloride (2m)

Compound (2m) was prepared following general procedure described in Scheme 1-4. The crude reaction mixture was purified by preparative HPLC (0^20 % B in A) to afford the title compound (16.2 mg, 6 % over two steps) after 3 evaporations from 1M HCI to isolate as a white HCI salt. H NMR (400 MHz, D₂0) <5: 9.32 (s, 1H), 9.22 (d, J = 1.4 Hz, 2H), 8.00 - 7.98 (m, 2H), 7.89 (t, J = 1.7 Hz, 1H), 4.47 (d, J = 9.9 Hz, 1H), 3.76 (td, J = 10.3, 7.5 Hz, 1H), 3.66 (ddd, J = 11.7, 8.2, 3.2 Hz, 1H), 3.50 (ddd, J = 12.0, 10.3, 6.8 Hz, 1H), 2.54 (dtd, J = 13.9, 7.1, 3.1 Hz, 1H), 2.23 (dtd, J = 13.5, 10.4, 8.2 Hz, 1H). ¹³C NMR (100 MHz, D₂0) δ: 170.18, 168.52, 154.94, 152.31, 140.47, 134.04, 132.28, 131.68, 131.28, 130.10, 127.58, 64.35, 47.23, 45.83, 32.86. LC-MS (m/z) calcd for Ci₆Hi₆N₃0₄ [M + H⁺], 314.3; found, 314.1.

(2S,3R)-3-(3-carboxy-5-(2-oxo-l,2-dihydropyrimidin-5- yl)phenyl)pyrrolidine-2-carboxylic acid hydrochloride (2n)

Compound (2n) was prepared following general procedure described in Scheme 1-4. The crude reaction mixture was purified by preparative HPLC (0- 20 % B in A) followed by recrystallization from H₂0/acetone to afford the title compound (18 mg, 10 % over two steps) after 3 evaporations from 1M HCI to isolate as an off-white HCI salt. ^ NMR (400 MHz, D₂0) δ: 8.91 (s, 2H), 8.18 (t, J = 1.7 Hz, 1H), 8.14 (t, J = 1.5 Hz, 1H), 7.87 (t, J = 1.6 Hz, 1H), 4.41 (d, J = 9.7 Hz, 1H), 3.82 - 3.77 (m, 1H), 3.74 (ddd, J = 11.6, 8.1, 3.2 Hz, 1H), 3.59 (ddd, J = 12.3, 10.3, 6.8 Hz, 1H), 2.64 (dtd, J = 13.8, 7.0, 3.1 Hz, 1H), 2.36 (dtd, J = 13.5, 10.3, 8.1 Hz, 1H).¹³C NMR (100 MHz, D₂0) δ: 171.59, 169.46, 164.45, 156.45, 153.91, 140.59, 132.85, 131.65, 130.54, 128.42, 126.65, 65.51, 47.92, 45.67, 32.98. LC-MS (m/z) calcd for Ci₆Hi₆N₃0₅ [M + H⁺], 330.3; found, 330.2.

(S)-tert-Butyl-2-(((tert-butyldimethylsilyl)oxy)methyl)-5- oxopyrrolidine-l-carboxylate (4).

(a) To a solution of commercially available (S)-pyroglutaminol (3)

(1.00 g, 8.69 mmol, 1.0 equiv) in DCM (10 mL) was added imidazole (1.48 g, 21.7 mmol, 2.5 equiv) and TBDMS-CI (1.56 g, 10.4 mmol, 1.2 equiv). The mixture was stirred at r.t. for 24 hours. The solution was diluted with Et₂0 (100 mL) and the organic phase was washed with H₂0 (2 x 100 mL) and brine (2 x 100 mL) respectively. The organic phase was dried over MgS0₄, filtered and concentrated in vacuo to yield a yellow oil (1.90 g). (b) The oil (1.90 g, 8.2 mmol, 10.0 equiv) was dissolved in MeCN (70 mL), cooled to 0° C and added DMAP (0.11 g, 0.83 mmol, 1.0 equiv) and Boc₂0 (3.60 g, 16.5 mmol, 2.0 equiv). The reaction mixture was left to stir at r.t. overnight. The organic phase was washed with brine (3 x 100 mL) and dried over MgS0₄. The solution was filtered and concentrated in vacuo to yield a dark, red oil, which was purified using flash chromatography (EtOAc : heptane (1 : 9)) affording 4 as a thick, yellow oil (2.61 g, 91%). ^ NMR (300 mHz, CDCI₃) : δ 0.04 (3H, s), 0.05 (3H, s), 0.88 (9H, s), 1.54 (9H, s), 1.95 - 2.20 (2H, m), 2.37 (1H, ddd, J = 18, 9, 2 Hz), 2.71 (1H, dt, J = 18, 11 Hz), 3.68 (1H, dd, J = 10, 2 Hz), 3.91 (1H, dd, J = 11, 4 Hz), 4.16 (1H, m). ¹³C NMR (75 MHz, CDCI₃) : δ -5.4, -5.3, 18.3, 21.3, 26.0, 28.2, 32.5, 59.0, 64.4, 82.7,

150.0, 174.9 OR: [a]²² _D: -71.57° (c = 0.55, EtOAc); TLC: R_f: 0.13 (EtOAc: heptane (1 :9)).

(S)-tert-Butyl 2-(((tert-butyldimethylsilyl)oxy)methyl)-5-oxo-

2,5-dihydro-lH-pyrrole-l-carboxylate (5).

(a) Pyrrolidone 4 (7.00 g, 21.2 mmol, 1.00 equiv) was dissolved in dry THF (12.5 mL), cooled to -78 °C and dropwise added 1M LiHMDS (48.0 mL, 48.0 mmol, 2.26 equiv) over the course of one hour. The mixture was left to stir at -78 °C for lh after which a solution of PhSeCI (5.50 g, 28.7 mmol, 1.35 equiv) in dry THF (8 mL) was added dropwise over the course of 30 min. The mixture was left to stir at -78 °C for 45 min, before quenched with sat. NH₄CI (10 mL) and stirred for 10 min. The mixture was transferred to a separation funnel containing sat. NaHC0₃ (100 mL) and the flask flushed with Et₂0 (2 x 50 mL), which was also transferred to the separation funnel. The organic phase was isolated and filtered through a plug of celite to remove undissolvable material. The aqueous phase was reextracted with 2 x 75 mL Et₂0 and the combined organic phases was washed with brine (75 mL), dried over MgS0₄, filtered, concentrated in vacuo and purified using DCVC (7 cm, 75 mL fractions, 0-20% EtOAc in heptanes) to yield an orange solid (7.52 g). (b) The selenyl diastereomers were dissolved in EtOAc (60 mL), cooled to 0 °C and added 30 % H₂0₂ (15 mL) over the course of 10 min. The mixture was left at 0 °C for 15 min before stirred at r.t. for one hour. The mixture was poured in to a separation funnel containing sat. NaHC0₃ (100 mL). The phases were separated and the aqueous phase extracted with EtOAc (2 x 75 mL). The combined organic phases was washed with brine (75 mL), dried over MgS0₄, concentrated in vacuo and purified using DCVC (diameter 7 cm, 75 mL fractions, 0-30% EtOAc in heptanes) to yield enone 5 as a white solid (4.42 g, 64%). ^ NMR (300 mHz, CDCI₃) : δ 0.01 (3H, s), 0.05 (1.5H, s), 0.06 (1.5H, s), 0.88 (9H,s), 1.57 (9H, s), 3.72 (1H, dd, J = 7, 10 Hz), 4.16 (1H, dd, J = 4, 10 Hz), 4.60 (1H, m), 6.13 (1H, dd, J = 1.5, 6 Hz), 7.26 (1H, dd, J = 2, 6 Hz); ¹³C NMR (75 MHz, CDCI₃) : δ -5.5, -5.4, 18.1, 25.7, 28.2, 62.4, 63.6, 82.9, 127.0, 149.4, 149.7, 169.4; LCMS: m/z [M + H] ⁺ : calc:

228.1, found : 228.0; TLC: R_f : 0.25 (EtOAc: heptanes (1 :4)); OR: [a]³¹ _D: - 173.35° (c = 0.77, abs EtOH). 6-Bromo-2,2-dimethyl-4H-benzo[d][l,3]dioxane (6a).

A round-bottomed flask was charged with 4-bromo-2- (hydroxymethyl)phenol (5.46 g, 26.88 mmol, 1.00 equiv) and anhydrous ZnCI₂ (9.89 g, 72.58 mmol, 2.70 equiv) and an atmosphere of nitrogen was applied. Dry acetone (40 mL) was added via a syringe followed by 2,2- dimethoxypropane (16.49 mL, 13.99 g, 134.39 mmol, 5.00 equiv). The reaction mixture was heated to 40 °C and stirred for l¹/_ hours and then cooled to ambient temperature. Sat. aqueous Na₂C0₃ (50 mL) was added to quench the reaction and filtered by suction to remove ZnC0₃. The solid was washed with EtOAc (40 mL). The biphasic filtrate was transferred to a separatory funnel and the yellow organic layer was separated. The colorless aqueous layer was extracted with EtOAc (2 x 20 mL). The combined organic layers were quickly dried over anhydrous MgS0₄, filtered and evaporated in vacuo to dryness. The crude product was purified by dry column vacuum chromato- graphy (10% EtOAc in heptane) affording the desired product as a yellow liquid. To remove excess solvents the product was co-evaporated with DCM (3 x 25 mL) followed by drying in high vacuum overnight (5.73 g, 88%). The product 6a crystallized upon storage in the refrigerator. R_f 0.57 (15% EtOAc in heptane, KMn0₄ staining). ^ NMR (CDCI₃) : δ 7.23 (dd, J = 7.4, 1.5 Hz, 1H), 7.08 (d, J = 1.5 Hz, 1H), 6.68 (d, J = 8.5 Hz, 1H), 4.79 (s, 2H), 1.52 (s, 6H).

((3-Bromo-5-propoxybenzyl)oxy)(fert-butyl)dimethylsilane

(6b).

Phenol 16 (4.00 g, 12.6 mmol, 1.00 equiv) was dissolved in DMF (25 mL) and added K₂C0₃ (3.48 g, 25.2 mmol, 2.00 equiv) and propyl bromide (2.30 mL, 3.11 g, 25.3 mmol, 2.01 equiv). The mixture was left to stir at r.t. for 18 h. The mixture was added Et₂0 (200 mL) and washed with water (3 x 100 mL), brine (75 mL), dried over MgS0₄, filtered and concentrated in vacuo. The mixture was purified by DCVC (dia. = 6 cm, 75 mL fractions, 0 - 10% EtOAc in heptanes) to yield 6b as a clear, colorless oil (4.09 g, 90%). ^ NMR (300 MHz, CDCI₃) : δ 0.12 (6H, s), 0.96 (9H, s), 1.04 (3H, t, J = 8 Hz), 1.81 (2H, sextet, 3 = 1 Hz), 3.90 (2H, t, J = 7Hz), 4.67 (2H, s), 6.81 (1H, s), 6.92 (1H, s), 7.02 (1H, s); ¹³C NMR: (75 MHz, CDCI₃) : δ -5.0, 10.7, 18.7, 22.7, 26.2, 64.4, 69.9, 111.1, 116.2, 121.1, 122.6, 144.7, 159.9; TLC: R_f : 0.77 (EtOAc: heptanes (1 : 10)). ((3-(Benzyloxy)-5-bromobenzyl)oxy)(£er£-butyl)dimethylsilane

(6c).

Phenol 16 (3.50 g, 11.0 mmol, 1.00 equiv) was dissolved in acetone (50 mL) and added K₂C0₃ (3.10 g, 22.4 mmol, 2.04 equiv) and benzyl bro- mide (2.10 mL, 3.02 g, 17.7 mmol, 1.61 equiv). The mixture was left to stir at reflux for 24 h. Piperazine (4.75 g, 55.1 mmol, 5.01 equiv) was added and the mixture refluxed for another 2.5 h. The mixture was cooled to r.t. and concentrated in vacuo. The mixture was added water (50 mL) and EtOAc (50 mL) and transferred to a separation funnel containing EtOAc (100 mL) and sat. NH₄CI (100 mL). After separation the aqueous phase was reextracted with EtOAc (50 mL). The combined organic phases was washed with brine (80 mL), dried over MgS0₄, filtered and concentrated in vacuo. The mixture was purified by DCVC (dia. = 7 cm, 75 mL fractions, 0 - 8 % EtOAc in heptanes) to yield 7 as a clear, colorless oil (4.25 g, 10.4 mmol, 95%). H NMR (300 MHz, CDCI₃) : δ 0.12 (6H, s), 0.96 (9H, s), 4.68 (2H, s), 5.05 (2H, s), 6.90 (1H, s), 7.02 (1H, s), 7.06 (1H, s), 7.30-7.45 (5H, m); ¹³C NMR (75 MHz, CDCI₃) : δ -5.01, 18.6, 26.2, 64.3, 70.3, 111.3, 116.6, 121.5, 122.6, 127.5, 128.1, 128.6, 136.5, 144.8, 159.5; TLC: R_f : 0.65 (EtOAc: heptanes (1 : 10)).

((3-([l,l'-Biphenyl]-3-ylmethoxy)-5-bromobenzyl)oxy)(£er£- butyl)dimethylsilane (6d).

Phenol 16 (3.00 g, 9.46 mmol, 1.00 equiv) was dissolved in acetone (50 mL) and added K₂C0₃ (2.61 g, 18.9 mmol, 2.00 equiv) and 3- phenylbenzyl bromide (3.52 g, 14.2 mmol, 1.50 equiv). The mixture was left to stir at reflux for 24 h. Piperazine (4.10 g, 47.6 mmol, 5.03 equiv) was added and the mixture refluxed for another 2.5 h. The mixture was cooled to r.t. and concentrated in vacuo. The mixture was added water (50 mL) and EtOAc (50 mL) and transferred to a separation funnel containing EtOAc (100 mL) and sat. NH₄CI (100 mL). After separation the aqueous phase was reex- tracted with EtOAc (50 mL). The combined organic phases was washed with brine (80 mL), dried over MgS0₄, filtered and concentrated in vacuo. The mixture was purified using DCVC (dia. = 7 cm, 75 mL fractions, 0 - 8% EtOAc in heptanes) to yield 6d as a clear, colorless oil (4.21 g, 92%). H NMR (300 MHz, CDCI₃) : δ 0.11 (6H, s), 0.96 (9H, s), 4.68 (2H, s), 5.11 (2H, s), 6.92 (1H, s), 7.02-7.09 (2H, m), 7.32-7.51 (5H, m), 7.53-7.67 (4H, m); ¹³C NMR (75 MHz, CDCI₃) : δ -4.99, 18.6, 26.2, 64.3, 70.3, 111.3, 116.6, 121.6, 122.6, 126.3, 126.4, 127.0, 127.2, 127.5, 128.8, 129.1, 137.0; TLC: R_f : 0.58 (EtOAc: heptanes (1 : 10)).

(2S,3/?)-tert-Butyl 2-(((tert-butyldimethylsilyl)oxy)methyl)-3- (salicyl alcohol isopropylidene acetal-6-yl)-5-oxopyrrolidine-l- carboxylate (7a). A dry round-bottomed flask was charged with the bromide 6a (1.86 g, 7.63 mmol, 2.50 equiv) and a nitrogen atmosphere was applied thoroughly. Dry Et₂0 (25 mL) was added via a syringe and the clear, pale yellow solution was cooled to -78 °C. tert-BuLi in pentane (10.16 mL, 978 mg, 15.27 mmol, 5.00 equiv, 1.50M) was added dropwise over the course of 25 minutes. The reaction mixture became milky due to precipitation. After 10 minutes of stirring at -78 °C, a suspension of CuCN (342 mg, 3.82 mmol, 1.25 equiv) in dry Et₂0 (2.4 mL) was added portion wise. The resulting suspension was stirred at -78 °C for 5 minutes and then at -42 °C for 10 min, after which it was re-cooled to -78 °C. Enone 5 (1.00 g, 3.05 mmol, 1.00 equiv) was dissolved in dry Et₂0 (3.0 mL) and added dropwise to the cuprate mixture at -78 °C, which resulted in a slight color change to orange. The temperature was raised to -42 °C and the reaction mixture was stirred at this temperature for 1 hour. The dark brown solution with barely any precipitation was quenched by addition of sat. NH₄CI(aq) (5 mL), allowed to warm up to ambient temperature and then transferred to a separating funnel with brine (30 mL) and EtOAc (30 mL). The organic layer was separated and the blue aqueous layer was extracted with EtOAc (2 x 30 mL). The combined organic layers were dried over anhydrous MgS0₄, filtered and eva- porated in vacuo to dryness. Purification by dry column vacuum chromatography (0→20% EtOAc in heptane) afforded the desired product 7a as a pale yellow oil (1.05 g, 70%). R_f 0.40 (25% EtOAc in heptane, PMA staining). ^ NMR (CDCI₃) : δ 6.98 (dd, J = 8.5, 2.2 Hz, 1H), 6.78 (dd, J = 5.1, 3.2 Hz, 2H), 4.82 (s, 2H), 4.05-3.97 (m, 2H), 3.80 (dd, J = 9.9, 1.7 Hz, 1H), 3.38 (dt, J = 9.4, 2.5, 1H), 3.15 (dd, J = 17.7, 9.5 Hz, 1H), 2.50 (dd, J = 17.6, 2.5 Hz, 1H), 1.56 (s, 6H), 1.55 (s, 9H), 0.93 (s, 9H), 0.10 (s, 3H), 0.09 (s, 3H). ¹³C NMR (CDCI₃) : δ 174.1, 150.1, 149.8, 136.1, 126.2, 122.2, 119.7, 117.5, 99.9, 99.5, 83.1, 67.0, 63.6, 60.9, 40.1, 38.2, 28.2, 25.9, 24.9, 24.8, 18.3, -5.4. MS (m/z) calcd. for C₂iH₃₄N0₄Si [M-Boc + H]⁺ 392.2, found 392.2. [a]²⁵D -20.7° (c = 0.28, EtOH). (2S,3/?)-tert-Butyl 2-(((tert-butyldimethylsilyl)oxy)methyl)-3- (3-(((£er£-butyldimethylsilyl)oxy)-methyl)-5-propoxyphenyl)-5- oxopyrrolidine-l-carboxylate (7b).

Solution A: Thiophene (482 mg, 5.74 mmol, 1.57 equiv) was dissolved in dry Et₂0 (6 mL) in a dry vial under N₂. The mixture was cooled to 0 °C and n-BuLi (2.34 mL, 5.85 mmol, 1.60 equiv, 2.50M) added dropwise over the course of 15 min. The mixture was left to stir at 0 °C for 15 min. then at r.t. for 2 h (a white, colloid precipitate was formed).

Bromide 6b (1.65 g, 4.59 mmol, 1.25 equiv) was dissolved in dry Et₂0 (50 mL) in a dry flask under N₂ and cooled to -78 °C. t-BuLi (5.76 mL, 9.22 mmol, 2.52 equiv, 1.60 M) was added dropwise over the course of 20 min. The mixture was left to stir at -78 °C for 45 min. (The solution became slightly colored and unclear) before a suspension of CuCN (410 mg, 4.58 mmol, 1.25 equiv) in dry Et₂0 (4 mL) was added dropwise over the course of 6 min. The mixture was left to stir at -78 °C for 10 min, then 10 min at -42 °C before recooled to -78 °C. To the mixture was added dropwise Solution A (7.1 mL, 4.6 mmol, 1.25 equiv) over the course of 20 min. and left to stir at - 78 °C for 10 min, then at -42 °C for 10 min before recooled to -78 °C. A solution of enone 5 (1.20 g, 3.66 mmol, 1.00 equiv) dissolved in Et₂0 (10 mL) was dropwise added over the course of 25 min. (The mixture instantly turned highly yellow). The mixture was left to stir at -78 °C for 10 min., then at -42 °C for 45 min before quenched using sat. NH₄CI (8 mL). The mixture was transferred to a separation funnel containing sat. NaHCC>3 (50 mL) and EtOAc (50 mL). The phases were separated and the aqueous phase extracted with EtOAc (2 x 50 mL). The combined organic phases were washed with brine (50 mL), dried over MgS0₄, filtered and concentrated in vacuo. Purification by DCVC (0 - 12 % EtOAc in heptanes and 0 - 5 % EtOAc in PhMe) to yield 1.38 g (62%) of 7b as a clear, colorless oil. ^ NMR (300 MHz, CDCI₃) : δ 0.08 (3H, s), 0.10 (3H, s), 0.12 (6H, s), 0.92 (9H, s), 0.96 (9H, s), 1.04 (3H, t, J = 8 Hz), 1.54 (9H, s), 1.81 (2H, h, J = 7 Hz), 2.54 (1H, dd, J = 18, 3 Hz), 3.12 (1H, dd, J = 18, 10 Hz), 3.40 (1H, dt, J = 10, 2 Hz), 3.79 (1H, dd, J = 11, 2 Hz), 3.91 (2H, t, J = 7 Hz), 4.00 (1H, dd, J = 10, 4 Hz), 4.07 (1H, m), 4.68 (2H, s), 6.60 (1H, m), 6.68 (1H, s), 6.80 (1H, m); ¹³C NMR (75 MHz, CDCI₃) : δ -5.2, -5.0, 10.7, 18.4, 18.6, 22.8, 26.1, 26.2, 28.3, 38.9, 40.0, 63.8, 64.9, 66.8, 69.6, 83.0, 110.5, 111.6, 116.0, 143.9, 145.6, 149.8, 159.7, 174.1; LCMS: m/z [M + H]⁺ : calc: 607.4, found : 508.1; TLC: R_f = 0.49 (EtOAc : toluene (1 : 10)); OR: [a]²³ _D: -22.33° (c = 0.30, abs EtOH).

(2S,3/?)-tert-Butyl 3-(3-(benzyloxy)-5-(((tert- butyldimethylsilyl)oxy)methyl)phenyl)-2-(((£er£-butyldime- thylsilyl)oxy)methyl)-5-oxopyrrolidine-l-carboxylate (7c).

Solution A: Thiophene (518 mg, 6.16 mmol, 1.56 equiv) was dissolved in dry Et₂0 (8 mL) in a dry vial under N₂. The mixture was cooled to 0 °C and dropwise added 2.29M n-BuLi (2.74 mL, 6.27 mmol, 1.59 equiv) over the course of 15 min. The mixture was left to stir at 0 °C for 15 min. before re- moved from the ice bath and stirred at r.t. for 2 h (a white, coloide precipitate was formed).

Bromide 6c (2.01 g, 4.93 mmol, 1.25 equiv) was dissolved in dry Et₂0 (60 mL) in a dry flask under N₂ and cooled to -78 °C. t-BuLi (6.18 mL, 9.89 mmol, 2.51 equiv, 1.60M) was added dropwise over the course of 15 min and the mixture was left to stir at -78 °C for 30 min. (The solution became slightly yellow colored and unclear) before a suspension of CuCN (440 mg, 4.91 mmol, 1.25 equiv) in dry Et₂0 (4 mL) was added dropwise over the course of 5 min. The mixture was left to stir at -78 °C for 10 min, then 10 min at -42 °C before recooled to -78 °C. To the mixture was added dropwise Solution A (9.0 mL, 4.9 mmol, 1.34 equiv) over the course of 15 min. and left to stir at -78 °C for 10 min, then at -42 °C for 10 min before recooled to -78 °C. A solution of enone 5 (1.29 g, 3.94 mmol, 1.00 equiv) dissolved in Et₂0 (4 mL) was dropwise added over the course of 15 min. (The mixture instantly turned highly yellow). The mixture was left to stir at -78 °C for 15 min., then at -42 °C for 40 min before quenched using sat. NH₄CI (10 mL). The mixture was transferred to a separation funnel containing sat. NaHCC>3 (75 mL) and EtOAc (75 mL). The phases were separated and the aqueous phase was extracted with EtOAc (2 x 50 mL). The combined organic phases were washed with brine (75 mL), dried over MgS0₄, filtered and concentrated in vacuo. Purification by DCVC (dia. = 7, 75 mL fractions, 0 - 10 % EtOAc in heptanes) to yield 1.11 g (43%) of 7c as a clear, colorless oil. ^ NMR (300 MHz, CDCI₃) : δ 0.09 (3H, s), 0.10 (3H, s), 0.11 (6H, s), 0.93 (9H, s), 0.95 (9H, s), 1.54 (9H, s), 2.53 (1H, dd, J = 18, 2 Hz), 3.13 (1H, dd, J = 18, 10 Hz), 3.31 (1H, dm, J = 9 Hz), 3.79 (1H, dd, J = 11, 2 Hz), 4.00 (1H, dd, J = 11, 4 Hz), 4.07 (1H, m), 4.69 (2H, s), 5.05 (2H, s), 6.67 - 6.73 (2H, m), 6.89 (1H, s), 7.28 - 7.45 (5H, m). ¹³C NMR (75 MHz, CDCI₃) : δ -5.0, -4.8, 18.6, 18.8, 26.3, 26.4, 28.5, 39.1, 40.2, 64.0, 65.1, 67.0, 70.2, 83.2, 111.0, 112.2, 116.6, 127.7, 128.2, 128.8, 137.0, 144.2, 145.8, 150.0, 159.5, 174.1; LCMS: m/z [M + H] ⁺ : calc: 655.4, found : 556.3; TLC: R_f = 0.44 (EtOAc : heptanes (1 : 4)); OR: [a]³⁵ _D: -22.22° (c = 0.89, abs. EtOH).

(2S,3/?)-tert-Butyl 3-(3-([ l,l'-biphenyl]-3-ylmethoxy)-5- (((£er£-butyldimethylsilyl)oxy)-methyl)phenyl)-2-(((£er£- butyldimethylsilyl)oxy)methyl)-5-oxopyrrolidine-l-carboxylate (7d).

Solution A: Thiophene (700 mg, 8.32 mmol, 1.58 equiv) was dissolved in dry Et₂0 (8 mL) in a dry vial under N₂.The mixture was cooled to 0 °C and dropwise added n-BuLi (3.70 mL, 8.47 mmol, 1.60 equiv, 2.29 M) over the course of 20 min. The mixture was left to stir at 0 °C for 15 min. then at r.t. for 2 h (a white, coloide precipitate was formed).

Bromide 6d (3.17 g, 6.56 mmol, 1.24 equiv) was dissolved in dry Et₂0 (80 mL) in a dry flask under N₂ and cooled to -78 °C. t-BuLi (8.28 mL, 13.25 mmol, 2.51 equiv, 1.60M) was then added dropwise over the course of 30 min. The mixture was left to stir at -78 °C for 45 min. (The solution became yellow colored) before a suspension of CuCN (590 mg, 6.59 mmol, 1.25 equiv) in dry Et₂0 (4 mL) was added dropwise over the course of 15 min. The mixture was left to stir at -78 °C for 10 min (mixture turned wine red), then 15 min at -42 °C before recooled to -78 °C over the course of 10 min. The mixture was dropwise added Solution A (9.9 mL, 6.6 mmol, 1.25 equiv) over the course of 30 min. and left to stir at -78 °C for 10 min, then at -42 °C for 10 min before recooled to -78 °C. A solution of enone 5 (1.73 g, 5.28 mmol, 1.00 equiv) dissolved in Et₂0 (4 mL) was dropwise added over the course of 15 min. (The mixture turned slightly yellow). The mixture was left to stir at - 78 °C for 15 min., then at -42 °C for 90 min before quenched using sat. NH₄CI (12 mL). The mixture was transferred to a separation funnel containing sat. NaHC0₃ (75 mL) and EtOAc (75 mL). The phases were separated and the aqueous phase extracted with EtOAc (2 x 50 mL). The combined organic phases were washed with brine (75 mL), dried over MgS0₄, filtered and concentrated in vacuo. Purification by DCVC (0 - 10% EtOAc in heptanes and 0 - 4% EtOAc in PhMe) to yield 1.62 g (42%) of 7d as a clear, colorless oil. ^ NMR (300 MHz, CDCI₃) : δ 0.10 (3H, s), 0.11 (3H, s), 0.12 (6H, s), 0.94 (9H, s), 0.96 (9H, s), 1.55 (9H, s), 2.57 (1H, dd, J = 18, 3 Hz), 3.16 (1H, dd, J = 18, 9 Hz), 3.44 (1H, dm, J = 10 Hz), 3.81 (1H, dd, J = 10, 2 Hz), 4.02 (1H, dd, J = 10, 4 Hz), 4.10 (1H, m), 4.71 (2H, s), 5. 13 (2H, s), 6.74 (2H, m), 6.94 (1H, m), 7.33-7.52 (5H, m), 7.53-7.70 (4H, m). ¹³C NMR (75 MHz, CDCI₃) : δ -5.2, -5.0, 18.4, 18.6, 26.1, 26.2, 28.3, 38.9, 40.1, 63.8, 64.9, 66.8, 70.1, 83.1, 110.6, 112.1, 116.4, 126.3, 126.4, 126.9, 127.2, 127.4, 128.8, 129.1, 137.3, 140.8, 141.6, 144.0, 145.7, 149.8, 159.3; LCMS : m/z [M + H]⁺ : calc: 731.4, found : 632.4; TLC : R_f = 0.38 (EtOAc : Heptanes (1 : 4)); OR: [a]³¹ _D: -22.68 (c = 0.71 g/100 mL; Abs. EtOH).

(2S,3/?)-tert-Butyl 2-(((tert-butyldimethylsilyl)oxy)methyl)-3- (2,2-dimethyl-4H-benzo[d] [ l,3]-dioxin-6-yl)pyrrolidine-l- carboxylate (8a).

A round-bottomed flask charged with the conjugated product 7a (558 mg, 1.14 mmol, 1.00 equiv) and equipped with a condenser and an atmosphere of nitrogen was applied. Through the septum, dry THF (15 mL) and 1M BH₃-THF (7.5 mL, 648 mg, 7.54 mmol, 6.00 equiv) were added via syringes and the colorless reaction mixture was heated to reflux (80 °C) for 3¹/₂ hours. Then cooled to 0 °C and THF (10 mL), H₂0 (1 mL), 2M aqueous NaOH (13 mL) and 30% H₂0₂ (4 mL) were added sequentially. Stirred for 3¹/₂ hours at room temperature and then quenched by addition of sat. aqueous NaHC0₃ (30 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over anhydrous MgS0₄, filtered and evaporated in vacuo to dryness. Purification by dry column vacuum chromatography (0→15% EtOAc in heptane) afforded the desired product 8a as a colorless, viscous oil (248 mg, 46%). R_f 0.47 (25% EtOAc in heptane, PMA staining). ^ NMR (CDCI₃) : δ 7.05-6.96 (m, 1H), 6.81-6.75 (m, 2H), 4.83 (s, 2H), 4.01 (dd, J = 10.3, 3.7 Hz, 1H), 3.79-3.60 (m, 4H), 3.45 (td, J = 7.2, 5.4 Hz, 1H), 3.37-3.26 (m, 1H), 2.30-2.16 (m, 1H), 1.94- 1.79 (m, 1H), 1.56 (s, 6H), 1.50 (s, 9H), 0.91 (s, 9H), 0.06 (s, 6H); ¹³C NMR (CDCI₃) : δ (rotamers present) 154.2, 149.6, 135.7, 135.1, 127.0, 126.8, 123.2, 123.1, 119.2, 117.0, 99.4, 79.4, 65.7, 65.5, 62.8, 61.4, 61.0, 47.0, 46.4, 46.0, 44.9, 33.0, 31.8, 28.7, 26.0, 24.9, 18.3, -5.2; MS (m/z) calcd. for C₂iH₃₆N0₃Si [M-Boc + H]⁺ 378.3, found 378.2; [a]²⁵D +9.7° (c = 0.68, EtOH).

(2S,3/?)-tert-Butyl- 2-(((tert-butyldimethylsilyl)oxy)methyl)-3- (3-(((£er£-butyldimethylsilyl)oxy)-methyl)-5- propoxyphenyl)pyrrolidine-l-carboxylate (8b). 7c The compound 7b (1.43 g, 2.35 mmol, 1.0 equiv) was dissolved in dry THF (25 mL) and added IM BH₃ THF complex (25 mL, 25 mmol, 10.6 equiv) over the course of 5 min. The mixture was refluxed under N₂ for 20 h. The mixture was cooled to 0 °C and dropwise added H₂0 (5 mL) over the course of 10 min., NaOH (2M, 25 mL) dropwise over the course of 20 min and H₂0₂ (30%, 5 mL) over the course of 5 min (organic/aqueous ratio important). After 5 min the mixture was remove from the icebath and left to stir at r.t. for 1 h. The mixture was poured into sat. NaHC0₃ (100 mL) and EtOAc (75 mL). After separation the aqueous phase was extracted with EtOAc (2 x 75 mL) and the combined organic phases was washed with brine, dried over MgS0₄, filtered, concentrated in vacuo and purified using DCVC (dia = 4 cm, 30 mL fractions, 0 - 5% EtOAc in PhMe) to yield 820 mg (59%) of 8b as a clear, colorless oil. ^ NMR (300 MHz, CDCI₃) : δ 0.06 (6H, s), 0.12 (6H, s), 0.91 (9H, s), 0.96 (9H, s), 1.04 (3H, t, J = 7 Hz), 1.49 (9H, s), 1.81 (2H, h, J = 7 Hz), 1.82 - 1.95 (1H, m), 2.17 - 2.32 (1H, m), 3.25 - 3.42 (1H, m), 3.49 (1H, m), 3.55-3.80 (3H, m), 3.80 - 3.87 (0.5H, m), 3.91 (2H, t, J = 6 Hz), 3.98-4.07 (0.5H, m), 6.66 (1H, m), 6.73 (1H, s), 6.75 (1H, m). ¹³C NMR (75 MHz, CDCI₃) : δ -5.1, -4.9, 10.8, 18.4, 18.7, 22.8, 26.1, 26.2, 28.8, 31.8, 32.8, 45.7, 46.7, 47.2, 61.5, 62.9, 65.1, 65.5, 65.7, 69.5, 79.1, 79.5, 109.9, 110.2, 112.3, 117.1, 117.4, 143.1, 143.2, 144.9, 145.4, 154.2, 154.3, 159.4. LCMS: m/z [M + H] ⁺ : calc: 593.4, found : 494.4 TLC: R_f = 0.44 (EtOActoluene (1 : 20)); OR: [a]²³ _D: +11.48° (c = 0.30, abs EtOH).

(2S,3 ?)-tert-Butyl-3-(3-(benzyloxy)-5-(((tert- butyldimethylsilyl)oxy)methyl)phenyl)-2-(((£er£-butyldime- thylsilyl)oxy)methyl)pyrrolidine-l-carboxylate (8c). 7c

The compound 7c (1.66 g, 2.53 mmol, 1.00 equiv) was dissolved in dry THF (20 mL) and added IM BH₃ THF complex (25 mL, 25 mmol, 9.88 equiv) over the course of 5 min. The mixture was refluxed under N₂ for 20 h. The mixture was cooled to 0 °C, added THF (40 mL) and dropwise added H₂0 (6 mL) over the course of 15 min. NaOH (2M, 30 mL) was dropwise over the course of 15 min and H₂0₂ (30 %, 10 mL) over the course of 15 min (organic/aqueous ratio important). After 5 min the mixture was remove from the icebath and left to stir at r.t. for 1 h. The mixture was poured into sat. NaH- C0₃ (100 mL) and EtOAc (75 mL). After separation the aqueous phase was extracted with EtOAc (2 x 75 mL) and the combined organic phases was washed with brine (100 mL), dried over MgS0₄, filtered, concentrated in vacuo and purified using DCVC (dia = 4 cm, 30 mL fractions, 0 - 2% EtOAc in PhMe) to yield 976 mg (60%) of 8c as a clear, colorless oil. H NMR (300 MHz, CDCI₃) : δ 0.08 (6H, s), 0.12 (6H, s), 0.93 (9H, s), 0.97 (9H, s), 1.51 (9H, s), 1.85-2.00 (1H, m), 2.18 - 2.35 (1H, m), 3.27 - 3.43 (1H, m), 3.46 - 3.55 (1H, m), 3.58 - 3.80 (3H, m), 3.86 (0.5H, m), 4.05 (0.5H, dd, J = 10, 4 Hz), 4.71 (2H, s), 5.06 (2H, s), 6.71-6.80 (2H, m), 6.86 (1H, m), 7.30- 7.47 (5H, m). ¹³C NMR (75 MHz, CDCI₃) : δ -5.1, -4.9, 18.4, 18.7, 26.1, 26.2, 28.8, 31.8, 32.8, 45.7, 46.7, 47.2, 61.5, 62.8, 65.0, 65.5, 65.6, 70.0, 76.7, 77.2, 77.6, 79.2, 79.5, 110.2, 110.4, 112.7, 117.5, 117.7, 127.5, 127.9, 128.6, 136.99, 137.03, 143.2, 143.3, 145.0, 145.4, 154.1, 154.2, 159.1; LCMS: m/z [M + H]⁺ : calc: 641.4, found : 542.4; TLC: R_f = 0.20 (EtOAc : toluene (1 : 40)); OR: [a]³⁵ _D: +3.20° (c = 0.50, abs EtOH).

(2S,3/?)-tert-Butyl- 3-(3-([ l,l'-biphenyl]-3-ylmethoxy)-5- (((£er£-butyldimethylsilyl)oxy)methyl)-phenyl)-2-(((£er£- butyldimethylsilyl)oxy)methyl)pyrrolidine-l-carboxylate (8d).

The compound 7d (1.77 g, 2.42 mmol, 1.00 equiv) was dissolved in dry THF (20 mL) and added 1M BH₃ THF complex (25 mL, 25 mmol, 10.3 equiv) over the course of 5 min. The mixture was refluxed under N₂ for 20 h. The mixture was cooled to 0 °C, added THF (40 mL) and dropwise added H₂0 (6 mL) over the course of 15 min. NaOH (2M, 30 mL) was dropwise over the course of 15 min and H₂0₂ (30 %, 10 mL) over the course of 15 min (organic/aqueous ratio important). After 5 min the mixture was remove from the icebath and left to stir at r.t. for 1 h. The mixture was poured into sat. NaH- C0₃ (100 mL) and EtOAc (75 mL). After separation the aqueous phase was extracted with EtOAc (2 x 75 mL) and the combined organic phases was washed with brine (100 mL), dried over MgS0₄, filtered, concentrated in vacuo and purified using DCVC (dia = 4 cm, 30 mL fractions, 0 - 2% EtOAc in PhMe) to yield 887 mg (51%) of 8d as a clear, colorless oil. ^ NMR (300 MHz, CDCI₃) : δ 0.10 (6H, s), 0.14 (6H, s), 0.95 (9H, s), 0.99 (9H, s), 1.53 (9H, s), 1.94 (1H, m), 2.28 (1H, m), 3.38 (1H, m), 3.55 (1H, m), 3.62 - 3.86 (3H, m), 3.90 (0.5H, m), 4.08 (0.5H, dd, J = 10, 4 Hz), 4.74 (2H, s), 5.14 (2H, s), 6.78 - 6.84 (2H, m), 6.91 (1H, m), 7.33 - 7.52 (5H, m), 7.55 - 7.72 (4H, m). ¹³C NMR (75 MHz, CDCI₃): δ -5.1, -4.9, 18.4, 18.6, 26.1, 26.2, 28.8, 31.8, 32.8, 45.7, 46.7, 47.2, 61.5, 62.8, 65.0, 65.5, 65.6, 70.0, 79.2, 79.5, 110.1, 110.3, 112.8, 117.6, 117.8, 126.35, 126.44, 126.8, 127.2, 127.4, 128.8, 129.0, 137.49, 137.54, 140.9, 141.6, 143.26, 143.34, 145.0, 145.4, 154.15, 154.23, 159.1; LCMS: m/z [M + H] ⁺ : calc: 717.4, found : 618.4; TLC: R_f = 0.21 (EtOActoluene (1 :40)); OR: [a]³⁵ _D: +1.94° (c = 0.67, abs EtOH).

(2S,3/?)-tert-Butyl 3-(2,2-dimethyl-4H-benzo[d] [l,3]dioxin-6- yl)-2-(hydroxymethyl)-pyrrolidine-l-carboxylate (9a).

The compound 8a (448 mg, 0.94 mmol, 1.0 equiv) was dissolved in dry THF (9 mL) under an atmosphere of N₂ and 1M TBAF in THF (2.8 mL, 736 mg, 2.81 mmol, 3.0 equiv) was added at room temperature. The reaction mixture was stirred for two. H₂0 (20 mL) and sat. aqueous NaHC0₃ (20 mL) were added and then extracted with EtOAc (3 x 30 mL). The combined organic phases were dried over anhydrous Na₂S0₄, filtered and evaporated in vacuo to dryness. Purified by dry column vacuum chromatography (15→35% EtOAc in heptane), followed by drying in high vacuum overnight afforded the desired alcohol as a colorless, viscous oil, which crystallized to a white solid upon drying in high vacuum (295 mg, 87%). ^ NMR (CDCI₃) : δ 7.02 (dd, J = 8.4, 2.3 Hz, 1H), 6.84 (broad s, 1H), 6.76 (d, J = 8.3 Hz, 1H), 5.13 (broad d, J = 8.0 Hz, 1H), 4.82 (s, 2H), 3.86 (t, J = 7.8 Hz, 1H), 3.73 (t, J = 9.4 Hz, 2H), 3.64-3.57 (m, 1H), 3.33 (dt, J = 10.6, 6.3 Hz, 1H), 2.84-2.76 (m, 1H), 2.15-2.08 (m, 1H), 1.99-1.85 (m, 1H), 1.55 (s, 6H), 1.51 (s, 9H). ¹³C NMR (CDCI₃) : δ 156.7, 150.1, 132.2, 127.2, 123.5, 119.4, 117.2, 99.5, 80.5, 67.2, 66.0, 60.9, 47.3, 47.1, 33.1, 28.5, 24.8, 24.7. MS (m/z) calcd. for C16H22NO5 [M-^fBu + H]⁺ 308.2, found 308.1. [a]²⁵ _D +14.2° (c = 0.86, EtOH). Mp 110-112 °C.

(2S,3R)-tert-Buty\ 2-(hydroxymethyl)-3-(3-(hydroxymethyl)-5- propoxyphenyl)pyrrolidine-l-carboxy-late (9b).

Compound 8b (1.30 g, 2.19 mmol, 1.00 equiv) was dissolved in dry THF (12 mL) in a dry vial and added 1M TBAF (8.80 mL, 8.80 mmol, 4.02 equiv). The mixture was left to stir at r.t. for 18 h. The mixture was quenched using 50% sat. NaHC0₃ (50 mL) and transferred to a separation funnel containing EtOAc (25 mL). The aqueous phase was extracted with EtOAc (2 x 50 mL) and the combined organic phases was washed with brine (50 mL), dried over MgS0₄, filtered concentrated in vacuo and purified using DCVC (dia = 3 cm, 25 mL fractions, 0 - 90% EtOAc in heptanes) to yield 736 mg (92%) of diol 9b as a clear, colorless oil. ^ NMR (300 MHz, CDCI₃) : δ

I.05 (3H, t, J = 7 Hz), 1.51 (9H, s), 1.81 (2H, h, J = 7 Hz), 1.90 - 2.07 (2H, m), 2.15 (1H, m), 2.86 (1H, m), 3.35 (1H, m), 3.62 (1H, dd, J = 11, 7 Hz), 3.68 - 3.90 (3H, m), 3.92 (2H, t, J = 7 Hz), 4.65 (2H, s), 5.07 (1H, m), 6.70 (1H, m), 6.78 - 6.84 (2H, m). ¹³C NMR (75 MHz, CDCI₃) : δ 10.8, 22.8, 28.7, 33.1, 47.4, 48.1, 65.4, 66.2, 67.2, 69.7, 80.7, 111.3, 113.6, 118.2, 142.5, 142.9, 156.8, 159.7; LCMS: m/z [M + H] ⁺ : calc: 365.2, found : 310.2; TLC: R_f = 0.37 (EtOAc : heptanes (3 : 1)); OR: [a]²³ _D: +23.85° (c = 0.31, abs EtOH).

(2S,3/?)-tert-Butyl 3-(3-(benzyloxy)-5-

(hydroxymethyl)phenyl)-2-(hydroxymethyl)pyrrolidine-l- carboxylate (9c).

The compound 8c (967 g, 1.51 mmol, 1.00 equiv) was dissolved in dry THF (15 mL) in a dry vial and added 1M TBAF (6 mL, 6 mmol, 3.97 equiv). The mixture was left to stir at r.t. for 18 h. The mixture was quenched using 50% sat. NaHC0₃ (50 mL) and transferred to a separation funnel containing EtOAc (50 mL). The aqueous phase was reextracted with EtOAc (2 x 50 mL) and the combined organic phases was washed with brine (75 mL), dried over MgS0₄, filtered, concentrated in vacuo and purified using DCVC (dia = 4 cm, 30 mL fractions, 0 - 100% EtOAc in heptanes) to yield 572 mg (92%) of diol 9c as a clear, colorless oil. 1H NMR (300 MHz, CDCI₃) : δ 1.51 (9H, s), 1.89 -

2.08 (2H, m), 2.14 (1H, m), 2.87 (1H, m), 3.34 (1H, m), 3.61 (1H, dd, J =

II, 7 Hz), 3.67 - 3.90 (3H, m), 3.95 (1H, m), 4.65 (2H, s), 5.06 (2H, s),

5.09 (1H, m), 6.79 (1H, m), 6.85 (1H, m), 6.88 (1H, m), 7.28 - 7.45 (5H, m). ¹³C NMR (75 MHz, DMSO) : δ 28.2, 30.5, 31.2, 44.5, 45.3, 45.8, 46.0,

60.7, 60.8, 62.8, 65.5, 69.0, 78.4, 78.5, 110.4, 111.8, 117.4, 127.5, 127.7,

128.3, 137.0, 144.2, 144.8, 145.0, 153.2, 153.6, 158.3; LCMS: m/z [M +

H]⁺ : calc: 413.2, found : 358.2; TLC: R_f = 0.42 (EtOAc : heptanes (3 : 1));

OR: [a]³⁵ _D: +12.27° (c = 0.44, abs EtOH).

(2S,3/?)-tert-Butyl 3-(3-([ l,l'-biphenyl]-3-ylmethoxy)-5-

(hydroxymethyl)phenyl)-2-(hydroxymethyl)-pyrrolidine-l- carboxylate (9d).

The compound 8d (800 g, 1.11 mmol, 1.00 equiv) was dissolved in dry THF (15 mL) in a dry vial and added 1M TBAF (5 mL, 5 mmol, 4.50 equiv). The mixture was left to stir at r.t. for 18 h. The mixture was quenched using phosphate buffer (50 mL, Ph 7) and transferred to a separation funnel containing EtOAc (50 mL). The aqueous phase was reextracted with EtOAc (2 x 50 mL) and the combined organic phases was washed with brine (50 mL), dried over MgS0₄, filtered, concentrated in vacuo and purified using DCVC (dia = 4 cm, 30 mL fractions, 0 - 90 % EtOAc in heptanes) to yield 512 mg (94%) of diol 9d as a clear, colorless oil. ^ NMR (300 MHz, CDCI₃) : δ 1.51 (9H, s), 1.97 (IH, m), 2.14 (IH, m), 2.60-3.00 (2H, m), 3.34 (IH, m), 3.63 (IH, dd, J = 11, 7 Hz), 3.65 (2H, m), 3.96 (IH, m), 4.63 (2H, s), 5.10 (2H, s), 5.24 (IH, m), 6.81 (IH, m), 6.86 (IH, s), 6.91 (IH, m), 7.32-7.50 (5H, m), 7.53-7.60 (4H, m). ¹³C NMR (75 MHz, CDCI₃) : δ 28.6, 32.9, 47.2, 47.9, 64.9, 65.9, 67.0, 70.1, 80.7, 111.3, 113.7, 118.5, 126.4, 126.5, 126.8, 127.2, 127.4, 128.8, 129.0, 137.3, 140.8, 141.5, 142.5, 143.2, 156.7, 159.2; LCMS: m/z [M + H] ⁺ : calc: 489.3, found : 434.2; TLC: R_f = 0.39 (EtOAc : heptanes (3 : 1)); OR: [a]³⁵ _D: + 10.19 ⁰ (c = 0.53, abs EtOH).

(2S,3 ?)-l-(tert-Butoxycarbonyl)-3-(2,2-dimethyl-4-oxo-4H- benzo[d] [l,3]dioxin-6-yl)pyrrolidine-2-carboxylic acid (10a) and (2S,3 ?)-l-(tert-butoxycarbonyl)-3-(2,2-dimethyl-4H- benzo[d] [l,3]dioxin-6-yl)pyrrolidine-2-carboxylic acid (11).

To an ice-cooled mixture of the protected alcohol (150 mg, 0.413 mmol, 1.0 equiv) in MeCN (2.5 mL) and EtOAc (2.5 mL) was added dropwise NaI0₄ (883 mg, 4.13 mmol, 10.0 equiv) and RuCI₃ H₂0 (4 mg, 0.017 mmol, 0.04 equiv) dissolved in H₂0 (4 mL). The reaction was stirred at 0 °C for V/2 hours. The brownish reaction mixture was filtered through a plug of Celite^® and washed with EtOAc (15 mL). The filtrates were transferred to a separating funnel and the organic layer was isolated. The aqueous layer was extracted with EtOAc (2 x 15 mL) and the combined organic phases were washed with brine (25 mL) and dried over anhydrous Na₂S0₄. The crude product was isolated as a dark brown oil by evaporation in vacuo (179 mg). Purification by dry column vacuum chromatography (5→ 25% EtOAc in heptane containing 1% AcOH) afforded compound 10a and 11, respectively. For 10a: White foam (36 mg, 22%). R_f 0.25 (50% EtOAc in heptane + 1% AcOH). ^ (CDCI₃) : δ 7.88-7.84 (m, IH), 7.49 (t, J = 7.7 Hz, IH), 6.98-6.94 (m, IH), 4.36 (d, J = 5.9 Hz, 0.5H), 4.25 (d, J = 7.0 Hz, 0.5H), 3.86-3,73 (m, 2H), 3.64-3.45 (m, IH), 2.40-2.30 (m, IH), 2.13-2.02 (m, IH), 1.76 (s, 6H), 1.54 (s, 5H), 1.45 (s, 4H). ¹³C NMR (CDCI₃) : δ 196.3, 183.3, 174.9, 174.4, 173.7, 172.8, 161.1, 155.6, 154.9, 153.6, 135.5, 135.2, 134.9, 127.8, 127.5, 117.6, 113.3, 106.5, 81.1, 80.8, 65.6, 65.3, 61.4, 61.2, 49.8, 49.0, 48.1, 47.3, 46.3, 45.9, 45.4, 32.6, 32.4, 29.7, 28.4, 28.2, 25.8 (sever- al rotamers present! ). MS (m/z) calcd. for Ci₅Hi₈N0₅ [M-Boc + H]⁺ 292.1, found 292.1. [a]²⁵ _D +21.8° (c 0.21 EtOH). Mp 200 °C (decomp.). For 11 : White solid (62 mg, 40%). R_f 0.35 (50% EtOAc in heptane + 1% AcOH, KMn0₄ staining). ^ NMR (CDCI₃) : δ 10.77 (broad s, 1H), 7.04 (d, J = 8.0 Hz, 1H), 6.85 (s, 1H), 6.78 (d, J = 8.3 Hz, 1H), 4.84 (s, 2H), 4.36 (broad s, 0.5H), 4.21 (d, J = 6.1 Hz, 0.5H), 3.81-3.41 (m, 3H), 2.38-2.22 (m, 1H), 2.04- 1.94 (m, 1H), 1.55 (s, 6H), 1.51 (s, 4H), 1.44 (s, 5H). ¹³C NMR (CDCI₃) : δ 178.1, 155.3, 153.6, 150.2, 132.5, 132.0, 126.6, 126.5, 123.1, 123.0, 119.4, 117.2, 99.5, 81.1, 80.7, 65.8, 60.8, 49.3, 47.3, 46.3, 46.0, 33.0, 32.6, 28.5, 28.3, 24.8 (several rotamers present! ). MS (m/z) calcd. for Ci₅H₂₀NO₄ [M-Boc + 2H]⁺ 278.1, found 278.0. [a]₂₅ ^D +49.4° (c = 0.23, abs EtOH). Mp 128- 130 °C.

(2S,3/?)-l-(£er£-Butoxycarbonyl)-3-(3-carboxy-5- propoxyphenyl)pyrrolidine-2-carboxylic acid (10b).

Suspension A : NaI0₄ (1.92 g, 8.98 mmol, 9.98 equiv) was suspended in H₂0 (6 ml_) and after stirring at r.t. for 5 min. RuCI₃ ^■ H₂0 (8 mg, 0.035 mmol, 0.04 equiv) was added. The black suspension was stirred for 1 min at r.t. prior to use.

Diol 9b (276 mg, 0.90 mmol, 1.00 equiv) was dissolved in CH₃CN (5 ml_) and EtOAc (5 ml_), cooled to 0 °C and dropwise added suspension A. The flask containing suspension A was washed with H₂0 (2 ml_), which was added the mixture. The mixture was left to stir at 0 ° C for 1.5 h. The mixture was filtered through a plug of celite and the plug was afterwards washed with EtOAc (2 x 5 ml_). The organic phases were pooled in a separation funnel and added H₂0 (20 ml_). After separation of the two phases the aqueous phase was extracted with EtOAc (2 x 20 ml_). The pooled organic phases was washed with brine (20 ml_), dried over MgS0₄, filtered, concentrated in vacuo and purified using DCVC (dia = 3 cm, 30 ml_ fractions, 0 - 50% EtOAc in heptanes containing 2 % AcOH) to yield 196 mg (66%) of diacid 10b as a clear, colorless oil. ^ NMR (300 MHz, CDCI₃) : δ 1.06 (3H, t, J = 7 Hz), 1.44 (5H, s), 1.52 (4H, s), 1.83 (2H, h, J = 7 Hz), 2.09 (1H, m), 2.35 (1H, m), 3.50 - 3.86 (3H, m), 3.97 (2H, t, J = 7 Hz), 4.30 (0.6H, d, J = 7 Hz), 4.46 (0.4H, d, J = 6 Hz), 7.06 (1H, m), 7.49 (1H, m), 7.59 (1H, m), 11.0 (2H, bs). ¹³C NMR (75 MHz, CDCI₃) : δ 28.4, 28.6, 32.7, 33.1, 46.2, 46.4, 48.1, 49.8, 65.2, 65.7, 69.9, 81.2, 81.3, 113.7, 113.8, 119.7, 119.9, 121.0, 121.1, 130.9, 131.0, 142.1, 142,6, 153.8, 155.0, 159.4, 171.4, 171.5, 176.7, 178.3; LCMS: m/z [M + H] ⁺ : calc: 393.2, found : 294.1; TLC: R_f = 0.36 (EtOAc: heptanes: AcOH (40: 20: 1)).

(2S,3/?)-3-(3-(Benzyloxy)-5-carboxyphenyl)-l-(£er£- butoxycarbonyl)pyrrolidine-2-carboxylic acid (10c).

Suspension A: NaI0₄ (2.40 g, 11.22 mmol, 10.0 equiv) and RuCI₃ ^■

H₂0 (10 mg, 0.044 mmol, 0.04 equiv) were suspended in H₂0 (7.5 mL) and stired at r.t. for 1 min. prior to use.

Diol 9c (462 mg, 1.12 mmol, 1.00 equiv) was dissolved in CH₃CN (10 mL) and EtOAc (10 mL), cooled to 0 °C and dropwise added suspension A over the course of 15 min. The flask containing suspension A was washed with H₂0 (7.5 mL), which was added the mixture over the course of 5 min. The mixture was left to stir at 0 °C for 2 h. The mixture was filtered through a plug of celite and the plug was afterwards washed with EtOAc (2 x 20 mL). The organic phases were pooled in a separation funnel and added H₂0 (40 mL). After separation of the two phases the aqueous phase was extracted with EtOAc (2 x 50 mL). The pooled organic phases was washed with brine (50 mL), dried over MgS0₄, filtered, concentrated in vacuo and purified using DCVC (dia = 3 cm, 30 mL fractions, 0 - 50% EtOAc in heptanes containing 2% AcOH) to yield 410 mg (83%) of diacid 10c as a clear, colorless oil. ^ NMR (300 MHz, CDCI₃) : δ 1.44 (4.5H, s), 1.52 (4.5H, s), 2.06 (1H, m), 2.34 (1H, m), 3.45 - 3.85 (3H, m), 4.28 (0.5H, d, J = 7 Hz), 4.44 (0.5H, d, J = 6 Hz), 5.10 (2H, s), 7.14 (1H, t, J = 7 Hz), 7.30-7.47 (5H, m), 7.57-7.64 (2H, m), 7.75-9.40 (2H, vbs). ¹³C NMR (75 MHz, DMSO) : δ 28.0, 28.2, 32.1, 32.6, 46.0, 48.0, 49.1, 65.1, 65.4, 69.4, 79.1, 113.3, 118.5, 118.7, 120.6, 120.7, 127.7, 127.8, 128.3, 132.2, 136.6, 142.7, 143.1, 152.7, 153.2, 158.4, 166.8, 172.8, 173.3; LCMS : m/z [M + H] ⁺ : calc: 441.2, found : 342.2; TLC: R_f = 0.36 (EtOAc: heptanes: AcOH (10: 5: 0.1)); OR: [a]³⁵ _D: +49.74° (c = 0.39, abs EtOH).

(2S,3 ?)-3-(3-([l,l'-Biphenyl]-3-ylmethoxy)-5-carboxyphenyl)- l-(£er£-butoxycarbonyl)-pyrrolidine-2-carboxylic acid (lOd). Suspension A : NaI0₄ (1.71 g, 11.46 mmol, 16.4 equiv) and R11CI₃ ^' H₂0 (8 mg, 0.035 mmol, 0.05 equiv) were suspended in H₂0 (6 ml_) and stired at r.t. for 1 min. prior to use.

Diol 9d (342 mg, 0.699 mmol, 1.00 equiv) was dissolved in CH₃CN (8 mL) and EtOAc (8 ml_), cooled to 0 ° C and dropwise added suspension A over the course of 15 min. The flask containing suspension A was washed with H₂0 (6 mL), which was added the mixture over the course of 5 min. The mixture was left to stir at 0 °C for 2 h. The mixture was filtered through a plug of ce- lite and the plug was afterwards washed with EtOAc (2 x 15 mL). The organic phases were pooled in a separation funnel and added H₂0 (40 mL). After separation of the two phases the aqueous phase was extracted with EtOAc (2 x 50 mL). The pooled organic phases was washed with brine (50 mL), dried over MgS0₄, filtered, concentrated in vacuo and purified using DCVC (dia = 3 cm, 30 mL fractions, 0 - 45% EtOAc in heptanes containing 2% AcOH) to yield 250 mg (69%) of diacid lOd as a clear, colorless oil. H NMR (300 MHz, CDCI₃) : δ 1.44 (4.5H, s), 1.52 (4.5H, s), 2.07 (1H, m), 2.35 (1H, m), 3.45 - 3.86 (3H, m), 4.29 (0.5H, d, J = 8 Hz), 4.45 (0.5H, d, J = 6 Hz), 5.16 (2H, s), 7.17 (1H, t, J = 2 Hz), 7.31-7.50 (5H, m), 7.54-7.69 (6H, m). ¹³C NMR (75 MHz, CDCI₃) : δ 28.5, 28.7, 32.8, 33.1, 46.3, 46.6, 47.8, 50.0, 65.4, 65.7, 70.5, 81.3, 81.8, 114.1, 120.3, 121.7, 122.0, 126.6, 126.7, 127.2, 127.3, 127.6, 128.9, 129.2, 131.1, 136.8, 140.8, 141.8, 142.3, 142.9, 153.7, 155.6, 159.2, 171.3, 175.5, 177.4, 178.3; LCMS : m/z [M + H] ⁺ : calc: 517.2, found : 418.2; TLC: R_f = 0.40 (EtOAc: heptanes: AcOH (10 : 5 : 0.1)); OR: [a]³⁵ _D: +42.73° (c = 0.33, abs EtOH).

3-Bromo-5-(((£er£-butyldimethylsilyl)oxy)methyl)phenol (16) .

(a)

Commercially available acid 15 (10.0 g, 46.8 mmol, 1.00 equiv) was dissolved in dry THF (60 mL), under N₂, cooled to 0 ° C. To this solution was added THF · BH₃ complex (70 mL, 70 mmol, 1.50 equiv) over the course of 30 min (gas formation). After stirring at 0 °C for 15 min the reaction mixture was left to stir at r.t. over night. The mixture was transferred to a separation funnel containing phosphate buffer (100 mL, pH 7) and added Et₂0 (100 mL). The phases were separated and the aqueous phase extracted with EtOAc (2 x 75 mL). The combined organic phases was washed with brine (80 mL), dried over MgS0₄, filtered and concentrated in vacuo to yield a white solid, (b) The solid was dissolved in DMF (20 mL) and cooled 0 °C under N₂. Imidazole (4.13 g, 60.7 mmol, 1.30 equiv) was added followed by portion wise addition of TBDMS-CI (7.95 g, 52.7 mmol, 1.13 equiv) over 1 min. The mixture was left to stir at 0 °C for 15 min and then 10 min at r.t. before DMF (10 mL) was added due to extensive formation of solid material. The mixture was left to stir at r.t. over night. The mixture was transferred to a separation funnel containing Et₂0 (100 mL), EtOAc (100 mL) and sat. NaHC0₃ (100 mL). The organic phase was washed with water (3 x 100 mL), brine (100 mL), dried over MgS0₄, filtered and concentrated in vacuo. The mixture was purified by DCVC (dia. = 6 cm, 50 mL fractions, 0-30% EtOAc in heptanes) three times to yield 16 as a clear, colorless oil (10.4 g, 71 %). ^ NMR (300 MHz, CDCI₃) : δ 0.13 (6H, s), 0.96 (9H, s), 6.66 (2H, s), 5,64 (1H, s), 6.74 (1H, s), 6.86 (1H, s), 7.01 (1H, s). ¹³C NMR (75 MHz, CDCI₃) : δ -5.0, 18.7, 26.2, 64.3, 112.0, 117.4, 121.5, 122.6, 144.8, 156.3; TLC: R_f : 0.20 (EtOAc: heptanes (1 : 10)).

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Claims

P A T E N T C L A I M S

1. A compound of Formula (I)

and pharmaceutically acceptable derivatives, as well as all tautomers and stereoisomers of compound of Formula (I), wherein

^Q represents compounds of Formula (la) or (lb);

— in each case may represent if appropriate the presence of at least one double bond between T₂ and (Z₂ or Z₃), or between Z₂ and (Zi or Z₃), or between Zi and Ti, or between Ti and Z_4; or between Z₄ and T₂; or

Ti is C, or CH,

T₂ is C, or CH,

Zi is CR₂, C(R₂)₂, N, S, O, or NR₃,

Z₂ is CR₂, C(R₂)₂, N, S, O, or NR₃,

Z₃ is CR₂, C(R₂)₂, N, S, O, or NR₃,

Z₄ is CR₂, C(R₂)₂, N, S, O, or NR₃,

wherein the residues Zi, Z₂, and Z₃ cannot represent adjacent O or S;

Ri may together with Zi or Z₄, or

Z₂ may together with Zi or Z₃,

form a saturated or unsaturated C₅- or C₆-cycloalkyl, or a saturated or unsaturated heterocyclyl containing 5 or 6 ring atoms, wherein the satu- rated or unsaturated C₅- or C₆-cycloalkyl, or the saturated or unsaturated heterocyclyl containing 5 or 6 ring atoms, may be substituted with one or more substituents selected from the group comprising OR₄ or R₄,

Ri is H, OR₄, Ci-Ce-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, COOR₄, N(OH)H, or NHR₄,

R₂ is independently selected among R₄, O, OR₄, halogen, N(OH)H, N(OH)R₄, NHR₄, COR₄, CONHR₄, CN, CF₃, CCI₃, SH, or S0₂NHR₄,

R₃ is independently selected among R₄, O, OR₄, or halogen,

R₄ is independently selected among H, OH, Ci-C₆-alkyl, C₂-C₆- alkenyl, C₂-C₆-alkynyl, phenyl, Ci-C₆-alkylphenyl, or saturated or unsaturated C₅- or C₆-cycloalkyl, or saturated or unsaturated Ci-C₆-alkyl C₅- or C₆- heterocyclyl, wherein Ci-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, phenyl, Ci-C₆- alkylphenyl, or saturated or unsaturated C₅- or C₆-cycloalkyl, or saturated or unsaturated Ci-C₆-alkyl C₅- or C₆- heterocyclyl may be substituted with one or more substituents selected from the group comprising d-C₆-alkyl, Ci-C₆- alkoxy, aryl, halogen, and amine,

halogen represents CI, Br, or I, and

with the proviso that Zi, Z₂, Z₃ and Z₄ are not all CH, and Ti and T₂ are not both C, when Ri is OH.

2. A compound according to claim 1, comprising Formula (II)

(II),

wherein

^Q represents compounds of Formula (Ia l) or (Ib2);

— in each case may represent if appropriate the presence of at least one double bond between T₂ and (Z₂ or Z₃), or between Z₂ and (Zi or Z₃), or between Zi and Ti, or between Ti and Z_4; or between Z₄ and T₂; or

Ti is C, or CH,

T₂ is C, or CH,

Zi is CR₂, C(R₂)₂, N, S, O, or NR₃,

Z₂ is CR₂, C(R₂)₂, N, S, O, or NR₃,

Z₃ is CR₂, C(R₂)₂, N, S, O, or NR₃,

Z₄ is CR₂, C(R₂)₂, N, S, O, or NR₃,

wherein the residues Zi, Z₂, and Z₃ cannot represent adjacent O or

S;

Ri may together with Zi or Z₄, or

Z₂ may together with Zi or Z₃,

form a saturated or unsaturated C₅- or C₆-cycloalkyl, or a saturated or unsaturated heterocyclyl containing 5 or 6 ring atoms, wherein the saturated or unsaturated C₅- or C₆-cycloalkyl, or the saturated or unsaturated heterocyclyl containing 5 or 6 ring atoms, may be substituted with one or more substituents selected from the group comprising OR₄ or R₄;

Ri is H, OR₄, Ci-Ce-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, COOR₄, N(OH)H, or NHR₄,

R₂ is independently selected among R₄, O, OR₄, halogen, N(OH)H, N(OH)R₄, NHR₄, COR₄, CONHR₄, or S0₂NHR₄,

R₃ is independently selected among R₄, O, OR₄, or halogen,

R₄ is independently selected among H, d-C₆-alkyl, C₂-C₆-alkenyl, C₂- C₆-alkynyl, phenyl, Ci-C₆-alkylphenyl, or saturated or unsaturated C₅- or C₆- cycloalkyl, or saturated or unsaturated Ci-C₆-alkyl C₅- or C₆-heterocyclyl, wherein Ci-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, phenyl, Ci-C₆-alkylphenyl, or saturated or unsaturated C₅- or C₆-cycloalkyl, or saturated or unsaturated Ci-C₆-alkyl C₅- or C₆- eterocyclyl may be substituted with one or more subs- tituents selected from the group comprising d-C₆-alkyl, Ci-C₆-alkoxy, aryl, halogen, and amine,

halogen represents CI, Br, or I, and

with the proviso that Zi, Z₂, Z₃ and Z₄ are not all CH, and Ti and T₂ are not both C, when Ri is OH.

3. A compound according to claims 1 or 2, wherein

Q represents

wherein

Ti is C,

T₂ is C,

Zi is CR₂, N, S, O, or NR₃,

Z₂ is CR₂, or N,

Z₃ is CR₂, or N,

Z₄ is CR₂, or N,

wherein the residues Zi, Z₂, and Z₃ cannot represent adjacent O or

S; Ri may together with Zi or Z₄, or

Z₂ may together with Zi or Z₃,

form a saturated or unsaturated C₅- or C₆-cycloalkyl, or a saturated or unsaturated heterocyclyl containing 5 or 6 ring atoms, wherein the satu- rated or unsaturated C₅- or C₆-cycloalkyl, or the saturated or unsaturated heterocyclyl containing 5 or 6 ring atoms, may be substituted with one or more substituents selected from the group comprising OR₄ or R₄;

Ri is H, OR₄, Ci-Ce-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, COOR₄, N(OH)H, or NHR₄,

R₂ is R₄, O, OR₄, halogen, N(OH)H, N(OH)R₄, NHR₄, COR₄, CONHR₄, or S0₂NHR₄,

R₃ is R₄, O, OR₄, or halogen,

R₄ is H, Ci-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, phenyl, Ci-C₆- alkylphenyl, or saturated or unsaturated C₅- or C₆-cycloalkyl, or saturated or unsaturated Ci-C₆-alkyl C₅- or C₆-heterocyclyl, wherein Ci-C₆-alkyl, C₂-C₆- alkenyl, C₂-C₆-alkynyl, phenyl, Ci-C₆-alkylphenyl, or saturated or unsaturated C₅- or C₆-cycloalkyl, or saturated or unsaturated Ci-C₆-alkyl C₅- or C₆- heterocyclyl may be substituted with one or more substituents selected from the group comprising Ci-C₆-alkyl, Ci-C₆-alkoxy, aryl, halogen, and amine, halogen represents CI, Br, or I, and

with the proviso that Zi, Z₂, Z₃ and Z₄ are not all CH, and Ti and T₂ are not both C when Ri is OH .

4. A compound according to any of the claims 1 to 3, wherein Ri may together with Zi or Z₄, or Z₂ may together with Zi or Z₃, form a satu- rated or unsaturated C₅- or C₆-cycloalkyl or a 5- or 6- membered heterocyclyl ring, the heterocyclyl ring containing one, two, three or four heteroatoms selected from the group comprising sulfur, oxygen and nitrogen .

5. A compound according to claim 4, wherein the 5- or 6-membered ring is selected from the group consisting of pyrrolidine, pyrrole, tetrahydro- furan, furan, thiolane, thiophene, imidazolidine, pyrazolidine, imidazole, pyra- zole, oxazolidine, isoxazolidine, oxazole, isoxazole, thiazolidine, isothiazoli- dine, thiazole, isothiazole, dioxolane, dithiolane, triazoles, furazan, oxadia- zole, thiadiazole, dithiazole, tetrazole, piperidine, pyridine, oxane, pyran, thiane thiopyran, piperazine, diazines, morpholine, oxazine, thiomorpholine, thiazine, dioxane, dioxine, dithiane, dithiine, triazine, trioxane, or tetrazine, and wherein the 5- or 6-membered heterocyclic ring may be substituted with 1 to 3 substituents.

6. A compound according to claims 4 or 5

(IV),

wherein

Z₅ is CR₂, C(R₂)₂, N, S, O, or NR₃,

wherein the residues Zi, Z₂, Z₃ and Z₅ cannot represent adjacent O or S,

— , Ti, T₂, Zi, Z₂, Z₃, Z₄, R₂, R₃, R₄ have the same meaning as giv- en under claim 1.

7. A compound according to claims 4 or 5

(V),or

wherein

Z₅ is CR₂, C(R₂)₂, N, S, O, or NR₃,

Z₆ is CR₂, C(R₂)₂, N, S, O, or NR₃,

Z₇ is CR₂, C(R₂)₂, N, S, O, or NR₃,

wherein the residues Zi, Z₂, Z₃, Z₅, Z₆, Z₇ cannot represent adjacent

O or S,

— , Ti, T₂, Zi, Z₂, Z₃, Z₄, R₂, R₂, R₃, R₄ have the same meaning as given under claim 1.

8. A compound according to any of the claims 1 to 7, wherein R₂ is

OR₄, halogen, N(OH)H, N(OH)R₄, NHR₄, COR₄, CONHR₄, or S0₂NHR₄.

9. A compound according to any of the claims 1 to 8, wherein R₄ is H, Ci-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, or Ci-C₆-alkylphenyl, wherein Ci- C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, or Ci-C₆-alkylphenyl may be substi- tuted with one to four substituents selected from the group comprising Ci-C₆- alkyl, Ci-C₆-alkoxy, aryl, halogen, and amine.

10. A compound according to any of the claims 1 to 5, and claims 8 or 9,

wherein

R₄ has the same meaning as given under claim 1.

11. A compound according to claim 10, wherein

R₄ is alkyl, benzyl, alkylbiphenyl, preferably propyl, benzyl, or 3- methyl[l,l'-biphenyl].

12. A compound according to any of the claims 1 to 11 selected from the group consisting of

(1) (2S,3R)-2-Carboxy-3-(3-carboxy-4-hydroxyphenyl)pyrrolidin-l-ium- 2,2,2-trifluoroacetate,

(2) (2S,3R)-3-(3-Carboxy-5-propoxyphenyl)pyrrolidine-2-carboxylic acid hydrochloride,

(3) (2S,3R)-3-(3-(Benzyloxy)-5-carboxyphenyl)pyrrolidine-2-carboxylic acid hydrochloride,

(4) (2S,3R)-3-(3-([l,l'-Biphenyl]-3-ylmethoxy)-5- carboxyphenyl)pyrrolidine-2-carboxylic acid, (2S,3R)-2-Carboxy-3-(3- carboxy-5-hydroxyphenyl)pyrrolidin-l-ium 2,2,2-trifluoroacetate,

(5) (2S,3R)-tert-butyl 2-(((tert-butyldimethylsilyl)oxy)methyl)-3-(2,2- dimethyl-4H-benzo[d][l,3]dioxin-6-yl)-5-oxopyrrolidine-l-carboxylate, (6) (2S,3R)-tert-Butyl 2-(((tert-butyldimethylsilyl)oxy)methyl)-3-(3- (((tert-butyldimethylsilyl)oxy)-methyl)-5-propoxyphenyl)-5-oxopyrrolidine-l- carboxylate,

(7) (2S,3R)-tert-Butyl 3-(3-(benzyloxy)-5-(((tert- butyldimethylsilyl)oxy)methyl)phenyl)-2-(((tert-butyldime- thylsilyl)oxy)methyl)-5-oxopyrrolidine-l-carboxylate, (8) (2S,3R)-tert-Butyl 3-(3-([l,l'-biphenyl]-3-ylmethoxy)-5-(((tert- butyldimethylsilyl)oxy)methyl)phenyl)-2-(((tert- butyldimethylsilyl)oxy)methyl)-5-oxopyrrolidine-l-carboxylate,

(9) (2S,3R)-tert-Butyl 2-(((tert-butyldimethylsilyl)oxy)methyl)-3-(2,2- dimethyl-4H-benzo[d][l,3]-dioxin-6-yl)pyrrolidine-l-carboxylate,

(10) (2S,3R)-tert-Butyl- 2-(((tert-butyldimethylsilyl)oxy)methyl)-3-(3- (((tert-butyldimethylsilyl)oxy)-methyl)-5-propoxyphenyl)pyrrolidine-l- carboxylate,

(11) (2S,3R)-tert-Butyl-3-(3-(benzyloxy)-5-(((tert- butyldimethylsilyl)oxy)methyl)phenyl)-2-(((tert- butyldimethylsilyl)oxy)methyl)pyrrolidine-l-carboxylate

(12) (2S,3R)-tert-Butyl- 3-(3-([l,l'-biphenyl]-3-ylmethoxy)-5-(((tert- butyldimethylsilyl)oxy)methyl)-phenyl)-2-(((tert- butyldimethylsilyl)oxy)methyl)pyrrolidine-l-carboxylate,

(13) (2S,3R)-tert-Butyl 3-(2,2-dimethyl-4H-benzo[d][l,3]dioxin-6-yl)-2- (hydroxymethyl)-pyrrolidine-l-carboxylate,

(14) (2S,3R)-tert-Butyl 2-(hydroxymethyl)-3-(3-(hydroxymethyl)-5- propoxyphenyl)pyrrolidine-l-carboxylate,

(15) (2S,3R)-tert-Butyl 3-(3-(benzyloxy)-5-(hydroxymethyl)phenyl)-2- (hydroxymethyl)pyrrolidine- l-carboxylate,

(16) (2S,3R)-tert-Butyl 3-(3-([l,l'-biphenyl]-3-ylmethoxy)-5- (hydroxymethyl)phenyl)-2-(hydroxymethyl)-pyrrolidine-l-carboxylate,

(17) (2S,3R)-l-(tert-Butoxycarbonyl)-3-(2,2-dimethyl-4-oxo-4H- benzo[d][l,3]dioxin-6-yl)pyrrolidine-2-carboxylic acid,

(18) (2S,3R)-l-(tert-butoxycarbonyl)-3-(2,2-dimethyl-4H- benzo[d][l,3]dioxin-6-yl)pyrrolidine-2-carboxylic acid,

(19) (2S,3R)-l-(tert-Butoxycarbonyl)-3-(3-carboxy-5- propoxyphenyl)pyrrolidine-2-carboxylic acid,

(20) (2S,3R)-3-(3-(Benzyloxy)-5-carboxyphenyl)-l-(tert- butoxycarbonyl)pyrrolidine-2-carboxylic acid, and

(21) (2S,3R)-3-(3-([l,l'-Biphenyl]-3-ylmethoxy)-5-carboxyphenyl)-l-(tert- butoxycarbonyl)-pyrrolidine-2-carboxylic acid.

13. A compound according to any one of the preceding claims for use as a medicament.

14. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12 in combination with one or more therapeutically acceptable diluents or carriers.

15. A compound according to any one of claims 1 to 12 or a pharmaceutical composition according to claim 14 or a method for treatment of dis- eases or conditions binding one or more of the GluAl, GluA2, GluA3, GluA4, GluKl, GluK2, GluK3, GluK4, GluK5, GluN2A, GluN2B, GluN2C or GluN2D receptor subunits to obtain a beneficial therapeutic effect.

16. A method for treating a disease or disorder mediated by one or more of the GluAl, GluA2, GluA3, GluA4, GluKl, GluK2, GluK3, GluK4, GluK5, GluN2A, GluN2B, GluN2C or GluN2D receptor subunits, wherein the disease or disorder is selected from the group consisting of psychiatric diseases or neurological disorders or a disease or disorder associated with abnormal activities of one or more of the GluAl, GluA2, GluA3, GluA4, GluKl, GluK2, GluK3, GluK4, GluK5, GluN2A, GluN2B, GluN2C or GluN2D receptor subunits in a pa- tient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound according to any of claims 1 to 12, or a pharmaceutically acceptable salt or solvate thereof, optionally together with a pharmaceutically acceptable carrier.

17. A compound according to any one of claims 1 to 12 or a pharma- ceutical composition according to claims 14 to 15 or a method for treatment of disorders of the central nervous system, neuro-physiological processes such as memory, cognition; as well as neuronal plasticity and development, psychiatric diseases or neurological disorders such as depression, anxiety, addiction, pain, migraine, and schizophrenia, and neurodegenerative diseas- es; such as Alzheimer, Huntington disease, amyotrophic lateral sclerosis (ALS), cerebral stroke, and epilepsy; and diseases including aching, ADHD, Autism, Diabetes, Huntington's disease, ischemia, multiple sclerosis, Parkinson's disease (Parkinsonism), Rasmussen's encephalitis, seizures, AIDS dementia complex, amyotrophic lateral sclerosis, combined systems disease (vitamin B12 deficiency), drug addiction, drug tolerance, drug dependency, glaucoma, hepatic encephalopathy, hydroxybutyric aminoaciduria, hyperho- mocysteinemia and homocysteinuria, hyperprolinemia, lead encephalopathy, leber's disease, MELAS syndrome, MERRF, mitochondrial abnormalities (and other inherited or acquired biochemical disorders), neuropathic pain syn- dromes (e.g. causalgia or painful peripheral neuropathies), nonketotic hyper- glycinemia, olivopontocerebellar atrophy, essential tremor, Rett syndrome, sulfite oxidase deficiency, Wernicke's encephalopathy or cancer.

18. A pharmaceutical composition according to any of the claims 14 to 17 wherein the pharmaceutical composition is administered in doses of 0.5-1500 mg/day, preferably 0.5-200 mg/day, more preferably 0.5-60 mg/day, even more preferably 0.5-30 mg/day.

19. A pharmaceutical composition according to any of the claims 14 to 18 for oral, rectal, nasal, pulmonary, buccal, sublingual, transdermal or parenteral administration.