Abstract:
Provided herein are halogenated indole and benzofuran derivatives of isoquinuclidene and intermediates thereto, and processes, preferably enantioselective processes, for preparing such derivatives including processes for preparing (−) and (+) noribogaine, in substantially enantiomerically pure forms.

Description:
CROSS-REFERENCE TO PRIORITY APPLICATIONS 
     This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application Ser. No. 62/013,771, filed on Jun. 18, 2014, which is incorporated herein by reference in its entirety. 
    
    
     FIELD OF THE INVENTION 
     Provided herein are halogenated indole and benzofuran derivatives of isoquinuclidene and intermediates thereto, and processes, preferably enantioselective processes, for preparing such derivatives including processes for preparing (−) and (+) noribogaine, in substantially enantiomerically pure forms. 
     STATE OF THE ART 
     Noribogaine is a well-known compound whose structure combines the features, for example, of tyrptamine, and isoquinuclidene. The naturally occurring enantiomer of noribogaine can be depicted by the following formula: 
     
       
                 
         
             
             
         
      
     
     This enantiomer of noribogaine and its pharmaceutically acceptable salts have recently received significant attention as a non-addictive alkaloid useful in treating drug dependency (U.S. Pat. No. 6,348,456) and as a potent analgesic (U.S. Pat. No. 7,220,737). Both of these patents are incorporated herein by reference in their entirety. 
     Synthesizing compounds to include the isoquinuclidene moiety, especially in a substantially enantiomerically pure form is a challenging task. Heretofore, Iboga alkaloids, such as ibogaine: 
                                
were conventionally prepared from one of its naturally occurring precursors such as voacangine:
 
                                
or isolated from plant sources. The naturally occurring enantiomer of noribogaine is prepared by O-demethylation of naturally occurring ibogaine or prepared by decarboxylation and O-demethylation of naturally occurring voacangine. Voacangine and Ibogaine are obtained from plants where both the supply is limited and the quality of the supply is unpredictable.
 
     SUMMARY OF THE INVENTION 
     Provided herein are halogenated indole and benzofuran derivatives of isoquinuclidene and intermediates thereto, and processes, preferably enantioselective processes, for preparing such derivatives including processes for preparing (−) and (+) noribogaine, in substantially enantiomerically pure forms. Also provided herein are intermediates and processes for preparing noribogaine following the Nenitzescu indole synthesis. 
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     Before this invention is described in greater detail, the following terms will be defined. 
     DEFINITIONS 
     As used herein and in the appended claims, the singular forms “a”, “an”, and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a salt” includes a plurality of such salts. 
     As used herein, “alkenyl” refers to hydrocarbyl groups having from 2 to 10 carbon atoms and at least one and up to 3 carbon carbon double bonds. Examples of alkenyl include vinyl, allyl, dimethyl allyl, and the like. 
     As used herein, “alkoxy” refers to —O-alkyl. 
     As used herein, “alkyl” refers to hydrocarbyl groups having from 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, and still more preferably 1-4 carbon atoms. The alkyl group may contain linear or branched carbon chains. This term is exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, n-pentyl, n-decyl and the like. 
     As used herein, “alkynyl” refers to hydrocarbyl groups having from 2 to 10 carbon atoms and at least one and up to 2 carbon carbon triple bonds. Examples of alkynyl include ethynyl, propargyl, dimethylpropargyl, and the like. 
     As used herein, “under amide formation conditions” refers to conditions, as is well known to the skilled artisan, under which a —CO 2 H group or a —CO-L 1  group, wherein L 1  is a leaving group reacts with an amine to form an amide. A —COL 1  moiety can react with a suitable amine in the presence of a base, and optionally a nucleophilic catalyst such as N,N-dimethylamino pyridine or the likes, in an inert solvent such as dichloromethane, tetrahydrofuran, or the likes. Suitable bases include triethyl amine, pyridine, and well known modifications of each thereof. A CO 2 H moiety reacts with a suitable amine in the presence of a reagent such as a carbodiimide or a variety of such reagents well known in chemistry and peptide chemistry. 
     As used herein, “amino” refers to —NR x R y  wherein each R x  and R y  independently is hydrogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 6 -C 10  aryl, C 3 -C 8  cycloalkyl, C 2 -C 10  heteroaryl, or C 3 -C 8  heterocyclyl, or R x  and R y  together with the nitrogen atom they are bonded to form a 5-10 membered heterocyclyl ring containing 1-2 nitrogen and/or oxygen atoms, which heterocyclyl ring is optionally substituted with 1-3, preferably, 1-2, or more preferably, a single, C 1 -C 3  alkyl group. 
     As used herein, “aryl” refers to an aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl) which condensed rings may or may not be aromatic (e.g., 2-benzoxazolinone, 2H-1,4-benzoxazin-3(4H)-one-7-yl, and the like) provided that the point of attachment is at an aromatic carbon atom. 
     As used herein, “base” refers to a compound that can accept a proton or donate a lone electron pair. Examples of bases include, alkali (Oft), carbonate, bicarbonate, alkoxides (alkyl-On), hydrides (alkali metal hydrides and CaH 2 ), amides (NH 2 ( − ), R b NH( − ), or (R b ) 2 N( − ), wherein R b  is alkyl or 2 R b s together with the nitrogen form a 5-6 membered ring), and neutral nitrogen containing bases such as (R b ) 3 N, pyridine, 4-N,N-dialkylpyridine, and the like. As used herein nucleophilic bases refer to preferably neutral nitrogen containing bases that can catalyze the addition of an acyl halide or a sulfonyl halide(such as R b COX or R b SO 2 X) to an —OH, —NH 2 , or an —NHR b  group. Preferred examples include, 4-N,N-dialkylpyridines. 
     As used herein, the term “comprising” or “comprises” is intended to mean that the compositions and methods include the recited elements, but not excluding others. “Consisting essentially of” when used to define compositions and methods, shall mean excluding other elements of any essential significance to the combination for the stated purpose. Thus, a composition consisting essentially of the elements as defined herein would not exclude other materials or steps that do not materially affect the basic and novel characteristic(s) of the claimed invention. “Consisting of” shall mean excluding more than trace elements of other ingredients and substantial method steps. Embodiments defined by each of these transition terms are within the scope of this invention. 
     As used herein, “a condition suitable for reductive Heck coupling” refers to a Heck coupling reaction condition where a β-hydride elimination is limited or is not possible. A Heck coupling, including obvious variants thereof, are well known to the skilled artisan. The reaction scheme below illustrates, without limitation, a reaction condition where a reductive Heck reaction takes place. 
                                
For example, a reaction may take place with a suitable hydride donor. In that case, a Heck reaction is carried out on a substrate which will not allow β-hydride elimination. The addition, for example, of formic acid or ammonium formate leads to a σ-alkyl palladium intermediate and causes a “reductive Heck” reaction.
 
     As used herein, “cycloalkyl” refers to cyclic hydrocarbyl groups of from 3 to 10 carbon atoms having single or multiple condensed rings, which condensed rings may be aromatic or contain a heteroatom, provided that the point of attachment is at a cycloalkyl carbon atom. Cycloalkyl includes, by way of example, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl and the like. Cycloalkyl rings are preferably saturated, though, cycloalkyl rings including 1-2 carbon carbon double bonds are also contemplated provided that the ring is not aromatic. 
     As used herein, “C x ” refers to a group having x carbon atoms, wherein x is an integer, for example, C 4  alkyl refers to an alkyl group having 4 carbon atoms. 
     As used herein, “ee” refers to enantiomeric excess and is expressed as (e 1 -e 2 )% where e 1  and e 2  are the two enantiomers. For example, if the % of e 1  is 95 and the % of e 2  is 5, then the e 1  enantiomer is present in an ee of 90%. The ee of an enantiomer in a mixture of enantiomers is determined following various methods well known to the skilled artisan, such as using chiral lanthanide based nuclear magnetic resonance shift reagents, forming derivatives with chiral compounds such as chiral hydroxyacids, amino acids, and the like. Various physical measurements such as circular dichroism, optical rotation, etc. are also useful in determining the ee of a mixture of enantiomers. 
     As used herein, —CO 2 H “ester” refers to —CO 2 R E  wherein R E  is selected from the group consisting of C 6 -C 10  aryl and C 1 -C 6  alkyl optionally substituted with 1-3 C 6 -C 10  aryl groups. 
     As used herein, “halo” refers to F, Cl, Br, or I. 
     As used herein, “halogenating agent” refers to a compound that can convert an indole, to a 2-halo indole. Non-limiting examples of such reagents include N-halosuccinimides such as N-iodosuccinimide. Conditions suitable for halogenation include contacting the reactants in an inert solvent. 
     As used herein, “heteroaryl” refers to an aromatic group of from 1 to 10 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, sulfur within the ring, wherein the nitrogen and/or sulfur atom(s) of the heteroaryl are optionally oxidized (e.g., N-oxide, —S(O)— or —S(O) 2 —), provided that the ring has at least 5 ring atoms and up to 14, or preferably from 5-10, ring atoms. Such heteroaryl groups can have a single ring (e.g., pyridyl or furyl) or multiple condensed rings (e.g., indolizinyl or benzothienyl) wherein the condensed rings may or may not be aromatic and/or contain a heteroatom provided that the point of attachment is through an atom of the aromatic heteroaryl group. Examples of heteroaryls include pyridyl, pyrrolyl, indolyl, thiophenyl, furyl, and the like. 
     As used herein, “heterocyclyl” or heterocycle refers to a cycloalkyl group of from 1 to 10 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, sulfur within the ring, wherein the nitrogen and/or sulfur atom(s) of the heteroaryl are optionally oxidized (e.g., N-oxide, —S(O)— or —S(O) 2 —), provided that the ring has at least 3 and up to 14, or preferably from 5-10 ring atoms. Such heterocyclyl groups can have a single ring or multiple condensed rings wherein the condensed rings may not contain a heteroatom and/or may contain an aryl or a heteroaryl moiety, provided that the point of attachment is through an atom of the non-aromatic heterocyclyl group. Examples of heterocyclyl include pyrrolidinyl, piperadinyl, piperazinyl, and the like. Heterocyclyl rings are preferably saturated, though, heterocyclyl rings including 1-2 carbon carbon double bonds are also contemplated provided that the ring is not aromatic. 
     As used herein, “hydrogenation conditions” refer to conditions including hydrogen gas at atmospheric or higher pressure and catalysts that catalyze the reaction of the hydrogen with a hydrogen reactive group, such as a benzyl group or a carbon carbon double/triple bond. Catalysts useful for hydrogenation include palladium, platinum, and rhodium metals and their oxides or hydroxides, preferably supported on a material such as carbon or alumina. 
     As used herein, “leaving group” refers to a group or an atom that can be displaced by a nucleophile such as an amine. Non-limiting examples of leaving groups include halo, preferably, chloro, bromo, or iodo, and —OSO 2 R 60  wherein R 60  is is C 1 -C 6  alkyl optionally substituted with 1-3 substituents selected from the group consisting of C 6 -C 10  aryl, C 3 -C 8  cycloalkyl, C 2 -C 10  heteroaryl, or is C 3 -C 8  heterocyclyl, C 6 -C 10  aryl, C 3 -C 8  cycloalkyl, C 2 -C 10  heteroaryl, or C 3 -C 8  heterocyclyl; wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl, is optionally substituted with 1-3 substituents selected from the group consisting of C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 6 -C 10  aryl, cycloalkyl, C 2 -C 10  heteroaryl, C 3 -C 8  heterocyclyl, halo, or C 1 -C 6  alkoxy. 
     As used herein, “nucleophilic substitution conditions” refer to those suitable for a nucleophilic substitution at an aliphatic saturated carbon atom, with a nucleophile such as an amine. The reaction are carried out preferably in an aprotic solvent. A non-nucleophilic base, e.g., a base that does not compete with the reacting amine as a nucleophile, such as K 2 CO 3  may be employed to neutralize any acid generated in the process. 
     As used herein, “protecting group” or “Pg” refers to well known functional groups which, when bound to a functional group, render the resulting protected functional group inert to the reaction to be conducted on other portions of the compound and the corresponding reaction condition, and which can be reacted to regenerate the original functionality under deprotection conditions. The protecting group is selected to be compatible with the remainder of the molecule. In one embodiment, the protecting group is an “amine protecting group” which protects an —NH— or an —NH 2 — moiety, for example during the syntheses described here. Examples of amine protecting groups include, for instance, benzyl, acetyl, oxyacetyl, carbonyloxybenzyl (Cbz), Fmoc, and the like. In another embodiment, the protecting group is a “hydroxy protecting group” which protects a hydroxyl functionality during the synthesis described here. Examples of hydroxyl protecting groups include, for instance, benzyl, p-methoxybenzyl, p-nitrobenzyl, allyl, trityl, dialkylsilylethers, such as dimethylsilyl ether, and trialkylsilyl ethers such as trimethylsilyl ether, triethylsilyl ether, and t-butyldimethylsilyl ether; esters such as benzoyl, acetyl, phenylacetyl, formyl, mono-, di-, and trihaloacetyl such as chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl; and carbonates such as methyl, ethyl, 2,2,2-trichloroethyl, allyl, and benzyl. As the skilled artisan would appreciate, one or more of these protecting groups are also useful as amine protecting groups. Additional examples of amine, hydroxy, and keto protecting groups are found in standard reference works such as Greene and Wuts, Protective Groups in Organic Synthesis., 2d Ed., 1991, John Wiley &amp; Sons, and McOmie Protective Groups in Organic Chemistry, 1975, Plenum Press. Methods for protecting and deprotecting hydroxyl, —NH—, —NH 2 —, and keto groups disclosed herein can be found in the art, and specifically in Greene and Wuts, supra, and the references cited therein. 
     As used herein, “reducing agent” refers to a compounds that can donate electrons or a hydride in a reaction. Preferred examples include aluminum hydrides, such as LiAlH 4 , borohydrides such as NaBH 4 /CeCl 3 , and alanes such as diisobutyl aluminum hydride. A reducing agent reduces under reduction conditions. Typically the reducing agent and the compound to be reduced, such as a keto-containing compound is reacted in an inert solvent such as ether, tetrahydrofuran, or dioxane. The reaction mixture can be refluxed. 
     As used herein, a salt refers to preferably a salt of a mineral acid, or an organic acid such as a carboxylic acid or a sulfonic acid, and/or to alkali, alkaline earth, and various ammonium (including tetraalkyl ammonium, pyridinum, imidazolium and the like) salts. Non limiting examples of acid salts include salts of hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methane sulfonic acid, phosphorous acid, nitric acid, perchloric acid, acetic acid, tartaric acid, lactic acid, succinic acid, and citric acid. 
     As used herein, “substantially enantiomerically enriched,” “substantially enantiomerically pure” or “substantial enantiomeric excess” or grammatical equivalents thereof refers to an enantiomer in an enantiomeric mixture with at least 95% ee, preferably 98% ee, or more preferably 99% ee. 
     Compounds 
     In one aspect, provided herein is a compound of Formula (I): 
                                
or a tautomer thereof or a salt of each thereof wherein
 
     R 1  is selected from the group consisting of hydrogen, —CO 2 R 11 , —COR 12 , —C(R 13 ) 3 , an amine protecting group, and 
     
       
                 
         
             
             
         
      
     
     R 11  is selected from the group consisting of C 1 -C 6  alkyl optionally substituted with 1-3 substituents selected from C 6 -C 10  aryl, C 3 -C 8  cycloalkyl, C 2 -C 10  heteroaryl, C 3 -C 8  heterocyclyl, halo, amino, —N 3 , hydroxy, C 1 -C 6  alkoxy, silyl, nitro, cyano, and CO 2 H or an ester thereof, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 6 -C 10  aryl, C 2 -C 10  heteroaryl, C 3 -C 8  cycloalkyl, and C 3 -C 8  heterocyclyl, 
     R 12  and R 13  independently are selected from the group consisting of hydrogen, C 1 -C 6  alkyl optionally substituted with 1-3 substituents selected from C 6 -C 10  aryl, C 3 -C 8  cycloalkyl, C 2 -C 10  heteroaryl, C 3 -C 8  heterocyclyl, halo, amino, —N 3 , hydroxy, C 1 -C 6  alkoxy, silyl, nitro, cyano, and CO 2 H or an ester thereof, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 6 -C 10  aryl, C 2 -C 10  heteroaryl, C 3 -C 8  cycloalkyl, and C 3 -C 8  heterocyclyl; 
     k is 0, 1, 2, or 3; 
     each R 10  is independently a substituent (i.e., when k is 0, the indole moiety includes 4 hydrogens in the phenyl portion) selected from the group consisting of halo, amino, hydroxy, C 1 -C 6  alkoxy, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, cyano, nitro, —N 3 , and —CO 2 H or an ester thereof, wherein the alkyl, alkoxy, alkenyl, or the alkylnyl group is optionally substituted with 1-3 substituents selected from the group consisting of keto, halo, amino, hydroxy, cyano, nitro, —N 3 , phenyl optionally substituted with 1-3 substituents selected from the group consisting of C 1 -C 6  alkyl and C 1 -C 6  alkoxy, and —CO 2 H or an ester thereof; 
     R 20  is hydrogen or C(R 20 ) 2  is a keto group; 
     R 30  is selected from the group consisting of hydrogen, halo, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, wherein the alkyl, alkenyl, or the alkylnyl group is optionally substituted with 1-3 substituents selected from the group consisting of keto, halo, amino, hydroxy, cyano, nitro, —N 3 , and —CO 2 H or an ester thereof; 
     R 50  is selected from the group consisting of —O— and N—R 51 ; and 
     R 51  is selected from the group consisting of hydrogen and C 1 -C 6  alkyl optionally substituted with 1-3 substituents selected from the group consisting of keto, halo, amino, hydroxy, cyano, nitro, —N 3 , and —CO 2 H or an ester thereof; 
     X 10  is a leaving group, preferably, halo or —OSO 2 R 71 , more preferably bromo or iodo, or is —OH or hydrogen; 
     R 4  and R 5  independently are selected from the group consisting of hydrogen, halo, C 1 -C 6  alkyl optionally substituted with 1-3 substituents selected from the group consisting of C 6 -C 10  aryl, C 3 -C 8  cycloalkyl, C 2 -C 10  heteroaryl, C 3 -C 8  heterocyclyl, halo, amino, —N 3 , hydroxy, C 1 -C 6  alkoxy, silyl, nitro, cyano, vinyl, ethynyl, and CO 2 H or an ester thereof; 
     R 2  and R 3  are independently selected from hydrogen, —CHO, R 6 —C(═O)—, R 6 —CH(OR 7 )—, provided that at least one of R 2  and R 3  is hydrogen; or R 2  and R 3  together with the carbon atom they are bonded to, form a ═CHR 6  moiety; 
     R 6  is C 1 -C 6  alkyl optionally substituted with 1-3 substituents selected from the group consisting of C 6 -C 10  aryl, C 3 -C 8  cycloalkyl, C 2 -C 10  heteroaryl, or C 3 -C 8  heterocyclyl; 
     R 7  is hydrogen or SO 2 R 71 ; 
     R 71  is C 1 -C 6  alkyl optionally substituted with 1-3 substituents selected from the group consisting of C 6 -C 10  aryl, C 3 -C 8  cycloalkyl, C 2 -C 10  heteroaryl, or is C 3 -C 8  heterocyclyl, C 6 -C 10  aryl, C 3 -C 8  cycloalkyl, C 2 -C 10  heteroaryl, or C 3 -C 8  heterocyclyl; 
     wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl, is optionally substituted with 1-3 substituents selected from the group consisting of C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 6 -C 10  aryl, cycloalkyl, C 2 -C 10  heteroaryl, C 3 -C 8  heterocyclyl, halo, amino, —N 3 , hydroxy, C 1 -C 6  alkoxy, silyl, nitro, cyano, and CO 2 H or an ester thereof. 
     A keto substituent, as used herein, substitutes a —CH 2 — group to a —C(═O)-group. In one embodiment, X 10  is a leaving group, preferably, halo or —OSO 2 R 71 , more preferably bromo or iodo, or is —OH. In one embodiment, X 10  is more preferably, halo 
     In one embodiment, the compound is of Formula (II): 
     
       
                 
         
             
             
         
      
     
     wherein R 1 , R 2 , and R 3  are defined as above. 
     In another embodiment, R 1  is hydrogen or CO 2 R 11  and R 11  is C 1 -C 6  alkyl. 
     In another embodiment, provided herein is a compound of Formula (III): 
                                
wherein             refers to a cis or a trans stereochemistry and R 1  is defined as in any aspect or embodiment herein.

     In another embodiment, one of R 2  and R 3  is hydrogen, and the other is —CHO, COCH 3 , CHOHCH 3 , —CHOSO 2 R 71  wherein R 71  is defined as herein. 
     In another embodiment, provide herein is a compound of Formula (IV): 
                                
wherein the variables are defined as in any aspect or embodiment herein.
 
     In another embodiment, provided herein is a compound of Formula (IVA): 
                                
wherein the variables are defined as in any aspect and embodiment above.
 
     In another embodiment, provided herein is a compound of Formula (IVB): 
                                
wherein the variables are defined as in any aspect or embodiment above.
 
     In another embodiment, provided herein is a compound of Formula (IVC): 
                                
wherein the variables are defined as in any aspect or embodiment above.
 
     In another embodiment, provided herein is a compound of Formula (VA): 
                                
wherein R 110  is selected from the group consisting of
         hydrogen;   C 1 -C 6  alkyl optionally substituted with 1-3 substituents selected from the group consisting of halo, amino, hydroxy, cyano, nitro, —N 3 , —CO 2 H or an ester thereof, and phenyl optionally substituted with 1-3 substituents selected from the group consisting of C 1 -C 6  alkyl and C 1 -C 6  alkoxy;   —COR 11 ; and   —CO 2 R 11 ;       

     k is 0, 1 or 2; 
     and the remaining variables are defined as in any aspect and embodiment herein. 
     In another embodiment, provided herein is a compound of Formula (VB): 
                                
wherein the variables are as tabulated below:
 
     
       
         
               
               
               
               
               
               
             
           
               
                   
               
               
                 R 15   
                 R 110   
                 C(R 20 ) 2   
                 R 2   
                 R 3   
                 R 47   
               
               
                   
               
             
             
               
                 H, 4-Me, 6-Me,  
                 Bn 
                 C═O 
                 CR 2 R 3  is 
                 — 
                 — 
               
               
                 7-Me, 4-OH, 6- 
                   
                   
                 C═CR 48 H, 
                   
                   
               
               
                 OH, 7-OH, 4- 
                   
                   
                 R 48  is Me, 
                   
                   
               
               
                 OMe, 6-OMe, or 
                   
                   
                 Et, Pr, Bu 
                   
                   
               
               
                 7-OMe 
                   
                   
                   
                   
                   
               
               
                 H, 4-Me, 6-Me,  
                 Bn 
                 CH 2   
                 CR 2 R 3  is 
                 — 
                 — 
               
               
                 7-Me, 4-OH, 6- 
                   
                   
                 C═CR 48 H, 
                   
                   
               
               
                 OH, 7-OH, 4- 
                   
                   
                 R 48  is Me, 
                   
                   
               
               
                 OMe, 6-OMe, or 
                   
                   
                 Et, Pr, Bu 
                   
                   
               
               
                 7-OMe 
                   
                   
                   
                   
                   
               
               
                 H, 4-Me, 6-Me,  
                 Bn 
                 C═O 
                 CH 2 CH 2 R 47   
                 H 
                 C 1 —C 4  alkyl (e.g., Me, Et, Pr, Bu) 
               
               
                 7-Me, 4-OH, 6- 
                   
                   
                   
                   
                 optionally substituted with an 
               
               
                 OH, 7-OH, 4- 
                   
                   
                   
                   
                 OMe group (e.g., CH 2 OMe, 
               
               
                 OMe, 6-OMe, or 
                   
                   
                   
                   
                 (CH 2 ) 2 OMe, (CH 2 ) 3 OMe, and 
               
               
                 7-OMe 
                   
                   
                   
                   
                 (CH 2 ) 4 OMe), OH group (e.g., 
               
               
                   
                   
                   
                   
                   
                 CH 2 OH, (CH 2 ) 2 OH, (CH 2 ) 3 OH, 
               
               
                   
                   
                   
                   
                   
                 and (CH 2 ) 4 OH), an amide (e.g., 
               
               
                   
                   
                   
                   
                   
                 (CH 2 ) 2 NHCOMe, 
               
               
                   
                   
                   
                   
                   
                 (CH 2 ) 3 NHCOMe, and 
               
               
                   
                   
                   
                   
                   
                 (CH 2 ) 4 NHCCOMe) or with an 
               
               
                   
                   
                   
                   
                   
                 amino group (e.g., 
               
               
                   
               
               
                   
                   
                   
                   
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                   
                   
                   
                   
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                   
                   
                   
                   
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                   
                   
                   
                   
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 H, 4-Me, 6-Me,  
                 Bn 
                 CH 2   
                 CH 2 CH 2 R 47   
                 H 
                 C 1 —C 4  alkyl (e.g., Me, Et, Pr, Bu) 
               
               
                 7-Me, 4-OH, 6- 
                   
                   
                   
                   
                 optionally substituted with an 
               
               
                 OH, 7-OH, 4- 
                   
                   
                   
                   
                 OMe group (e.g., CH 2 OMe, 
               
               
                 OMe, 6-OMe, or 
                   
                   
                   
                   
                 (CH 2 ) 2 OMe, (CH 2 ) 3 OMe, and 
               
               
                 7-OMe 
                   
                   
                   
                   
                 (CH 2 ) 4 OMe), OH group (e.g., 
               
               
                   
                   
                   
                   
                   
                 CH 2 OH, (CH 2 ) 2 OH, (CH 2 ) 3 OH, 
               
               
                   
                   
                   
                   
                   
                 and (CH 2 ) 4 OH), an amide (e.g., 
               
               
                   
                   
                   
                   
                   
                 (CH 2 ) 2 NHCOMe, 
               
               
                   
                   
                   
                   
                   
                 (CH 2 ) 3 NHCOMe, and 
               
               
                   
                   
                   
                   
                   
                 (CH 2 ) 4 NHCCOMe) or with an 
               
               
                   
                   
                   
                   
                   
                 amino group (e.g., 
               
               
                   
                   
                   
                   
                   
                 CO 2 (CH 2 ) 2 NMe 2 , 
               
               
                   
               
               
                   
                   
                   
                   
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                   
                   
                   
                   
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                   
                   
                   
                   
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                   
                   
                   
                   
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 H, 4-Me, 6-Me,  
                 H 
                 C═O 
                 CH 2 CH 2 R 47   
                 H 
                 C 1 —-C 4  alkyl (e.g., Me, Et, Pr, Bu) 
               
               
                 7-Me, 4-OH, 6- 
                   
                   
                   
                   
                 optionally substituted with an 
               
               
                 OH, 7-OH, 4- 
                   
                   
                   
                   
                 OMe group (e.g., CH 2 OMe, 
               
               
                 OMe, 6-OMe, or 
                   
                   
                   
                   
                 (CH 2 ) 2 OMe, (CH 2 ) 3 OMe, and 
               
               
                 7-OMe 
                   
                   
                   
                   
                 (CH 2 ) 4 OMe), OH group (e.g., 
               
               
                   
                   
                   
                   
                   
                 CH 2 OH, (CH 2 ) 2 OH, (CH 2 ) 3 OH, 
               
               
                   
                   
                   
                   
                   
                 and (CH 2 ) 4 OH), an amide (e.g., 
               
               
                   
                   
                   
                   
                   
                 (CH 2 ) 2 NHCOMe, 
               
               
                   
                   
                   
                   
                   
                 (CH 2 ) 3 NHCOMe, and 
               
               
                   
                   
                   
                   
                   
                 (CH 2 ) 4 NHCCOMe) or with an 
               
               
                   
                   
                   
                   
                   
                 amino group (e.g., 
               
               
                   
                   
                   
                   
                   
                 CO 2 (CH 2 ) 2 NMe 2 , 
               
               
                   
               
               
                   
                   
                   
                   
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                   
                   
                   
                   
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                   
                   
                   
                   
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                   
                   
                   
                   
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 H, 4-Me, 6-Me,  
                 H 
                 CH 2   
                 CH 2 CH 2 R 47   
                 H 
                 C 1 —-C 4  alkyl (e.g., Me, Et, Pr, Bu) 
               
               
                 7-Me, 4-OH, 6- 
                   
                   
                   
                   
                 optionally substituted with an 
               
               
                 OH, 7-OH, 4- 
                   
                   
                   
                   
                 OMe group (e.g., CH 2 OMe, 
               
               
                 OMe, 6-OMe, or 
                   
                   
                   
                   
                 (CH 2 ) 2 OMe, (CH 2 ) 3 OMe, and 
               
               
                 7-OMe 
                   
                   
                   
                   
                 (CH 2 ) 4 OMe), OH group (e.g., 
               
               
                   
                   
                   
                   
                   
                 CH 2 OH, (CH 2 ) 2 OH, (CH 2 ) 3 OH, 
               
               
                   
                   
                   
                   
                   
                 and (CH 2 ) 4 OH), an amide (e.g., 
               
               
                   
                   
                   
                   
                   
                 (CH 2 ) 2 NHCOMe, 
               
               
                   
                   
                   
                   
                   
                 (CH 2 ) 3 NHCOMe, and 
               
               
                   
                   
                   
                   
                   
                 (CH 2 ) 4 NHCCOMe) or with an 
               
               
                   
                   
                   
                   
                   
                 amino group (e.g., 
               
               
                   
                   
                   
                   
                   
                 CO 2 (CH 2 ) 2 NMe 2 , 
               
               
                   
               
               
                   
                   
                   
                   
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                   
                   
                   
                   
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                   
                   
                   
                   
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                   
                   
                   
                   
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
         
       
     
     In another embodiment, provided herein is a compound of formula; 
                                
wherein X 10  is hydrogen, chloro, bromo, or iodo and R 110  is defined as in any aspect and embodiment above.
 
     In one embodiment, R 4 , R 5 , R 20 , and R 30  are hydrogen. 
     In another embodiment, R 50  is NR 51 . In one embodiment, R 50  is NH. In another embodiment, R 50  is O. 
     In another embodiment, CR 2 R 3  is ═CHMe. 
     In another embodiment, k is 0. In another embodiment, k is 0 and preferably, the phenyl ring is substituted with the —O—R 110  group. In another embodiment, R 110  is C 1 -C 6  alkyl optionally substituted with 1-3 substituents selected from phenyl optionally substituted with 1-3 substituents selected from the group consisting of C 1 -C 6  alkyl and C 1 -C 6  alkoxy. 
     Preparation 
     Cyclization e.g., by Reductive Heck Coupling 
     In another aspect, provided herein is a process of preparing a compound of Formula (VI): 
                                
or a tautomer thereof or a salt of each thereof wherein
 
     k is 0, 1, 2, or 3; 
     each R 10  is independently a substituent selected from the group consisting of halo, amino, hydroxy, C 1 -C 6  alkoxy, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, cyano, nitro, —N 3 , and —CO 2 H or an ester thereof, wherein the alkyl, alkoxy, alkenyl, or the alkylnyl group is optionally substituted with 1-3 substituents selected from the group consisting of keto, halo, amino, hydroxy, cyano, nitro, —N 3 , phenyl optionally substituted with 1-3 substituents selected from the group consisting of C 1 -C 6  alkyl and C 1 -C 6  alkoxy, and —CO 2 H or an ester thereof; 
     R 20  is hydrogen or C(R 20 ) 2  is a keto group; 
     R 30  is selected from the group consisting of hydrogen, halo, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, wherein the alkyl, alkenyl, or the alkylnyl group is optionally substituted with 1-3 substituents selected from the group consisting of keto, halo, amino, hydroxy, cyano, nitro, —N 3 , and —CO 2 H or an ester thereof; 
     R 50  is selected from the group consisting of —O— and N—R 51 ; and 
     R 51  is selected from the group consisting of hydrogen and C 1 -C 6  alkyl optionally substituted with 1-3 substituents selected from the group consisting of keto, halo, amino, hydroxy, cyano, nitro, —N 3 , and —CO 2 H or an ester thereof; 
     R 4  and R 5  independently are selected from the group consisting of hydrogen, halo, C 1 -C 6  alkyl optionally substituted with 1-3 substituents selected from the group consisting of C 6 -C 10  aryl, C 3 -C 8  cycloalkyl, C 2 -C 10  heteroaryl, C 3 -C 8  heterocyclyl, halo, amino, —N 3 , hydroxy, C 1 -C 6  alkoxy, silyl, nitro, cyano, vinyl, ethynyl, and CO 2 H or an ester thereof; 
     R 2  and R 3  are independently selected from hydrogen, —CHO, R 6 —C(═O)—, R 6 —CH(OR 7 )—, provided that at least one of R 2  and R 3  is hydrogen; or R 2  and R 3  together with the carbon atom they are bonded to, form a ═CHR 6  moiety; 
     R 6  is C 1 -C 6  alkyl optionally substituted with 1-3 substituents selected from the group consisting of C 6 -C 10  aryl, C 3 -C 8  cycloalkyl, C 2 -C 10  heteroaryl, or C 3 -C 8  heterocyclyl; 
     R 7  is hydrogen or SO 2 R 71 ; 
     R 71  is C 1 -C 6  alkyl optionally substituted with 1-3 substituents selected from the group consisting of C 6 -C 10  aryl, C 3 -C 8  cycloalkyl, C 2 -C 10  heteroaryl, or is C 3 -C 8  heterocyclyl, C 6 -C 10  aryl, C 3 -C 8  cycloalkyl, C 2 -C 10  heteroaryl, or C 3 -C 8  heterocyclyl; 
     wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl, is optionally substituted with 1-3 substituents selected from the group consisting of C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 6 -C 10  aryl, cycloalkyl, C 2 -C 10  heteroaryl, C 3 -C 8  heterocyclyl, halo, amino, —N 3 , hydroxy, C 1 -C 6  alkoxy, silyl, nitro, cyano, and CO 2 H or an ester thereof; 
     the process comprising subjecting a compound of Formula (IV): 
     
       
                 
         
             
             
         
      
     
     wherein X 10  is a leaving group, preferably, halo or —OSO 2 R 71 , more preferably bromo or iodo and 
     the remaining variables are defined as above, e.g., for Formula (VI); 
     to a condition suitable for reductive Heck coupling to provide the compound of Formula (VI). 
     In one embodiment, the compound prepared is of Formula (VIA): 
     
       
                 
         
             
             
         
      
     
     wherein R 110  is selected from the group consisting of
         hydrogen;   C 1 -C 6  alkyl optionally substituted with 1-3 substituents selected from the group consisting of halo, amino, hydroxy, cyano, nitro, —N 3 , —CO 2 H or an ester thereof, and phenyl optionally substituted with 1-3 substituents selected from the group consisting of C 1 -C 6  alkyl and C 1 -C 6  alkoxy;   —COR 11 ; and   —CO 2 R 11 ;       

     k is 0, 1 or 2; 
     and the remaining variables are defined as in any aspect and embodiment above, 
     wherein the compound of Formula (VIA) is prepared comprising subjecting a compound of Formula (VA): 
                                
wherein X 10  is halo, preferably, bromo or iodo, more preferably, iodo, to a condition suitable for reductive Heck coupling to provide the compound of Formula (VIA).
 
Amide and Amine Formation
 
     In one aspect, provided herein is a process of preparing a compound of formula (IV): 
                                
wherein X 10  is a leaving group, C(R 20 ) 2  is C═O, and the remaining variables are as defined herein, such as above, is prepared comprising contacting a compound of Formula (VIIIC):
 
                                
wherein L 1  is OH or another leaving group selected from halo, preferably chloro or bromo with a compound of Formula (IX):
 
                                
under amide formation conditions to prepare the compound of Formula (IV); or
 
wherein the compound of Formula (VIIC):
 
                                
wherein C(R 20 ) 2  is C═O and the remaining variables are as defined herein, such as above, is prepared comprising contacting a compound of Formula (VIIID)
 
                                
wherein L 1  is OH or another leaving group selected from halo, preferably chloro or bromo with a compound of Formula (IX):
 
                                
under amide formation conditions to prepare the compound of Formula (VIIC).
 
     In one aspect, provided herein is a process of preparing a compound of formula (IV): 
                                
wherein X 10  is a leaving group and C(R 20 ) 2  is CH 2  is prepared comprising contacting a compound of Formula (VIIIC):
 
                                
wherein L 1  is a leaving group with a compound of Formula (IX):
 
                                
under nucleophilic substitution conditions to prepare the compound of Formula (IV); or
 
wherein the compound of Formula (VIIC):
 
                                
wherein C(R 20 ) 2  is CH 2  is prepared comprising contacting a compound of Formula (VIIID)
 
                                
wherein L 1  is a leaving group with a compound of Formula (IX):
 
                                
under nucleophilic substitution conditions to prepare the compound of Formula (VIIC).
 
     In another embodiment, provided herein a process for preparing a compound of Formula (VIIA): 
                                
wherein C(R 20 ) 2  is C═O is prepared comprising contacting a compound of Formula (VIIIA)
 
                                
wherein L 1  is OH or another leaving group selected from halo, preferably chloro or bromo with a compound of Formula (IX):
 
                                
under amide formation conditions to prepare the compound of Formula (VIIIA); or wherein the compound of Formula (VIIB):
 
                                
wherein C(R 20 ) 2  is C═O is prepared comprising contacting a compound of Formula (VIIIB)
 
                                
wherein L 1  is OH or another leaving group selected from halo, preferably chloro or bromo with a compound of Formula (IX):
 
                                
under amide formation conditions to prepare the compound of Formula (VIIB).
 
     In one aspect, provided herein is a process of preparing a compound of formula (IV): 
                                
wherein C(R 20 ) 2  is CH 2  is prepared comprising contacting a compound of Formula (VIIIC):
 
                                
wherein L 1  is a leaving group with a compound of Formula (IX):
 
                                
under nucleophilic substitution conditions to prepare the compound of Formula (IV); or
 
wherein the compound of Formula (VIIC):
 
                                
wherein C(R 20 ) 2  is CH 2  is prepared comprising contacting a compound of Formula (VIIID)
 
                                
wherein L 1  is a leaving group with a compound of Formula (IX):
 
                                
under nucleophilic substitution conditions to prepare the compound of Formula (VIIC).
 
Halogenation
 
     In one aspect, provided herein is a process of preparing a compound of formula (IV): 
                                
wherein X 10  is halo is prepared comprising contacting a compound of Formula (VIIA):
 
                                
with a halogenating agent under conditions suitable for halogenation to provide the compound of Formula (IVA), or
 
     wherein the compound of Formula (VA) 
                                
wherein X 10  is halo is prepared comprising contacting a compound of Formula (VIIB):
 
                                
with a halogenating agent under conditions suitable for halogenation to provide the compound of formula (VA).
 
     As will be apparent to the skilled artisan, amides prepared as above can be reduced to the corresponding-CH 2 —N&lt; compounds by reacting with borohydrides or aluminum hydrides under reducing conditions. 
     Hydrogenation 
     In one aspect, provided herein is a method of subjecting a compound of formula: 
                                
under hydrogenation condition to provide a compound of formula:
 
                                
respectively.
 
Nenitzescu Reaction
 
     In another aspect, provided here is a method of making a compound of formula: 
                                
such as:
 
                                
wherein R 10  is defined as in any embodiment herein, k is 0, 1, or 2, L 20  is a leaving group, preferably tosyl, mesyl, or another sulfonate, and P is a nitrogen protecting group, preferably, benzyl, comprising contacting a compound of formula:
 
                                
such as
 
                                
where each R 25  independently is C 1 -C 6  alkyl or C 6 -C 10  aryl, preferably phenyl, with a compound of formula:
 
                                
under Nenitzescu indole formation condition to provide a compound of formula:
 
                                
In one embodiment, the compound provided is of formula:
 
                                
The protected alpha, beta unsaturated keto amine is reacted at a slight to about 2 fold molar excess of the quinone. Lewis acid catalysts may be employed optionally.
 
Other non limiting methods and intermediated are shown below:
 
     Illustrative Nenitzescu and Fischer Indole Syntheses 
     
       
                 
         
             
             
         
      
     
     In one embodiment, C(R 20 ) 2  is CH 2 . In another embodiment, C(R 20 ) 2  is C═O. A compound hereinabove, wherein C(R 20 ) 2  is C═O can be converted to one wherein C(R 20 ) 2  is CH 2  upon contacting with a reducing agent under reduction conditions. 
     In one embodiment, R 110  is benzyl or a substituted benzyl group that is deprotected to provide a compound with R 110  being hydrogen upon hydrogenation. 
     In one embodiment, X10 is halo. 
     In one embodiment, R 4 , R 5 , R 20 , and R 30  are hydrogen. 
     In another embodiment, R 50  is NR 51 . In one embodiment, R 50  is NH. In another embodiment, R 50  is O. 
     In another embodiment, CR 2 R 3  is ═CHMe. 
     In another embodiment, k is 0. In another embodiment, k is 0 and preferably, the phenyl ring is substituted with the —O—R 110  group. In another embodiment, R 110  is C 1 -C 6  alkyl optionally substituted with 1-3 substituents selected from phenyl optionally substituted with 1-3 substituents selected from the group consisting of C 1 -C 6  alkyl and C 1 -C 6  alkoxy. 
     Starting materials useful for preparing the compounds and in the processes provided herein are well known in the art and available commercially, for example, from Sigma-Aldrich Co. The reactions are carried out under suitable conditions to effect reaction completion. Typically, the reaction is carried out in an inert solvent for a period of time sufficient to provide a substantial amount of the product, which can be ascertained by using routine methods such as thin layer chromatography,  1 H-nuclear magnetic resonance (NMR) spectroscopy, and the likes. As the skilled artisan will know or can ascertain based on this disclosure, certain reactions can be heated. As the skilled artisan will also understand, certain functionalities may have to be protected with protecting groups during one or more preparative steps and eventually deprotected. The product can be isolated and optionally purified using standard purification techniques, such as liquid chromatography, crystallization, and precipitation, or the products may be used for a subsequent reaction without further purification. Procedures useful in this invention is disclosed in PCT patent application publication nos. WO 2013/112757 and WO 2013/112622, which can be adapted in view of this disclosure to prepare compounds and in methods provided herein. 
     EXAMPLES 
     Certain illustrative and non-limiting processes of synthesizing certain compounds provided herein are schematically disclosed below. 
     Example 1 
     
       
                 
         
             
             
         
      
     
     In addition to the selective approach, compound 4 can be made as a racemic mixture (by the alternative route). It is contemplated that the enantiomers of compound 4 can be separated via diastereomeric salt formation through the nitrogen atom or chiral high-performance column chromatography (HPLC), as would be well known to the skilled artisan. 
     Example 2 
     
       
                 
         
             
             
         
      
     
     Example 3 
     Nucleophilic Substitution 
     
       
                 
         
             
             
         
      
     
     Example 4 
     Nenitzescu Variation