Formation of 3-Aminophenols from Cyclohexane-1,3-diones.

meta-Aminophenols are formed by the action of DBU on 3-amino-2-chlorocyclohex-2-en-1-ones at room temperature in MeCN. The chloro compounds are generated by treating 3-aminocyclohex-2-en-1-ones with the easily prepared halogenating agent BnNMe3·ICl2 in MeOH-CH2Cl2. The amino group must carry two substituents, either two aryl, one aryl and one alkyl, or two alkyl groups; 3-aminocyclohex-2-en-1-ones of this type are readily made from cyclohex-2-en-1-one and a primary or secondary amine.

Formation of Enol Ethers by Radical Decarboxylation of α-Alkoxy ß-Phenylthio Acids.

Enol ethers are formed by radical decarboxylation of α-alkoxy ß-phenylthio acids via the corresponding Barton esters. The phenylthio acids were usually made by the known regioselective reaction of α,ß-epoxy acids with PhSH in the presence of InCl3, followed by O-alkylation of the resulting alcohol. In one case, thiol addition to an α,ß-unsaturated ethoxymethyl ester was used.

Formation of meta-Substituted Phenols by Transition Metal-Free Aromatization: Use of 2-Bromocyclohex-2-en-1-ones.

Addition of Grignard or other organometallic reagents to 2-halocyclohex-2-en-1-ones bearing an alkyl or aryl group at C-5, followed by mild acid treatment and exposure to 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) at room temperature, generates meta-substituted phenols in which the newly introduced meta substituent originates from the Grignard reagent. The range of effective organometallic reagents includes alkyl, allyl, alkynyl, aryl, and heteroaryl compounds including those with fluorine substituents. The initial halocyclohexenone can be deprotonated at C-6 and reacted with carbon, fluorine, or sulfur electrophiles before the Grignard addition so as to generate highly substituted phenols.

Conversion of cycloalk-2-enones into 2-methylcycloalkane-1,3-diones--assessment of various Tamao-Fleming procedures and mechanistic insight into the use of the Me3SiMe2Si unit.

Conjugate addition of Me3SiMe2SiLi to cycloalk-2-en-1-ones, ketalization, Tamao-Fleming oxidation (Bu4NF, then H2O2, KHCO3), TPAP oxidation and acid hydrolysis generates 2-methyl cycloalkane-1,3-diones. Ketalization is needed in order to prevent addition of Me3Si(-) to the carbonyl. The pentamethyldisilanyl group has advantages over other silicon units that are used in Tamao-Fleming procedures.

A Family of Routes to Substituted Phenols, Including Meta-Substituted Phenols.

A new family of routes to substituted phenols has been developed. 2-Bromo-3-methoxycyclohex-2-en-1-ones are readily deprotonated at C-6, and the resulting anions react smoothly with a variety of electrophiles; treatment with DBU in PhMe at room temperature then results in efficient aromatization to benzene derivatives of a regiochemically defined substitution pattern. This sequence affords phenolic azides (ArN3), sulfides (ArSR, ArSAr'), selenides (ArSePh), alcohols [ArCH(OH)R], amino derivatives [ArCH(NHSO2Ar')R), and 1,2-benzenediols. A complementary set of substitution patterns is obtained by DIBAL-H reduction or reaction with a Grignard reagent before aromatization; the latter process gives compounds in which the newly introduced substituent is meta to the phenolic hydroxyl.

Synthesis of (+)-Ipalbidine Based on 6-exo-trig Radical Cyclization of a ß-Amino Radical.

N-Boc (S)-proline was converted into (2S)-2-[(phenylselanyl)methyl]pyrrolidine, which was alkylated on nitrogen with 2-bromo-1-(4-methoxyphenyl)ethan-1-one. Reaction with vinyllithium, 6-exo-trig radical cyclization (Bu3SnH, AIBN, PhMe, 110 °C), dehydration (P2O5, H3PO4), and demethylation (BBr3) gave (+)-ipalbidine with ee >99%.

Synthesis of substituted resorcinol monomethyl ethers from 2-bromo-3-methoxycyclohex-2-en-1-ones.

2-Bromo-3-methoxycyclohex-2-en-1-ones are readily alkylated at C-6 with reactive halides, and then treatment with DBU (2 equiv) in PhMe at room temperature results in smooth loss of bromide and aromatization to resorcinol monomethyl ethers of defined substitution pattern.

Synthetic studies on CP-225,917 and CP-263,114: access to advanced tetracyclic systems by intramolecular conjugate displacement and [2,3]-Wittig rearrangement.

An advanced intermediate related to the structures of CP-225,917 and CP-263,114 was constructed by a sequence based on the use of Grob-like fragmentation, intramolecular conjugate displacement, and [2,3]-Wittig rearrangement. A variant of the [2,3]-Wittig rearrangement was developed.

A general route to 1,3'-bipyrroles.

A general method is described for the synthesis of 1,3'-bipyrroles. The route involves constructing a pyrrole ring on the nitrogen of a substituted 1H-pyrrole, so as to generate the 1,3'-bipyrrole. In this approach the nitrogen of the starting pyrrole was alkylated with a special Michael acceptor having an allylic leaving group, and the product was then modified in such a way that the second pyrrole ring could be formed by a Paal-Knorr reaction. Two variants of this sequence were examined, one of which led to formation of a 3-hydroxypyridine instead of the second pyrrole ring; the other variant used phenacyl bromide instead of the special Michael acceptor.

Asymmetric synthesis of carbocycles: use of intramolecular conjugate displacement.

Intramolecular conjugate displacement (ICD), the process illustrated in , has been applied to the Morita-Baylis-Hillman adducts formed from (5S)-5-(l-menthyloxy)-2(5H)-furanone and aldehydes that are substituted in the γ- or δ-position by geminal phenylthio groups. When the initial Morita-Baylis-Hillman alcohols are acetylated and oxidized to geminal sulfones, deprotonation causes ring closure by ICD (2.5→2.6). Hydrogenation, DIBAL-H reduction and desulfonylation releases an optically pure carbocycle.

Formation of optically pure cyclic amines by intramolecular conjugate displacement.

Intramolecular conjugate displacement (ICD) has been applied to the Morita-Baylis-Hillman adducts formed from (5S)-5-(l-menthyloxy)-2(5H)-furanone and aldehydes that carry a protected ß- or γ-amino group. DIBAL-H reduction of the resulting ICD products releases optically pure six- or seven-membered cyclic amines having a stereogenic center α to nitrogen.

A Dieckmann cyclization route to piperazine-2,5-diones.

Piperazine-2,5-diones are formed by Dieckmann cyclization (NaH, THF) of substructures of the type CH(2)-N(R)C(O)CH(2)N(R')CO(2)Ph in which the terminal methylene (CH(2)) that is adjacent to nitrogen closes onto the carbonyl group of the phenyl carbamate unit at the other end of the chain. R and R' are alkyl groups, and the terminal methylene is activated by a ketone carbonyl, a nitrile, an ester, or a phosphoryl group. The starting materials are assembled by standard acylation and oxidation processes, starting from a ß-(alkylamino)alcohol, an (alkylamino)acetonitrile, an (alkylamino) ester, or an (alkylamino)methyl phosphonate.

Formation of unusual seven-membered heterocycles incorporating nitrogen and sulfur by intramolecular conjugate displacement.

Baylis-Hillman alcohols derived from methyl acrylate or acrylonitrile and carrying an N-Boc group ß to the hydroxyl (CH(OH)CHNBoc) can be converted into unusual seven-membered heterocycles containing both nitrogen and sulfur by O-acylation (AcCl or EtOCOCl), N-deprotection (CF(3)CO(2)H), and reaction with CS(2). In a modification of this process, when the original nitrogen is substituted in the form PhSCH(2)CON(Me), an azepine derivative is then generated. The ring closures occur by intramolecular conjugate displacement.

2,6-Disubstituted and 2,2,6-trisubstituted piperidines from serine: asymmetric synthesis and further elaboration.

4-Hydroxy-3,4-dihydro-2H-pyridine-1-carboxylic acid benzyl esters, which are readily prepared from serine and terminal acetylenes, undergo Claisen rearrangement to piperidine derivatives when heated with butyl vinyl ether in the presence of Hg(OAc)(2) and Et(3)N. This route to optically pure piperidines having substituents alpha to nitrogen is general, and the rearrangement products are versatile intermediates for making a broad range of amines containing a substituted piperidine subunit.

Conversion of 1,4-diketones into para-disubstituted benzenes.

Reaction of acetylides with aldehydes to form but-2-yne-1,4-diols, followed by triple bond reduction and oxidation of the hydroxyl groups, gives 1,4-diketones; these react with vinyllithium, and the resulting diols undergo ring-closing metathesis to form 2-cyclohexene-1,4-diols. Dehydration, usually by acid treatment, then gives benzenes carrying substituents in a 1,4 relationship. Use of substituted vinyllithiums provides further substitution on the final benzene rings. The method can be applied to the synthesis of C5-aryl carbohydrates.

Formation of carbocycles by intramolecular conjugate displacement: scope and mechanistic insights.

A detailed study has been made of a method of ring closure categorized as an all-carbon intramolecular conjugate displacement (ICD). This reaction involves intramolecular addition of a carbanion, which is stabilized by at least one electron-withdrawing group, to a Michael acceptor which has a leaving group in an allylic position. The process formally resembles a combination of Michael addition and S(N)2' displacement. The overall result is formation of a ring with loss of the allylic leaving group and shift of the original double bond to a new location spanning the positions of the electron-withdrawing substituent of the Michael acceptor subunit and the original allylic leaving group. The starting materials are easily prepared by a selenium-based version of the Morita-Baylis-Hillman reaction. The cyclizations are transition metal free and occur under mild conditions, using DBU or Cs(2)CO(3) in MeCN or THF. Acetate is a suitable leaving group and the electron-withdrawing substituent of the Michael acceptor unit can be CO(2)R, SO(2)Ph, or CN. Six- and seven-membered rings are formed efficiently, and complex structures, such as those resembling the core of CP-225,917, are easily assembled. The products of these ICD reactions are themselves classical Michael acceptors. A range of mechanisms probably operates, depending on the structure of the starting material and the reaction conditions, but conclusive evidence for a stepwise mechanism was obtained in a suitably biased case, while other observations are compatible with a concerted process or a stepwise path involving a short-lived carbanion that evades capture by a proton source.

Asymmetric synthesis of the ABC-ring system of the antitumor antibiotic MPC1001.

trans-4-Hydroxy-L-proline was converted into a tricyclic compound representing three contiguous rings of the anticancer antibiotic MPC1001. The tricyclic model contains the dihydrooxepin and diketopiperazine subunits, as well as one of the sulfur atoms of the natural product. The diketopiperazine unit was formed by a new method that involves cyclization of an enolate onto the carbonyl of a phenyl carbamate, and the dihydrooxepin ring was generated by using an acid-induced cyclization of an alcohol onto the beta-carbon of a vinylogous amide.

Conversion of Weinreb amides into benzene rings incorporating the amide carbonyl carbon.

Esters, acids and acid chlorides can be converted via the intermediacy of their corresponding Weinreb amides into benzene derivatives that incorporate the original carbonyl carbon as part of the benzene ring. The process involves treatment of the derived Weinreb amides with 3-butenylmagnesium bromide and an allylic Grignard reagent, followed by ring-closing metathesis, dehydration and dehydrogenation. The dehydration-dehydrogenation can be done under acidic conditions with a mixture of TsOH x H(2)O and DDQ or in two steps with SOCl(2)/pyridine, followed by treatment with DDQ. Application of the method to carbohydrates provides a convenient route to C-5 aryl pyranosides.

Total synthesis of the marine alkaloid halichlorine: development and use of a general route to chiral piperidines.

The total synthesis of the marine alkaloid halichlorine is described, based on an approach that involves constructing the fully substituted asymmetric center at an early stage. The five-membered ring is formed by 5-exo-trig radical cyclization and the unsaturated six-membered ring by a process that formally represents a sequential combination of conjugate addition and S(N)2' displacement-a method that is general for making bicyclic compounds with nitrogen at a ring fusion position. A formal synthesis of (+)-halichlorine is also reported, based on the development of a general method for preparing optically pure piperidines. The key step of this method, which was used to make one of our intermediates, is the Claisen rearrangement of a 4-vinyloxy-3,4-dihydro-2H-pyridine-1-carboxylic acid benzyl ester. Such O-vinyl compounds are easily generated in situ from the corresponding alcohols, which are themselves readily assembled from serine and terminal acetylenes.

The coumarin-->indole transformation--a method for preparing 4-halo-5-hydroxyindoles from coumarins.

Readily accessible 3-alkoxycarbonyl-6-hydroxy-5-halocoumarins can be converted into 4-halo-5-hydroxyindoles by a sequence whose essential steps are conjugate reduction or conjugate addition, decarboxylation, lactone opening with ammonia, phenolic oxygen protection, Hofmann rearrangement to an N-Boc ethylamine, oxidation to a quinone and deprotection of the nitrogen. The resulting beta-aminoethyl quinone cyclizes to a mixture of quinone imine and indole, and the imine tautomerizes to the indole spontaneously or on treatment with rhodium on alumina.