Macrocyclic enone

Tanaka et al. (152) demonstrated that a chiral copper alkoxide could be used substoichiometrically to deliver MeLi to an enone in conjugate fashion. The precatalyst is formed from amino alcohol 221, MeLi and Cul, Eq. 123a. Under stoichiometric conditions, this catalyst mediates the conjugate addition of MeLi to the macrocyclic enone, affording muscone in 91% ee. Lower enantioselectivity is observed using a substoichiometric amount of 222 (0.5 equiv), affording a 79% yield of muscone in 76% ee, Eq. 123b. These selectivities are attained by portion-wise addition of the substrate and MeLi to the alkoxy-cuprate. This catalyst also exhibits a complex nonlinear effect (78, 153). 

Termite soldiers produce a large number of different chemical defense agents. Several of these molecules are unusual bioactive terpenoids such as the secotrinervitanes that have been isolated and their structure elucidated. In the laboratory of T. Kato, the total synthesis of (+)-3a-acetoxy-7,16-secotrinervita-7,11-dien-15P-ol was accomplished. The Nagata hydrocyanation was used to introduce a carbon at the P-position of a macrocyclic enone intermediate. The substrate was treated with excess diethylaluminum cyanide in dry toluene and the addition resulted in the formation of a 1 1 mixture of diastereomers, which could be readily separated by column chromatography. The cyano group was later converted to the corresponding methyl ester. 

Muscone (40) is a sex pheromone of the musk deer and a chemical component of cosmetics. A 12-member library of racemic muscone analogs was synthesized by Nicolaou et al.," who anployed a cyclorelease method on solid support to form the macrocycle scaffold (Figure 11.17). A phosphonate-functionalized resin loaded on encoded SMART microreactors 36 was coupled to olelinic esters 35 to form the p-ketophosphonates 37. Sorting and cross olefin metathesis of 37 with two alkenols followed by oxidation with Dess-Martin reagent gave aldehydes 38. An intramolecular ketophosphonate-aldehyde condensation (Homer-Emmons-Wadsworth reaction) of 38 caused smooth cyclorelease of macrocyclic enones 39. Parallel solution-phase chemistry completed the sequence. 

The intramolecular version for synthesizing cyclic and polycyclic compounds offers a powerful synthetic method for naturally occurring macrocyclic and polycyclic compounds, and novel total syntheses of many naturally occurring complex molecules have been achieved by synthetic designs based on this methodology. Cyclization by the coupling of an enone and alkenyl iodide has been applied to the synthesis of a model compound of l6-membered car-bomycin B 162 in 55% yield. A stoichiometric amount of the catalyst was used because the reaction was carried out under high dilution conditions[132]. 

Mesylation of the alcohol 65 followed by deprotonation afforded the sul-fone-stabilized carbanion 66 that underwent a macrocyclization to afford the artificial dolabellane 67 in moderate yield (Scheme 9). Hydrolytic cleavage of the ketal (67) followed by a base-mediated double bond isomerization (into conjugation) afforded an enone containing an exocyclic carbonyl group. Nucleophilic 1,2-addition of methyl lithium introduced the missing... 

Isoxazolines can be transformed into a,p-enones by several methods from the initial aldol product. This strategy was applied by Barco et al. (285) toward the synthesis of (—)-pyrenophorin (98), a macrocyclic 6 (enone-lactone) with antifungal properties. The hydroxy group was introduced from the nitrile oxide component (95), while the carboxy function was derived from the acrylate dipo-larophile. Thus, cycloaddition of the optically active nitropentyl acetate 94 to methyl acrylate 95 afforded isoxazoline 96 as a mixture of optically active diastereomers. Reductive hydrolysis using Raney nickel/acetic acid gave p-hydro-xyketone (97), which was subsequently utilized for the synthesis of (—)-pyreno-phorin (98) (Scheme 6.63) (285). 

The chiral organocopper compound (186) adds diastereoselectively to 2-methyl-2-cyclopentenone, allowing the preparation of optically active steroid CD-ring building blocks (Scheme 68).202-204 A related method was applied to a synthesis of the steroid skeleton via an intramolecular (transannular) Diels-Alder reaction of a macrocyclic precursor.203 Chiral acetone anion equivalents based on copper azaeno-lates derived from acetone imines were shown to add to cyclic enones with good selectivity (60-80% ee, after hydrolysis).206-208 Even better ee values are obtained with the mixed zincate prepared from (187) and dimethylzinc (Scheme 69). Other highly diastereoselective but synthetically less important 1,4-additions of chiral cuprates to prochiral enones were reported.209-210... 

Michael reaction of macrocyclic ketene silyl acetals or a-enones occurs smoothly under electron-transfer conditions whereas the reaction of 6-membered analogs is more sluggish, indicating the importance of ring flexibility to enable the a,/8-carbon-carbon bonds of both reaction components to rotate when the radical species are generated [72c]. 

Monoprotonated diamines react with acetone or /3-enones, to form diamine-diimine macrocycle salts (20), with rings of up to [22]-members,32 with a variety of C-substituents33 (including 1,2-cyclohexdiyl (22), formed from trans-cyc 1 ohexane-1,2-diamine),34 or with X-substituents (Scheme 6)35 2 2... 

Many macrocycle syntheses yield products with alkyl or aryl C-substituents, or with fused 2,6-pyridiyl, o-phenylene, or 1,2-cyclohexdiyl rings. Template-style syntheses (see Section 1.20.3) are often substituent-sensitive, and yield products with particular substituent patterns. The (3-enone/ (diamineH+) method for preparing cyclic amines (Section 1.20.2) introduces a variety of substituents on the six-membered chelate rings of cyclam, but only 3-methyl and 3,10-dimethyl substituents on the five-membered rings. Cyclams with a variety of methyl and 1,2-cyclohexdiyl substituents on the five-membered chelate rings have been prepared and structurally characterized.71... 

The novel preparation of 5-cyano[n](2,4)pyridinophane-6-ones [n = 6 (5%), 7 (11%), 8 (63%), 9 (71%)] was conducted by allowing cyanoacetatoamide to react with cycloalk-2-enones <05OBC638>. Pd-Catalyzed amination of either 3,5-dibromo- or 3,5-dichloropyridine with linear polyamines led to the formation of a new family of pyridine-containing macrocycles (e.g. 6) possessing an exo -oriented pyridine iV-atoms <05HCA1983>. The treatment of 3,5-... 

Tsuji and coworkers have developed diisobutylaluminum phenoxide-pyridine as an effective aldol condensation catalyst and applied it to the macrocyclization of 2,15-hexadecanedione (equation 132). Addition of the diketone at high dilution to a solution of the catalyst in hexane provides a mixture of cis and trans isomers of the and A enones. Catalytic hydrogenation of the mixture affords ( )-muscone. The authors explain the regioselectivity of the process by assuming that the aluminum phenoxide functions as a Lewis acid, coordinating to the carbonyl group. Pyridine functions as a base to remove a proton from the less hindered methyl group. 

Other attempts to promote radical DA reactions were pursued, notably to open an entry into steroidal structures. An interesting case is the radical cyclization of ynone 153 in order to prepare tetracyclic ketone 155 through a 13-e rfo-dig macrocyclization-radical tandem transannular DA cascade. The unique resulting tetracyclic compound 158, displays a completely different structure with two contiguous quaternary sp carbons and two conjugated enone moieties (Scheme 42),... 

Phenyl ethers. Cs2(CO)3 has been used in the alkylation of phenols. Intramolecular Michael addition. Addition of a P-keto ester moiety to an enone to form a macrocycle (e.g., a 14-membered ring) using CSjiCOlj as the base is efficient. 

This idea is presented more formally in Scheme 5 with the thought that five of the six rings of the target molecule and seven of its stereocenters (as expressed in 34) could arise from a polyunsaturated precursor (30) through a series of two cycloaddition reactions and a macrocyclization event. For instance, if 30 initially participated in a Type I intramolecular Diels—Alder reaction with endo selectivity to afford 32, a subsequent intramolecular condensation of the Knoe-venagel type could then provide 33, a substrate poised for an intramolecular transannular hetero-Diels—Alder reaction between its electron-poor enone system and the proximal trisubstituted double... 

Macrocyclization has benefitted from a variety of approaches, of which intramolecular radical l,4-addition °, Pd-catalyzed diyne cy-cloisomerization and syntheses via sulfonium ylids and ketoketenes are notable. Tandem methodologies are also in vogue, one of which illustrates the theme of transient generation of a reactive enone function. For highly condensed systems, routes via transient formation of dipoles (cf. Synth. Meth. 44, 489) are fast developing as are serial radical approaches (example s. Synth. Meth. 44, 972). However, for a general overview of current cycliza-tion techniques a recent review is worthy of note. ... 

Reactions.—1,3-Dithianyl Anions. 1,3-Dithianyl anions continue to find wide-ranging utility in the synthesis of diverse structures, including 2-deoxy-L-lyxose derivatives, eburnamine precursors, " l,2-diformyl-6,6-dimethylcyclohex-2-en-l-ol, cannabinoids, tertiary acyloins, cyclitols, unsaturated carboxylic acids, the terpenes egomaketone and a- and jff-curcumene, (205)-20-hydroxycholesterol, norpyrenophorin, pyrenophorin, and vermiculine, compounds with chiral methyl groups, " (+)-rrans-burseran, enones, " the macrocyclic lactam A-methylmaysenine, olivin, macrocyclic acetylacetone crown ethers, [5.1]metacyclophane, ( )-laurencin, monosaccharides, y-keto-esters and their precursors, muscarine analogues, quinols, epi-... 

Thiophilic addition to dithioesters followed by capture of the thioacetal anion with an electrophile provides a useful approach to the formation of carbonyl compounds such as (42) and (43), and has been elegantly employed in the total synthesis of the macrocycles ( )-maysine and ( )-4,5-deoxymaysine. Trimethyl borate has been used to convert bis(phenylthio)methyl-lithium into the keten thioacetal (45) via the boron-containing carbanion (44), as shown in Scheme 4. Bis(phenylthio)methyl-lithium and related compounds are also the key reagents in the preparation of 2-(phenylthio)-enones, 2-(phenylthio)-butadienes, a-(phenyl-... 

In a paper discussing strategies for the synthesis of the macrocyclic diterpene jatrophone, brief comment is made disclosing that chromous sulphate can cleanly effect the stereospecific reduction of a-oxoacetylenes to the corresponding E-enone, analogous to the reduction of acetylenic alcohols." ... 

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