Intramolecular enediynes

A similar methodology offers an alternative access to the (+)-estrone skeleton (vide supra). In this case the C-ring is built up via intramolecular enediyne cyclization47,54 5fi. The same method can be applied to other steroidal skeletons3. 

The cyclization of the enediynes 110 in AcOH gives the cyclohexadiene derivative 114. The reaction starts by the insertion of the triple bond into Pd—H to give 111, followed by tandem insertion of the triple bond and two double bonds to yield the triene system 113, which is cyclized to give the cyclohexadiene system 114. Another possibility is the direct formation of 114 from 112 by endo-rype. insertion of an exo-methylene double bond[53]. The appropriately structured triyne 115 undergoes Pd-catalyzed cyclization to form an aromatic ring 116 in boiling MeCN, by repeating the intramolecular insertion three times. In this cyclization too, addition of AcOH (5 mol%) is essential to start the reaction[54]. 

Scheme 20. The intramolecular carbonyl addition reaction used by Danishefsky and coworkers to construct a 10-membered ring enediyne system.

Bicyclic cis- and frans-isoxazolidinyldiynes have been prepared by intramolecular nitrone cycloaddition of the two side chains of an acyclic enediyne-nitrone precursor (Scheme 2.233) (731). 

Rhodium carbonyl complexes also catalyze the cascade cyclization/hydrosilylation of 6-dodecene-l,l 1-diynes to form silylated tethered 2,2 -dimethylenebicyclopentanes. For example, reaction of ( )-85 with dimethylphenylsilane catalyzed by Rh(acac)(CO)2 in toluene at 50 °G under GO (1 atm) gave 86a in 55% yield as a single diastereomer (Equation (56)). Rhodium-catalyzed caseade cyclization/hydrosilylation of enediynes was stereospecific, and reaction of (Z)-85 under the conditions noted above gave 86b in 50% yield as a single diastereomer (Equation (57)). Rhodium(i)-catalyzed cascade cyclization/hydrosilylation of 6-dodecene-1,11-diynes was proposed to occur via silyl-metallation of one of the terminal G=G bonds of the enediyne with a silyl-Rh(iii) hydride complex, followed by two sequential intramolecular carbometallations and G-H reductive elimination. ... 

Intramolecular [2 + 2 + 2] cycloadditions belong to the same type of valence isomerization as those of 1,5-unsaturated compounds to cyclobutanes.70 The cobalt-mediated cyclization of l-en-5-ynes stereoselectively converts enediynes directly to bicyclo[4.2.0]hexa-l,3-dienes, as single diastereomers, when a stoichiometric amount of dicarbonyl(cyclopentadienyl)cobalt is used. This cyclization90 has a high efficiency (92%). An example is the synthesis of the protoilludane framework 23 from the enediyne precursor 22.71... 

A synthetic route to p-lactam-fused enediynes by intramolecular Kinugasa reaction has been successfully developed. The method has widened the scope of the Kinugasa reaction in the synthesis of sensitive systems like tricycle 193 (Scheme 69) [100]. 

Intramolecular transamidation in (3-lactam enediynes can induce concomitant Bergman type cycloaromatization. For instance, Scheme 67, amine 239, which can be stored as its hydrochloride salt in the freezer, reacts in THF at reflux in the presence of cyclohexadiene as a hydrogen donor to produce only trace amounts of the expanded lactam 240 along with aromatic compound 241 as the major compound [173]. 

Kinetic and DFT studies have found that the rapid cycloaromatization of 2,3-diethynyl-l-methoxybenzene compared with 1,2-diethynylbenzene can be attributed to intramolecular hydrogen abstraction by the p-bcnzyne diradical intermediate from the OMe substituent. This has been shown to render the cyclization effectively irreversible by leading to a more stable diradical, and may have significant implications for the action of therapeutic enediynes.57 In general, the Bergman cycloaromatizations of 1-substituted 2,3-diethynylbenzenes have been found to be highly sensitive to the nature of the ortho-substituent, but the measurements and even the relative trends... 

Intramolecular Lewis acid-promoted reaction of coordinated propargylic ether with the silyl enol ether in 158 has been applied successfully to the construction of the highly strained 10-membered cyclic enediyne system 159, present in esperamycin and calicheamycin [39,40]. The enediyne system 157 was prepared by the Pd-catalysed Sonogashira coupling of (Z)-l,2-dichloroethylene (154) with two different terminal alkynes 155 and 156. 

Intramolecular 2 + 2 + 2-cycloisomerizations of cyclic triynes and enediynes have been reported with RhCl(CO)(PPh3)2.126 The transition metal-catalysed rearrangement of alk-5-ynals to /-alkynyl ketones and cyclopent-l-enyl ketones was developed using [Rh(P(OPh)3)2]BF4 or Cu(OTf)2 as a catalyst and the effect of substituents on the partition to products was elaborated (Scheme 84).127... 

Nozaki reaction (12, 137 14, 96 15, 95). An intramolecular version of this reaction can effect cyclization even to a strained nine-membered ring. Thus 1 on treatment with CrCl2 at a low temperature cyclizes mainly to 2, a mixture of epimers in which a cyclononadiyne ring is fused to a cyclopentene ring. After acetylation of the secondary hydroxyl group, the mixture is dehydrated to 3, with a nine-membered enediyne ring. 

Cyclization of the enediynes 221 (X = 0 and CH2) in DMF were brought about by potassium carbonate and potassium iodide. The thermal stability of the cyclized products 222 (X = 0 and CH2) was evident and the occurrence of a radical intramolecular cyclization process at higher temperatures was shown <1996CG749>. 

Fiirstner and co-workers have demonstrated the utility of the PtCl2-catalyzed carboalkoxylation of protected o-alkynyl phenols in the synthesis of the pterocarpene nucleus of erypoegin H <2007AGE4760>. Naphthalene fused 2,3-dihydrofurans have been shown to be available through a Pt- and Ru-catalyzed aromatization of enediynes with concomitant intramolecular nucleophilic additions <2007S2050>. 

Estrones. An A —> BCD approach to estrones involves a cobalt catalyzed intramolecular 2 + 2 -y 2] cycloaddition of the enediyne 1 to form the B, C. and D rings in one step. The high stereoselectivity suggests that the cyclization involves a Dicls-Alder-type reaction of the vinyl group with a cobaltacyclopentadiene formed by coupling of the two alkyne units. The homoannular diene obtained on demetalation is isomcrized easily to the diene 3. 

The next three reactions (Scheme 3.38), cotrimerization of enediyne 146 with bis(trimethylsilyl)acetylene 150, thermolysis of the benzocyclobutene derivative 151, and the intramolecular Diels-Alder reaction of the intermediate 152, were... 

Intramolecular cyclohexadiene syntheses have been developed by Vollhardt [74], Enediynes with a terminal double bond react in isooctane at 100 °C in the presence of -Cp-cobalt dicarbonyl giving a three-ring system [75] according to eq. (26). 

With an appropriate precursor C-ring, dienyl steroids have been made accessible in a remarkably highly stereoselective process [77]. Intramolecular cycloaddition reactions of enediynes containing a terminal alkyne group have also been observed by Vollhardt [78] (eq. (27)). 

While obviously natural enediynes 2-4 behave in the same way, in dynemicin the cascade of events is different. However, this molecule also displays a delivery unit (the anthraquinone), a safety catch (the epoxide) and a trigger (the quinone). Bioreduction of the quinone unleashes two lone pairs (one on the nitrogen and one on the upper hydroquinone oxygen) which bring about intramolecular epoxide opening. ... 

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