Diels-Alder approach, enediynes

Scheme 7-45 An intramolecular Diels-Alder approach to the esperamicin enediyne core (Schreiber and co-workers).

Schreiber et al. have been able to apply their enediyne intramolecular Diels-Alder approach to the synthesis of dynemicin model systems [268-270], culminating in the total synthesis of di- and tri-O-methyl dynemicin A methyl esters 388 and 389 (Scheme 7-78) [271], derivatives of the natural product itself. Highlights of this synthetic approach include (a) intramolecular lactonization and concomitant Diels-Alder cyclization (380- 381) (b) allylic hydroxylation followed by an allylic diazene rearrangement in order to regiospecifically isomerize a double bond (381 - 382) (c) a-hydroxylation of the lactone 381 and subsequent conversion to the P-ketoester 383 (d) annelation of the anthraquinone unit (383- 384- 385- 386) (e) mild base-induced P-elimination of the N-protecting group of 386 to give the free amine 387 and (f) a final oxidation to complete the anthraquinone (387 - 388). 

Estrones An A —> BCD approach to estrones involves a cobalt-catalyzed intramolecular [2 + 2 + 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 Diels-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 isomerized easily to the diene 3. 

An alternative approach to the bicyclic enediyne core of esperamicin utilizing an intramolecular Diels-Alder reaction was reported by Schreiber and co-workers (Scheme 7-45) [195-197]. This approach was initially hampered by an unfavorable regiochemical outcome in the Diels-Alder reaction (195 - 196), but was successfully corrected by a clever maneuver involving a Tsuchihashi pinacol rearrangement [198, 199] with concomitant diastereoselective acyloin shift to secure the desired bicyclic ring skeleton (197 - 198 - 199). 

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