Synthetic and mechanistic studies on the antitumor antibiotics esperamicin A1 and calicheamicin .gamma.1: synthesis of 2-ketobicyclo[7.3.1.]enediyne and 13-ketocyclo[7.3.1]enediyne cores mediated by .eta.2]dicobalt hexacarbonyl alkyne complexes. Cycloaromatization rate studies

Abstract

M«0'^S^V'NH 'o chemists can play a leading role here. From their experiences in probing reaction mechanisms in vitro they can postulate likely intermediate metabolites and design experiments to follow the reaction sequences of drugs".2The majority of antitumor antibiotics inhibit cell division by interfering with the synthesis or use of nucleic acids.3 There is a constant need to discover new agents that interact with DNA in a mechanistically definable manner.4 In 1987 the Lederle5 and Bristol-Myers6 groups reported the unprecedented structures of calicheamicin 7i (1), esperamicin A, (2), Alb (3), and A2 (4), and the metabolite esperamicin X (5) (Chart I). They were isolated from fermentations of Micromonospora echinospora sp. calichensis and cultures of Actinomadura verrucosospora BBM 1675 and ATCC 39334, respectively. At present, these compounds are the most potent antitumor antibiotics known, being approximately 103 more active than adriamycin against murine tumors, and represent a new class of natural products based upon the Z-enediyne functionality.While they contain a number of unusual structural features such as the allylic trisulfide, a hydroxylamino sugar, and a Q-Q bridgehead double bond, it is the Z-enediyne that embues these molecules with a unique mechanism for cleaving DNA. It was proposed5'6 that the trisulfide is cleaved by nucleophilic attack at the central sulfur atom to give the thiol (or thiolate) 7, which can conjugatively add to Q to give the dihydrothiophene derivative(2) Ferguson, L. N. Chem. Soc. Rev. 1975, 4, 289.

Efficient and Accurate Characterization of the Bergman Cyclization for Several Enediynes Including an Expanded Substructure of Esperamicin A1

“…Magnus et al . found that the strain increased by 1.5 kcal·mol −1 (MM2/PRDDO) in moving from R to TS for 13 , but that strain was relieved by 6.0 kcal·mol −1 for the six-membered ring compound 12 74,120. This release is attributed to a boat-chair strain release mechanism available to the 6-membered ring, but not the 5-membered ring.…”

“…Calculation of strain relief using molecular mechanics allowed Magnus et al . to rationalize the rates of reaction as stemming more from strain relief than the separation of the acetylenic carbons 74,120. For the 6-membered ring in 12 , a boat to chair conversion in moving to products released more strain than was alleviated in the 5-membered case.…”

Geometric and Electronic Control of Thermal Bergman Cyclization

“…These considerations are especially important for bicyclic enediynes, or those possessing bulky substituents at the alkyne termini positions. To this end, Magnus used MM2 force-field calculations to explain the reactivities of a series of bicyclic enediynes, 66 and Maier subsequently developed an improved model to calculate the difference in strain energies between reactants and products in order to accurately predict enediyne …”

Unique Metal‐Diyne, ‐Enyne, and ‐Enediyne Complexes: Part of the Remarkably Diverse World of Metal‐Alkyne Chemistry

“…The first step is the copper-catalyzed addition of a,o-diynes to manganese carbyne complexes to give an intermediate bis(alkynylcarbene) species that rearranges to an enediyne unit below room temperature. In the second step, the manganese catalyst, which Magnus has been used effectively as an alkyne protecting-stabilizing group in natural product syntheses (378)(379)(380)(381)(382)(383), is released from the enediyne by photolysis, copper-catalyzed air oxidation, or stoichiometric Cu(II) oxidation. These new procedures have been applied to a variety of five-, six-, and seven-membered ring cyclic enediynes containing a range of ether, ester, and ketone functional groups (Scheme 31).…”