Naturally occurring enediyne antibiotics

In 2006 the preparation of simplified analogs of natural occurring enediynes, e.g. antitumor antibiotic dynemicin, was reported by Banfi and coworkers. They succeeded in synthesizing two different classes of such compounds where the embedded 10-membered enediyne system is fused either with a (3-lactam ring (lactenediynes) or with an epoxide. Biological tests on these molecules have demonstrated that some representatives are able to cleave the double strand of DNA even at very low concentrations [408]. 

Figure 7-1 Some naturally occurring enediyne antibiotics.

The coupling reaction has widespread use in the construction of enediyne systems present in naturally occurring anticancer antibiotics[234]. The Pd-Cul catalyzed coupling reaction of the alkenyl bromides 323 and 326 with the... 

The area of the chemistry of enediyne antibiotics is still very young. This field was only four years old when the first comprehensive review was published in 1991. As is stated in this review, rarely before has a newly discovered class of natural products created such stimulation and excitement in chemistry, biology, and medicine as the enediynes. Equally rare is the beauty and fascination associated with the molecular architecture and mode of action of these naturally occurring substances. The opportunities they offer for challenging and creative scientific endeavors may be overshadowed only by their potential therapeutic... 

There are only a few naturally occurring alkynes. Examples include capillin, which has fungicidal activity, and ichthyothereol, a convulsant used by the Amazon Indians for poisoned arrowheads. A class of naturally occurring compounds called enediynes has been found to have powerful antibiotic and anticancer properties. These compounds all have a nine- or ten-membered ring that contains two triple bonds separated by a double bond. Some enediynes are currently in clinical trials. 

Aryl iodides, bromides, and inflates are used for Sonogashira coupling. But so far few smooth reactions of aryl chlorides with alkynes have been reported. On the other hand, smooth coupling takes place with alkenyl chlorides. The Pd-catalyzed reaction of 1-alkynes with alkenyl chlorides, which are inert in many other Pd-catalyzed reactions, proceeds smoothly without special activation of the chlorides. For example, cw-l,2-dichloroethylene (31) can be coupled with 1-alkynes smoothly, and the coupling has wide synthetic applications, particularly for the synthesis of enediyne structures [30]. The reaction of 31 with two different 1-alkynes is extensively used for construction of highly strained enediyne structures present in naturally occurring anticancer antibiotics such as espermicin and calichemicin [31,32]. The asymmetric (Z)-enediyne 34 can be prepared by a one-pot reaction of 31 with two different 1-alkynes 32 and 33. Similarly the asymmetric ( )-enediyne 37 was obtained in a one-pot reaction of 1-alkynes 33 and 23 with 1,2-dichloroethylene 35. 

In spite of the fact that few cycloalkynes occur naturally, they gained recent attention when it was discovered that some of them hold promise as anticancer drugs. (See the boxed essay Natural and Designed Enediyne Antibiotics following this section.)... 

Z)-vinylic tellurides are the source of enynes 212 and enediynes 213 by transformation into vinylcopper species (Section 9.13.8.2.4), followed by reaction with haloalkynes (Scheme 113).278,279 The transformation occurs with retention of the double-bond stereochemistry. This is an efficient and straightforward route to important unsaturated units present in natural products, specially in enediyne antibiotics.280... 

---