Wound healing properties of plant extracts that contain the naphthoquinone natural products alkannin (1) and shikonin (2) have been known for many centuries. More recently, the biological properties of 1, 2, and related derivatives have been demonstrated experimentally, and their production both by cell cultures and chemical synthesis has been studied extensively.
Taxol, a substance originally isolated from the Pacific yew tree (Taxus brevifolia) more than two decades ago, has recently been approved for the clinical treatment of cancer patients. Hailed as having provided one of the most significant advances in cancer therapy, this molecule exerts its anticancer activity by inhibiting mitosis through enhancement of the polymerization of tubulin and consequent stabilization of microtubules. The scarcity of taxol and the ecological impact of harvesting it have prompted extension searches for alternative sources including semisynthesis, cellular culture production and chemical synthesis. The latter has been attempted for almost two decades, but these attempts have been thwarted by the magnitude of the synthetic challenge. Here we report the total synthesis of taxol by a convergent strategy, which opens a chemical pathway for the production of both the natural product itself and a variety of designed taxoids.
The bisorbicillinoids are a growing class of novel natural products endowed with unique biological
activity and are associated with fascinating hypotheses for their biosynthesis. A full account of our biomimetic
explorations toward the bisorbicillinoids including the total syntheses of bisorbicillinol (1), bisorbibutenolide
(2), and trichodimerol (4) from sorbicillin (3) is disclosed. Utilizing the novel dimerization reactions discovered
and fine-tuned en route to 1 and 4, several analogues of these natural products have been synthesized.
Furthermore, studies on the scope of these novel cycloaddition reactions and the isolation of a number of
unexpected products along with proposed mechanisms for their formation are reported. These findings add to
our knowledge of the largely unexplored chemistry of o-quinols and related aromatic systems.
The structural variety of naturally occurring diaryl ethers is illustrated and the various synthetic methods employed for the construction of diaryl ether linkages in related total syntheses are reviewed. Examples of successful applications of each method (including reaction conditions, diaryl ether substitution pattern, and, when appropriate, the size of the ring formed) are given in tabular format.
A successful strategy for the enantioselective synthesis of the natural stereoisomer of Taxol (1) has been developed. This strategy utilized the convergent assembly of Taxol's central eight-membered B ring from preformed synthons for rings A (10) and C (9) followed by late introduction of the D ring and side chain. Degradative studies confiied the viability of certain crucial manipulations including oxidation of the C13 position (35 -3) and regioselective introduction of the C I-hydroxyl, CZbenzoyloxy moiety (29 -31). Additionally, a convenient method for the large-scale production of 29, a derivative useful for C2 analog production, was developed.
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