Thursday, October 17, 2013

Baran's Total Synthesis of Racemic Steviol, the Aglycone of Stevia's Sweet Glycosides

A Steviol Glycoside.
          The prominent and detail-oriented 'Lydia' character from the AMC series 'Breaking Bad' was wont to partake of chamomile tea sweetened with a packet of 'Stevia' during cafe meetings. Walter White eventually took advantage of her fastidious nature to replace the single packet of Stevia on her table with his long ago-isolated ricin, a potent toxin derived from Castor beans. Steviol glycosides (a representative structure is depicted above) are responsible for the sweet taste of the leaves of the stevia plant (Stevia rebaudiana Bertoni), which range in sweetness from 40 to 300 times sweeter than sucrose. Moreover, steviol glycosides do not induce a glycemic response when ingested, rendering them attractive as natural sweeteners for diabetics. The diterpene steviol, the aglycone of Stevia's sweet glycosides, was the target of recent synthetic studies led by the recently crowned MacArthur fellow Phil Baran at the Scripps Research Institute. The Baran laboratory's campaign, which culminated in the development of a practical total synthesis of (+/-)-steviol, is the subject of this post.
          Steviol is an oxidized congener of ent-kaurene, the biosynthetic precursor to the well-known  diterpene plant hormone gibberellic acid. Baran's group constructed the key early-stage tricyclic intermediate 2 in a biomimetic fashion that drew inspiration from Nature's fascinating enzymatic conversion of geranylgeranyl pyrophosphate (GGDP) into ent-kaurene. The enone 3 was then obtained from 2 by a three-step sequence involving elimination of a secondary alcohol, hydrogenolysis and Birch reduction/isomerization. In the subsequent operation, a critical allene [2 + 2] photocycloaddition installed the hindered C8 quaternary center of the advanced cyclobutane intermediate 4. Several alternate methods to install the C8 stereocenter had failed.
          Ozonolysis of 4, when conducted in methanol, induced fragmentation of the strained cyclobutane framework to generate the intermediary methyl ester 5. Next, the [2.2.2]bicyclic system of 6 was fashioned by exposure of 5 to forcing acidic conditions and subsequent reductive cyclopropanation in the presence of acetic anhydride led to the advanced diacetate 7. Finally, controlled fragmentation of 7 with methanolic hydrochloric acid, followed by an expedient methylenation/oxidation endgame sequence produced fully synthetic steviol in only 17 total steps starting from geranyl acetate.
          Notably, an intriguing skeletal rearrangement of steviol, induced by HBr, provides access to the related beyerane diterpene natural product isosteviol, which is apparently thermodynamically favored compared to its kinetic precursor. This impressive work establishes a rapid and efficient synthetic route to access minimally oxidized members of the ent-kaurane and beyerane class of diterpenes. As noted above, members of this natural product family are commercially valuable in the flavor industry as precursors natural and/or semisynthetic sweeteners.

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