Sunday, October 20, 2013
Baran's Expedient Chemical Synthesis of (+)-Ingenol
The phorbol esters are well-known tigliane natural products derived from Croton tiglium, the source of croton oil, as well as from other plants of the family Euphorbiaceae. Phorbol esters such as 12-O-tetradecanoylphorbol-13-acetate (TPA) are useful pharmacological tool compounds in models of carcinogenesis due to their potent activity as mouse skin tumor promotors. Various esters of phorbol such as TPA, which mimic the chemical structure of diacylglycerol, bind to and activate protein kinase C. This type of modulation of one of the major signal transduction mechanisms within cells enables the phorbol esters to elicit a broad range of biological activities. TPA has been used extensively in biomedical research as a probe to identify the physiological systems in which protein kinase C is involved. Chemical syntheses of phorbol are notoriously challenging and have required between 36 and 52 total steps.
Ingenol mebutate (trade name Picato) is the ester derived from a related ingenane diterpene, ingenol, and angelic acid. This drug was recently approved by the FDA as a first-in-class treatment for actinic keratosis, a precancerous skin condition. Unlike the tigliane/phorbol-type diterpenoids, the ingenane carbocyclic framework consists of a unique in,out-[4.4.1]bicycloundecane core. This ring skeleton is quite strained due to the "inside-outside" intrabridgehead stereochemistry of the BC ring system, wherein the C8 and C10 configurations are trans to one another. This renders ingenol a formidable synthetic target for total synthesis. The cis-triol of the AB ring fragment is also difficult to elaborate and often requires lengthy synthetic sequences. The recent chemical synthesis of ingenol by Baran's group at the Scripps Research Institute will be the subject of this post.
Baran's route, like many previous synthetic studies targeting ingenol, starts from a readily available terpene, (+)-carene. The cyclohexanone intermediate 2 is assembled by means of a stereocontrolled aldol condensation between an elaborated carene derivative and the allene-containing aldehyde 1. Treatment of 2 with ethynyl magnesium bromide gave the diol 3 (d.r. 10:1) which was subsequently protected as the bis-silyl ether 4. Baran then beautifully applied Kay Brummond's (University of Pittsburgh) rhodium(I)-catalyzed allenic Pauson-Khand-type chemistry to the intricate substrate 4, which fashioned the carbocyclic tigliane carbon skeleton in an extremely concise manner compared to previously demonstrated synthetic strategies.
The key step in Baran's ingenol synthesis is the vinylogous 1,2-pinacol rearrangement of the advanced tigliane/phorbol-type system 6, which sets the requisite inside-outside (trans) intrabridgehead stereochemistry of 7. This fascinating skeletal transformation, speculated to be of biosynthetic relevance, involves a 1,2-alkyl shift and is reminiscent of the Tsuchihashi-Suzuki rearrangement of 2,3-epoxy alcohols. In order to be successful, the C9-C11 bond of 6 must selectively undergo the desired migration to the developing partial positive charge at C10. In the event, exposure of intermediate 6 to Lewis acidic conditions at low temperature induced the projected vinylogous pinacol-type rearrangement which established the quaternary center at C10 in a highly stereocontrolled fashion. The advanced intermediate 7 then underwent sequential, chemoselective oxidation reactions that culminated in fully synthetic ingenol in only 14 total operations.
It should be noted that pinacol-type rearrangements involving 1,2-alkyl migrations have been previously applied to the synthesis of ingenol. For example, in the second total synthesis of ingenol, Kuwajima and co-workers utilized this type of skeletal reorganization with a ring system (11) that was derived from a functionalized trans-decalin (10). In a related study, Cha's group assembled the Tsuchihashi-Suzuki rearrangement substrate 14 using olefin metathesis. In these examples, stereoelectronic requirements dictate that an antiperiplanar alignment of the C9-C11 bond with respect to the C10-O is required for the desired migration to occur. While the intended rearrangements in both examples were quite efficient from a yield perspective, both Kuwajima's and Cha's substrates lacked the intact cis-triol of the AB ring fragment and, thus, multistep oxidative elaboration following the skeletal reorganization was required. In comparison, Baran's substrate (6) is expertly designed. The relative stereochemistry of 6 satisfies all of the stereoelectronic requirements for bond migration and the vinylogous SN2' nature of the transformation directly installs the olefin between C1 and C2 of the A-ring. Baran clearly benefited from a discerning knowledge of the literature precedent, but also designed and executed a virtuosic refinement to the existing technology. His chemical synthesis compares favorably to isolated yields of ingenol from plant material and may facilitate the commercial manufacture of Picato.