Biomimetic Syntheses of Highly Complex Guaianolide Sesquiterpenoid Dimers

          Guaianolide-type sesquiterpenoid lactone dimers (e.g. 1) are characterized by complex heptacyclic ring systems, architectural features that are not easily accessed by conventional total synthesis methods. Moreover, from an organic synthetic perspective, it is difficult to envision a more daunting target than the ainsliatrimers (represented by 2), aesthetically pleasing sesquiterpene trimers characterized in 2008 by the laboratories of Hui-Zi Jin and Wei-Dong Zhang. Notably, the collective chemical synthesis of several guaianolide sesquiterpenoids related to (and including) 1 was recently reported in JACS by implementation of a concise and biomimetic strategy. The synthetic sequence, disclosed by Xiaoguang Lei and co-workers, features a brilliant one-pot cascade transformation that includes a Saegusa oxidation, intermolecular Diels-Alder cycloaddition and a radical-mediated allylic oxidation to install the tertiary hydroxyl functionality at C10.

          The advanced sesquiterpenoid lactone 3, derived synthetically from the natural product alpha-santonin (11 steps, protecting group-free), was first converted to its corresponding silyl enol ether by treatment with hexamethyldisilazane and trimethylsilyl iodide. A remarkable one-pot cascade transformation then completed the synthesis of gochnatiolide A (1).

          By exposure of 4 to Saegusa oxidation conditions in the presence of a stoichiometric excess of the dienophile (6 equivalents of 3), a Diels-Alder cycloaddition ensued (carbon connectivity shown above in brackets) that was accompanied by alkene isomerization to generate a thermodynamically favored cyclopentenone system. This olefin isomerization event then facilitates the generation of a tertiary radical at C10 (stabilized by the newly formed enone) and a subsequent reaction of the radical with molecular oxygen affords a peroxyl radical that is reduced in situ to generate 1 in a single operation. The endo transition state depicted above may or may not represent the operative pathway for this fascinating cascade transformation. Due to the concomitant alkene isomerization, it is difficult to discern the precise geometric arrangement of the cycloaddition transition state. 

          The rapid and biomimetic nature of this synthetic campaign is reminiscent of the cationic polyolefin cyclization chemistry developed by W. S. Johnson and E. J. Corey for the total synthesis of well known steroids and terpenoids. The authors report that studies directed toward the syntheses of the ainsliatrimers (e.g. 2) are underway.

New Antimetastatic Pregnane Alkaloids

Epidermal growth factor receptor (EGFR)-mediated chemotaxis is now recognized as an important mechanistic component in the process of metastasis in breast cancer. Hence, an investigation was initiated by Hong-Quan Duan and co-workers to identify experimental therapeutic candidates (natural products) that inhibit the migration of breast cancer cells induced by the chemokine EGF. Bioassay-guided phytochemical investigation of the ethanol extract of Pachysandra terminalis, a small shrub found in China and Japan, has resulted in the isolation and structural elucidation of the terminamines (e.g. terminamine C, structure shown below), pregnane alkaloids with unique antimetastatic therapeutic potential.

For example, terminamine C inhibited EGF-induced invasion of breast cancer cells with an IC50 of 80 nM. In addition, a close structural derivative of terminamine C was reported to dose-dependently inhibit the phosphorylation of integrin beta-1. Integrin beta-1 is a known component of a protein complex which binds to extracellular matrix molecules such as collagen and fibronectin in a process that mediates the attachment between a cell and the tissues that surround it. This biochemical phenomenon is associated with cancer cell adhesion and metastasis. Therefore, the inhibition of phosphorylation of integrin beta-1 by a terminamine natural product, along with generally potent in vitro antimetastatic activity, suggests a potential mechanism of action for this structurally interesting steroidal alkaloid natural product family.

Synthesis of B-Ring-Modified Steroids

It is difficult to envision a practical way to migrate the steroidal C19 angular methyl group from its position at the A/B ring junction onto C6 of the B-ring (with retention of configuration). Recently, a fascinating synthetic sequence was reported in Organic Letters that manages to accomplish just that (exact overall transformation shown above). The authors plan to use their chemistry to synthesize members of the cyclocitrinol natural product family. The methodology also provides stereocontrolled access to novel and therapeutically relevant B-ring (C6)-modified pregenolone derivatives.

The C19 angular methyl group is first functionalized by converting pregnenolone acetate (1) to its corresponding bromohydrin derivative. This provides the substrate for subsequent implementation of Meystre's hypoiodite C-H functionalization reaction (discussed here). Reduction of the lactol acetate product with concomitant elimination then gave 19-hydroxy pregnenolone acetate. This intermediate was converted into a cyclopropane derivative via the intermediacy of its corresponding mesylate. The cyclopropanated steroid was then exposed to Lewis acidic conditions (boron trifluoride diethyl etherate) which promoted rearrangement to a cyclopropyl-methyl cation species (shown above in brackets). Finally, regioselective nucleophilic ring-opening by formic acid efficiently generates the B-ring-modified steroid 2. Molecular entities derived from 2 are novel and potentially interesting from a pharmaceutical development persective. Moreover, they are not easily obtained by other known synthetic methods.

Semisynthetic Terpenoid Antifungal Agents from Scynexis and Merck (part 2)

We've highlighted the enfumafungin medicinal chemistry program previously at this site. Recently, a new series of semisynthetic antifungal glucan synthase inhibitors were disclosed in Bioorganic and Medicinal Chemistry Letters (currently In Press, 2012). I'm clearly not an unbiased observer in this case, but I would suggest that if you are interested in structurally complex bioactive terpenoid derivatives then this manuscript is probably worth taking a look at.

Corey's Total Synthesis of (+/-)-Retigeranic Acid A (1985)

In the previous post, we discussed a very recent synthesis of the trans-hydrindanone 4, a synthetic building block that intersects with Corey's route to retigeranic acid A, published in 1985. In this post, we will examine Corey's now classic work directed at this unique and complex pentacyclic sesterterpenoid, first isolated in 1965 from a Himalayan lichen. The conversion of the cyclohexenone 1 into the bicyclic enone 3 was first described by the laboratory of Barry Snider (then at Princeton) in 1980. In this powerful transformation, the Lewis acid acts as an initiator of a cation-olefin cyclization that proceeds via the intermediacy of the zwitterionic species 2. Two 1,2-hydride migrations then give rise to the bicyclic enone 3 in a process reminiscent of the biosynthesis of steroids and terpenes. Seven subsequent operations were then required to secure the diene component (5) of a critical Diels-Alder cycloaddition step. In the event, exposure of 5 to a dienophile with heating (98 - 105 degrees C) furnished a diastereomeric mixture of products from which the desired tricarbocyclic intermediate 6 was isolated in good yield (61%) after preparative HPLC purification.

Intermediate 6 was then advanced in a relatively straightforward way (5 steps) to the ketene 7 and this species smoothly underwent intramolecular [2+2] cycloaddition with the pendant exocyclic alkene to give the cyclobutanone 8 in excellent yield. Notably, this  reaction installs, with complete stereocontrol, the challenging all-carbon quaternary center of the eventual triquinane system. Construction of the triquinane substructure (from 8) now requires a ring expansion of the cyclobutanone and a ring contraction of the cyclohexene. The former is accomplished by addition of a lithio derivative to the western carbonyl followed by cuprous triflate-mediated thio-pinacol rearrangement and desulfurization, resulting in the advanced pentacycle 11.

In the endgame of the synthesis, dihydroxylation of 12 (obtained from 11) and oxidative glycol cleavage of the intermediate diol affords a seco keto aldehyde (13) that, under remarkably mild conditions, undergoes intramolecular aldol cyclization to forge the triquinane carbon skeleton. Finally, Pinnick oxidation (sodium chlorite) of retigeranic aldehyde furnishes the sesterpenoid target molecule in racemic form. It is interesting to note that no additional synthetic advancements targeting any pentacyclic sesterpenoid have been described in the literature since Wender's synthesis of retigeranic acid, published 22 years ago (in 1990). Additionally, retigeranic acid A is the only member in its natural product class that has been synthesized in a laboratory.