Function-Oriented Synthesis of Pentacyclic Triterpenoids and Discovery of an ent-Estrane as a Natural Product-Inspired Androgen Receptor Antagonist.

While pentacyclic triterpenoids have a rich history in chemistry and biology, the challenges associated with their asymmetric synthesis contribute to the current reality that medicinal exploration in the area is largely constrained to natural product derivatization. To address this deficiency, a function-oriented synthesis of pentacyclic triterpenoids was pursued. Overall, we report a divergent synthesis of 26-norgermanicol and 26-norlupeol and we have identified a new class of androgen receptor antagonist that is ∼6× more potent than lupeol.

Synthesis of Anhydroryanodol.

A stereoselective entry to ryanoids is described that culminates in the synthesis of anhydroryanodol and thus the formal total synthesis of ryanodol. The pathway described features an annulation reaction conceived to address the uniquely complex and highly oxygenated polycyclic skeleton common to members of this natural product class. It is demonstrated that metallacycle-mediated intramolecular coupling of an alkyne and a 1,3-diketone can proceed with a highly functionalized enyne and with outstanding levels of stereoselection. Furthermore, the first application of this technology in natural product synthesis is demonstrated here. More broadly, the advances described demonstrate the value that programs in natural product total synthesis have in advancing organic chemistry, here through the design and realization of an annulation reaction that accomplishes what previously established reactions do not.

A Complementary Process to Pauson-Khand-Type Annulation Reactions for the Construction of Fully Substituted Cyclopentenones.

A complementary process to the Pauson-Khand annulation is described that is well suited to forging densely substituted/oxygenated cyclopentenone products (including fully substituted variants). The reaction is thought to proceed through a sequence of metallacycle-mediated bond-forming events that engages an internal alkyne and a ß-keto ester in an annulation process that forges two C-C bonds. A variant of this annulation process has also been established that delivers deoxygenated cyclopentenones that lack the allylic tertiary alcohol.

The Anomeric Effect: It's Complicated.

The origin of the anomeric effect has been reexamined in a coordinated experimental and computational investigation. The results of these studies implicate a number of different, but correlated, interactions that in the aggregate are responsible for the anomeric effect. No single factor is uniquely responsible for the axial preference of a substituent that is the hallmark of the anomeric effect. A CH···G nonbonded attraction between a polar axial substituent (G) and the syn-axial hydrogen(s) in the heterocycle has been demonstrated experimentally. The hyperconjugation model involving electron transfer from a ring heteroatom to an excited state of an axial C-G bond was shown to be, at most, a minor contributor because of the very small changes in charge density at the ring heteroatom(s): the main charge transfer is from hydrogen to G in the H-C-G unit. This appears to result from lengthening the C-G bond to minimize repulsion with the ring atom lone pair(s) and the advantage of having a more positive hydrogen that leads to a stabilizing Coulombic interaction with the ring heteroatom(s). In short, the anomeric effect arises mainly from two separate CH···G nonbonded Coulombic attractions.

Experimental Demonstration of a Sizeable Nonclassical CH···G Hydrogen Bond in Cyclohexane Derivatives: Stabilization of an Axial Cyano Group.

Base-catalyzed equilibration of anancomeric cyanocyclohexanes demonstrates that replacement of cis-3,5-dimethyl holding groups with electron-withdrawing CF3 groups dramatically increases the proportion of the axial cyano isomer present at equilibrium. The CF3 groups exert an effect on the conformational energy of the cyano group worth about 0.6 kcal/mol. A nonclassical hydrogen bond between the axial CN group and the syn-axial hydrogens is a major contributor to the axial stability of the group.

Enhancement of the Oxidizing Power of an Oxoammonium Salt by Electronic Modification of a Distal Group.

The multigram preparation and characterization of a novel TEMPO-based oxoammonium salt, 2,2,6,6-tetramethyl-4-(2,2,2-trifluoroacetamido)-1-oxopiperidinium tetrafluoroborate (5), and its corresponding nitroxide (4) are reported. The solubility profile of 5 in solvents commonly used for alcohol oxidations differs substantially from that of Bobbitt's salt, 4-acetamido-2,2,6,6-tetramethyl-1-oxopiperidinium tetrafluoroborate (1). The rates of oxidation of a representative series of primary, secondary, and benzylic alcohols by 1 and 5 in acetonitrile solvent at room temperature have been determined, and oxoammonium salt 5 has been found to oxidize alcohols more rapidly than does 1. The rate of oxidation of meta- and para-substituted benzylic alcohols by either 1 or 5 displays a strong linear correlation to Hammett parameters (r > 0.99) with slopes (ρ) of -2.7 and -2.8, respectively, indicating that the rate-limiting step in the oxidations involves hydride abstraction from the carbinol carbon of the alcohol substrate.

Controlling the Conformational Energy of a Phenyl Group by Tuning the Strength of a Nonclassical CH···O Hydrogen Bond: The Case of 5-Phenyl-1,3-dioxane.

Anancomeric 5-phenyl-1,3-dioxanes provide a unique opportunity to study factors that control conformation. Whereas one might expect an axial phenyl group at C(5) of 1,3-dioxane to adopt a conformation similar to that in axial phenylcyclohexane, a series of studies including X-ray crystallography, NOE measurements, and DFT calculations demonstrate that the phenyl prefers to lie over the dioxane ring in order to position an ortho-hydrogen to participate in a stabilizing, nonclassical CH···O hydrogen bond with a ring oxygen of the dioxane. Acid-catalyzed equilibration of a series of anancomeric 2-tert-butyl-5-aryl-1,3-dioxane isomers demonstrates that remote substituents on the phenyl ring affect the conformational energy of a 5-aryl-1,3-dioxane: electron-withdrawing substituents decrease the conformational energy of the aryl group, while electron-donating substituents increase the conformational energy of the group. This effect is correlated in a very linear way to Hammett substituent parameters. In short, the strength of the CH···O hydrogen bond may be tuned in a predictable way in response to the electron-withdrawing or electron-donating ability of substituents positioned remotely on the aryl ring. This effect may be profound: a 3,5-bis-CF3 phenyl group at C(5) in 1,3-dioxane displays a pronounced preference for the axial orientation. The results are relevant to broader conformational issues involving heterocyclic systems bearing aryl substituents.

Metal-Free Oxidation of Primary Amines to Nitriles through Coupled Catalytic Cycles.

Synergism among several intertwined catalytic cycles allows for selective, room temperature oxidation of primary amines to the corresponding nitriles in 85-98% isolated yield. This metal-free, scalable, operationally simple method employs a catalytic quantity of 4-acetamido-TEMPO (ACT; TEMPO=2,2,6,6-tetramethylpiperidine N-oxide) radical and the inexpensive, environmentally benign triple salt oxone as the terminal oxidant under mild conditions. Simple filtration of the reaction mixture through silica gel affords pure nitrile products.