Achieving ready-enantioselective access to multistereocenter-containing cyclopentyl rings is an area of great significance to organic synthesis. In this work, we describe a general protocol for accessing multistereocenter-containing cyclopentanoids from simple N-alkynyloxazolidinones (Ox-ynamides). This protocol involves conversion of Ox-ynamides into Ox-activated divinyl and aryl vinyl ketones that undergo facile Nazarov cyclization with excellent chemo-, regio-, and stereocontrol. The Ox auxiliary directs all aspects of reactivity and selectivity, both in the electrocyclization and in the subsequent transformations of the resulting oxyallyl intermediate. Stereoinduction in the electrocyclization results from a “coupled-torque” mechanism in which rotation of the Ox group, driven by increasing orbital overlap of the nitrogen lone pair with the incipient oxyallyl cation, is coupled with the rotation of the termini of the pentadienyl cation, favoring a particular direction of conrotatory ring closure (torquoselectivity). The associated lone-pair stabilization of the transition state by Ox promotes cyclization of traditionally resistant substrates, broadening the scope of this asymmetric Nazarov cyclization. The Ox group also facilitates the stereo- and regioselective incorporation of nucleophiles (Nu) and dienes, giving more complex, multistereocenter containing cyclopentanoids. Finally, the Ox group is readily removed and recovered or can be converted into other amine functionalities.

Linear and angular heteroacenes are prepared from terminal alkynes bearing tethered nucleophiles in two steps. Linear heteroacenes are formed from the homocoupling of these alkynes followed by reaction with a double electrophile (ECl2) to induce a tricyclization reaction cascade involving double-electrophilic cyclization (DEC). Related angular heteroacenes are formed from the prior substitution of the chloro groups in ECl2 with the same terminal alkyne followed by reaction with AuCl3 to produce a DEC-reductive-elimination (DECRE) reaction.

The sphingosine kinase (SK) inhibitor, SKI-II, has been employed extensively in biological investigations of the role of SK1 and SK2 in disease and has demonstrated impressive anticancer activity in vitro and in vivo. However, interpretations of results using this pharmacological agent are complicated by several factors: poor SK1/2 selectivity, additional activity as an inducer of SK1-degradation, and off-target effects, including its recently identified capacity to inhibit dihydroceramide desaturase-1 (Des1). In this study, we have delineated the structure–activity relationship (SAR) for these different targets and correlated them to that required for anticancer activity and determined that Des1 inhibition is primarily responsible for the antiproliferative effects of SKI-II and its analogues. In the course of these efforts, a series of novel SK1, SK2, and Des1 inhibitors have been generated, including compounds with significantly greater anticancer activity.

Electrophilic activation of alkynylphosphine oxides and phosphonates provides a novel approach to the synthesis of P-substituted and P-centered heterocycles. Iodocyclization affords a heteroaryl iodide that can, among other things, be used in reiterative alkyne coupling and iodocyclization to give cyclic phosphonates and other cyclization reactions to give π-rich P-heterocycles.

Reductive coupling of α,β-unsaturated acid chlorides A with alkynoyls B provides convergent access to Nazarov cyclization precursors, α-carboxy divinyl ketones C. Cyclization of C gives an intermediate oxyallyl cation intermediate D, which can be trapped with tethered arenes (Ar). The resultant products can be further cyclized through nucleophilic displacement of suitable leaving groups X by tethered OH groups to give lactones (in a subsequent step). Where X is a suitable chiral auxiliary (e.g., oxazolidinone) this strategy affords access to homochiral cyclopentanoids.

Most applications of chiral oxazolidinone auxiliaries in asymmetric synthesis operate through a common set of stereocontrol principles. That is, the oxazolidinone is made to adopt a specific, coplanar conformation with respect to the prochiral substrate, and reaction occurs preferentially at whichever stereoheterotopic face is not blocked by the substituents on the oxazolidinone. In contrast to these principles, we report here the discovery of an alternative mechanism of oxazolidinone-based stereocontrol that does not require coplanarity and is driven instead by allylic strain. This pathway has been uncovered through computational studies of an asymmetric Nazarov cyclization. Chiral oxazolidinone auxiliaries provide essentially complete control over the torquoselectivity of ring closure and the regioselectivity of subsequent deprotonation. Density functional theory calculations (M06-2X//B3LYP) reveal that in the transition state of 4π electrocyclic ring closure, the oxazolidinone ring and the cyclizing pentadienyl cation are distorted from coplanarity in a manner that gives two transition state conformations of similar energy. These two conformers are distinguished by a 180° flip in the auxiliary orientation such that in one conformer the oxazolidinone carbonyl is oriented toward the OH of the pentadienyl cation (syn-conformer) and in the other it is oriented away from this OH (anti-conformer). Surprisingly, both conformations induce the same sense of torquoselectivity, with a 3–5 kcal/mol preference for the C5-β epimer of the ring-closed cation. In both conformations, the conrotatory mode that leads to the C5-α epimer is disfavored due to higher levels of allylic strain between the oxazolidinone substituent and adjacent groups on the pentadienyl cation (R4 and OH). The excellent torquoselectivities obtained in the oxazolidinone-directed Nazarov cyclization suggest that the allylic strain-driven stereoinduction pathway represents a viable alternative mechanism of stereocontrol for reactions of sterically congested substrates that lie outside of the traditional coplanar (N-acyloxazolidinone) paradigm.

An efficient, formal enantioselective synthesis of (+)- and (−)-pauciflorol F has been achieved using a recently introduced oxazolidinone controlled torquoselective Nazarov reaction. The absolute stereochemistry of pauciflorol F and its biosynthetic precursors has been unambiguously confirmed using X-ray crystallography.

N-(2-Iodophenyl)imines A are readily formed from Schiff’s base condensation of 2-iodoanilines with carbonyls and ketals. These imines provide useful substrates in scaffold-divergent synthesis through the attachment of an alkyne (Songashira coupling or acyl substitution of a Weinreb amide) followed by an iodonium-induced reaction cascade to give ring-fused indoles B, quinolines C, or quinolones D depending on the reaction conditions employed.

A convergent reaction sequence involving a reductive coupling and a chiral Brønsted acid catalyzed Nazarov reaction is utilized in a concise formal synthesis of (+)-roseophilin (11 steps via longest linear sequence, 10.2% yield, 95% ee).

Oxazolidinones are powerful promoters of the Nazarov reaction, enabling the cyclization of conventionally resistant substrates to be achieved under mild conditions. They exert excellent regio- and torquoselective control in both the conventional Nazarov reaction giving cyclopentenones and in the “interrupted” Nazarov reaction, giving more highly substituted multistereocenter containing products.

A structure–activity relationship (SAR) guided design of novel tubulin polymerization inhibitors has resulted in a series of benzo[b]furans with exceptional potency toward cancer cells and activated endothelial cells. The potency of early lead compounds has been substantially improved through the synergistic effect of introducing a conformational bias and additional hydrogen bond donor to the pharmacophore. Screening of a focused library of potent tubulin polymerization inhibitors for selectivity against cancer cells and activated endothelial cells over quiescent endothelial cells has afforded 7-hydroxy-6-methoxy-2-methyl-3-(3,4,5-trimethoxybenzoyl)benzo[b]furan (BNC105, 8) as a potent and selective antiproliferative. Because of poor solubility, 8 is administered as its disodium phosphate ester prodrug 9 (BNC105P), which is rapidly cleaved in vivo to return the active 8. 9 exhibits both superior vascular disrupting and tumor growth inhibitory properties compared with the benchmark agent combretastatin A-4 disodium phosphate 5 (CA4P).