: The unpolarized absorption and circular dichroism spectra of the fundamental vibrational transitions of the chiral molecule, 4-methyl-2-oxetanone, are calculated ab initio. Harmonic force fields are obtained using Density Functional Theory (DFT), MP2, and SCF methodologies and a 5S4P2D/3S2P (TZ2P) basis set. DFT calculations use the Local Spin Density Approximation (LSDA), BLYP, and Becke3LYP (B3LYP) density functionals. Mid-IR spectra predicted using LSDA, BLYP, and B3LYP force fields are of significantly different quality, the B3LYP force field yielding spectra in clearly superior, and overall excellent, agreement with experiment. The MP2 force field yields spectra in slightly worse agreement with experiment than the B3LYP force field. The SCF force field yields spectra in poor agreement with experiment.The basis set dependence of B3LYP force fields is also explored: the 6-31G* and TZ2P basis sets give very similar results while the 3-21G basis set yields spectra in substantially worse agreements with experiment. jg

Ab initio calculation of vibrational absorption and circular dichroism spectra using density functional force fields

Asymmetric Organocatalytic Cyclization and Cycloaddition Reactions

Despite the fact that halogenation of alkenes has been known for centuries, enantioselective variants of this reaction have only recently been developed. In the past three years, catalytic enantioselective versions of halofunctionalizations with the four common halogens have appeared and although important breakthroughs, they represent just the very beginnings of a nascent field. This Minireview provides a critical analysis of the challenges that accompany the development of general and highly enantioselective halofunctionalization reactions. Moreover, the focus herein, diverges from previous reviews of the field by identifying the various modes of catalysis and the different strategies implemented for asymmetric induction.

Catalytic, Asymmetric Halofunctionalization of Alkenes—A Critical Perspective

Enantioenriched fluorinated heterocycles can be prepared through fluorocyclizations of prochiral indoles (see scheme; Ts=tosyl, Bn=benzyl, Boc=tert-butoxycarbonyl). More than twenty examples for this cascade fluorination-cyclization, which is catalyzed by cinchona alkaloids and employs N-fluorobenzenesulfonimide as the electrophilic fluorine source have been explored, and an unprecedented catalytic asymmetric difluorocyclization has also been identified.

Organocatalyzed Enantioselective Fluorocyclizations

A catalytic enantioselective syn-1,4-bromolactonization of conjugated (Z)-enynes was reported. Diastereomeric ratios >20:1 and up to 99% enantiomeric excesses were observed. Di-, tri-, and tetra-substituted bromoallenes were prepared together with lactone heterocycles efficiently and stereoselectively. Preliminary investigations suggest that the chiral catalyst may serve as a bifunctional reagent by interacting with both a carboxylic acid nucleophile and NBS electrophile.

Enantioselective bromolactonization of conjugated (Z)-enynes.

A reagent controlled organocatalytic enantioselective chlorolactonization reaction has been developed. Several 4-aryl pentenoic acids were cyclized in the presence of 0.1 equiv of (DHQD)2PHAL, employing various N-chlorinated hydantoins as the terminal chlorenium source. Ten examples are presented with selectivities ranging from 43 to 90% ee. This work represents the first example of an enantioselective reagent-controlled chlorolactonization that approaches synthetically useful enantioselectivities.

An organocatalytic asymmetric chlorolactonization.

Stereodefined carbon–halogen bonds are ubiquitous in nature with several natural products exhibiting this motif. While the biogenetic origins of this unique chiral functionality has been a subject of several investigations in the past, attempts by organic chemists to forge the carbon–halogen bond stereoselectively have largely been unsuccessful. This problem has come into focus only recently. Several elegant reports of asymmetric halogenations of alkenes and alkynes followed by an intramolecular attack of a pendant nucleophile have appeared in the literature in the last decade. Kang et al. reported a cobalt–salen catalyzed iodoetherification reaction. An asymmetric fluorocyclization of allyl silanes mediated by a cinchona alkaloid dimer was reported by Gouverneur and co-workers. Tang and co-workers disclosed an asymmetric bromolactonization of enynes catalyzed by a cinchona alkaloid derived urea; other bromolactonizations have also appeared following the disclosure of their report. More recently, Veitch and Jacobsen reported an asymmetric iodolactonization reaction mediated by chiral thiourea catalysts. Polyene cyclizations induced by chiral halonium ions have also been realized as reported by the research groups of Ishihara and Snyder. However, given the fledgling nature of this research area, one may find it easy to highlight the many drawbacks and limitations even in the present state of the art—for example, the relatively large catalyst loadings (superstoichiometric quantities in some cases) to achieve meaningful levels of enantioselectivity or the lack of a robust catalytic system that can catalyze a number of diverse reactions rather than one specific reaction. Moreover, efficient asymmetric chlorocyclizations have remained underdeveloped. This situation is attributable, at least in part, to the highly reactive nature of chloronium ions, which are known to exist in equilibrium with the corresponding carbocation rather than exclusively as cyclic chloronium ions, thus making the development of chlorocyclizations a formidable challenge. Our research group has recently reported the catalytic asymmetric chlorolactonization of alkenoic acids. Herein, we disclose the efficient halocyclization of unsaturated amides to furnish chiral heterocycles. Furthermore, these heterocycles have been transformed into useful chiral building blocks such as amino alcohols. Chiral heterocycles such as oxazolines and dihydrooxazines are commonly encountered motifs in natural products, molecules of pharmaceutical interest, and in several chiral ligands. Their syntheses, however, usually employ stoichiometric quantities of chiral amino alcohols. With only one precedented method to access these molecules in a catalytic asymmetric fashion, we were intrigued by the possibility of one-step access to these versatile chiral heterocycles by a catalytic asymmetric halocyclization of easily accessed unsaturated amides. We chose the conversion of benzamide 1 into oxazoline 2 as our initial test reaction. Among the several ligands screened for the test reaction, (DHQD)2PHAL emerged as the best candidate, thus affording the desired oxazoline 2 in 57% ee (Table 1, entry 1) with DCDMH as the terminal chlorine source. Reactions with other chlorenium sources

A catalytic asymmetric chlorocyclization of unsaturated amides.

We introduce a previously unexplored parameter—halenium affinity (HalA)– as a quantitative descriptor of the bond strengths of various functional groups to halenium ions. The HalA scale ranks potential halenium ion acceptors based on their ability to stabilize a “free halenium ion”. Alkenes in particular but other Lewis bases as well, such as amines, amides, carbonyls, and ether oxygen atoms, etc., have been classified on the HalA scale. This indirect approach enables a rapid and straightforward prediction of chemoselectivity for systems involved in halofunctionalization reactions that have multiple nucleophilic sites. The influences of subtle electronic and steric variations, as well as the less predictable anchimeric and stereoelectronic effects, are intrinsically accounted for by HalA computations, providing quantitative assessments beyond simple “chemical intuition”. This combined theoretical–experimental approach offers an expeditious means of predicting and identifying unprecedented reactions.

A New Tool To Guide Halofunctionalization Reactions: The Halenium Affinity (HalA) Scale

The first example of a kinetic resolution via chlorofunctionalization of olefins is reported. The enantiomers of racemic unsaturated amides were found to have different hydrogen-bonding affinities for chiral Lewis bases in numerous solvents. This interaction was exploited in developing a kinetic resolution of racemic unsaturated amides via halocyclization. The same catalyst serves to both “sense chirality” in the substrate as well as mediate a highly face-selective chlorine delivery onto the olefin functionality, resulting in stereotriad products in up to 99:1 dr and up to 98.5:1.5 er. The selectivity factors were typically greater than 50 to allow for the simultaneous synthesis of both the products and unreacted substrates in highly enantioenriched form at yields approaching 50%. The reaction employs catalytic amounts (≤0.50 mol %) of a commercially available and recyclable organocatalyst.

Kinetic resolution of unsaturated amides in a chlorocyclization reaction: concomitant enantiomer differentiation and face selective alkene chlorination by a single catalyst.

A remarkable solvent-controlled enantiodivergence is seen in the hydroquinidine 1,4-phthalazinediyl diether ((DHQD)2PHAL)-catalyzed chlorocyclization of unsaturated carbamates. Eyring plot analyses of this previously unreported reaction are used to probe and compare the R- and S-selective pathways. In the CHCl3/hexanes solvent system, the pro-R process shows a surprising increase in selectivity with increasing temperature. These studies point to a strongly solvent-dependent entropy-enthalpy balance between the pro-R and pro-S pathways.

Arvind Jaganathan

Papers

An organocatalytic asymmetric chlorolactonization.

A catalytic asymmetric chlorocyclization of unsaturated amides.

A New Tool To Guide Halofunctionalization Reactions: The Halenium Affinity (HalA) Scale

Kinetic resolution of unsaturated amides in a chlorocyclization reaction: concomitant enantiomer differentiation and face selective alkene chlorination by a single catalyst.

Solvent‐Dependent Enantiodivergence in the Chlorocyclization of Unsaturated Carbamates