Submitted to the Faculty of the Graduate School of Vanderbilt University

Finally, I would like to thank all the members of the Johnston laboratory for providing advice, encouragement, and friendship. Finally, mechanistic understanding of the means of asymmetry is by no means consistent with the empirical discovery of a given competent catalyst.

Counterion Investigations

The silencing of the counterion effect that proved so important in the development of asymmetric iodolactonization with NIS under PIDA/KI conditions was. It was mentioned earlier that the original discovery of the PIDA/KI system led to a mechanistic postulate that seemed increasingly unlikely in light of later results.

Table 2. Results of Aniline-derived Counterions in StilbPBAM Catalyzed Iodolactonization

An example of the reaction can be seen in Scheme 23 where compound 3f is oxidized to give brassinolide 3g.25. Aniline substitution at the 4-position of the quinoline rings ( 4af ) significantly decreased the enantioselectivity relative to the pyrrolidine substituent ( 4e ).

Table 5. Solvent Screen (Solvents that Gave Conversion)

Discovery and Development of an Enantioselective Iodolactonization to give ε-Lactones

Experimental Methods

The reaction mixture was quenched with 1N aqueous HCl, extracted with dichloromethane, dried (Na 2 SO 4 ) and concentrated. The reaction mixture was stirred for 16 hours and then poured onto ice, extracted with diethyl ether, dried (MgSO 4 ) and concentrated.

Spectra

Diastereoselection of 3-Substituted Pent-4-enoic acids (Bartlett)

Diastereoselection of 2-Substituted Pent-4-enoic Acids (Bartlett)

Diastereoselection of 4-Substituted Hex-5-enoic Acids (Bartlett)

Bartlett also explored facial selectivity under kinetic conditions and remarkably found that these conditions caused an inversion of facial selectivity, favoring the formation of the cis-isomer over the trans-, a preference that increased with increasing steric bulk. Substitution at the 3-position was found to cause a preference for the cis-diastereomer of the γ-lactones under kinetic conditions, albeit with poor selectivity (3:1 ratio, Scheme 4).1,3,4 The same kinetic conditions were used in the iodolactonization to δ-lactones, with analogous, albeit less, results.

Diastereoselection of 3-Substituted Pent-4-enoic Acids under Kinetic Conditions (Bartlett)

This observation was explained by the formation of an acyl hypoiodite from the carboxylate and iodine which, upon delivery of iodine to the hindered face of the alkene, requires rotation of the resulting halonium species to accommodate back attack of the carboxylate, leading to an inversion of diastereoselection.

Diastereoselection of 4-Substituted Hex-5-enoic Acids under Kinetic Conditions (Bartlett)

These initial observations of the high diastereoselectivity arising in the iodolactonization reaction gave some hope that enantioselective variants of the reaction could be developed, especially that catalytic methods might one day be discovered and used. This initial discovery was supplemented in subsequent years by other competent iodonium sources derived from chiral amines.

Iodolactonization with Chiral Quinidine-Based Iodonium (Grossman)

In 1998, Grossman and colleagues reported the discovery that a quinidine-derived amine in conjunction with iodine a. Not long after Wirth's reports, Rousseau and co-workers reported a reaction similar to Grossman's initial discovery, albeit with improved enantioselection and a more accessible chiral amine (Scheme 8).7.

Iodolactonization with Chiral Aminotetraline-Based Iodonium (Wirth)

Despite these limitations, under favorable conditions, the enantioselection that could be achieved was much higher than Grossman's initial results. This can be rationalized by invoking different reaction rates for the different ring sizes since the timing of the.

Iodolactonization with N-Methylephedrine-Based Iodonium (Rousseau)

By this time, enantioselective approaches had been well established via a reagent-controlled approach, but enantioselections were relatively poor, and the necessity to rely on stoichiometric or even excess amounts of chiral reagents was an obvious drawback of the reaction. The next major advance of the reaction would have to depend not only on a significant improvement in enantioselection, but an ability to induce it in a catalytic manner.

Iodolactonization with Chiral Cinchonidinium Catalyst (Gao)

The same group also developed a chiral salen-CoII complex that was found to be competent for a catalytic asymmetric iodolactonization, presumably by acting as a Lewis acid (Scheme 10).10 In the presence of iodine monochloride as an active iodine source, the reaction proceeded with good enantioselection and the use of a terminal olefin dictated a single regiochemical result favoring the γ-lactone (compound 2i). Despite this, both required very high catalyst loadings and the cinchonidinium-based catalyst gave relatively little.

Iodolactonization with Chiral Salen-Co II Catalyst (Gao)

Unusually, it was found that both iodine (as a co-catalyst), and the N-iodophthalimide were required for reactivity to be observed. The exceptional degree of enantioselectivity in the formation of δ-lactones, combined with the absence of transition metals and lower catalyst loading made the discovery a significant improvement over existing ones.

Iodolactonization with Chiral Aminourea Catalyst (Jacobsen)

A massive advance in the methodology was achieved in 2010 by Jacobsen and co-workers with the discovery of a urea-based organocatalyst that gave unusually high enantioselections at In the same year, Martin and co-workers developed an asymmetric iodolactonization of an internal alkene using a chiral BINOL-derived organocatalyst (Scheme 13).13.

Iodolactonization with Chiral (Bis)AMidine Catalyst (Johnston)

A further improvement was noted in 2012 when Johnston and colleagues developed a Bis(AMidine)-based catalyst that was highly selective for an iodine lactonization to give δ-lactones (Scheme 12).12. The following year, Arai and co-workers were able to induce good enantioselection toward δ-lactones using a chiral PyBidine ligand in combination with a NiII catalyst (Scheme 14).14.

Iodolactonization with Chiral BINOL Catalyst (Martin)

Iodolactonization with PyBidine-Ni II Catalyst (Arai)

It should also be noted that the author cannot find evidence for asymmetric approximations of lactones with larger ring sizes than the δ-lactone. That is, all or most catalytic systems within the domain of asymmetric iodolactonization are discovered empirically and not through an a priori understanding of how a particular desire can be brought about.

Iodolactonization with Zinc Complex (Stenstrom)

It should also be noted that the adamantyl-derived backbone (2 g) gave an enantioselection corresponding to that of the free-base catalyst, which would be an unusual improvement for a significantly less acidic counterion. The success of the PIDA/KI oxidizing system led to an interest in structurally related hypervalent iodine species, and thus iodosobenzene (PhI=O) with KI and PIFA (phenyliodide (trifluoroacetate)) with KI were examined.

Table 1. Initial Counterion Screen (Dobish and Johnston)

Proposed Catalyst Interaction with Oxidant

During the investigation of the PIDA/KI oxidation system, it was observed that the PIDA/KI system had a damped counterion effect compared to that of NIS. Interestingly, using the PIDA/KI system, the free base StilbPBAM (entry 1), the corresponding mono- and bis-triflimide salts (entries 2 and 3), and the corresponding mono- and bisacetic acid salts (entries 5 and 6) all gave a similar enantioselection of 93–94% ee, with the bis-triflimide salt showing a significant drop in reactivity relative to the mono-triflimide salt, and the bis-acetic acid salt showing a more modest drop in reactivity (as reflected in lower yields).

Table 4. Counterion Screen of PIDA/KI and NIS

Proposed Catalytic Cycle with NIS as Oxidant

Proposed Catalytic Cycle with PIDA/KI as Oxidant

While succinimide anion, as previously mentioned, was basically enough to deprotonate the protonated catalyst, the equilibrium of acetate should actually lead to the promotion of protonation of the catalyst—that is, it should act as a second counterion. By this time it became clear that the PIDA/KI system, although mechanistically interesting, especially with respect to the dampening of the counterion effect, was not quite competitive with the previously reported BAM catalyzed one.

PIDA as a General Platform for Generating Electrophiles from Nucleophiles

With the acetate residue of the hypervalent iodine species providing a handle for coordinating the catalyst, it was hoped that PIDA could be coupled with other small nucleophiles to act as a general scaffold for their conversion into electrophilic species that could be manipulated in an enantioselective manner using StilbPBAM as catalyst (Scheme 19). Subsequent attempts to use TMSCN and TMSN3 as alternative sources of nucleophiles also failed, giving mostly decomposition of the starting material.

Exploration of Other Hypervalent Iodine Oxidants

The investigation of the BAM-catalyzed iodine lactonization reaction had exhausted many research avenues at this point and, with the notable exception of the discovery of the PIDA/KI system, yielded very few results of any synthetic utility. The discovery of the PIDA/KI system proved remarkably effective in the previously developed reaction, yet did not improve the previously reported yield and enantioselection achieved with NIS as oxidant.

Apart from the obvious dependence on prior asymmetry, this method is an excellent one for the synthesis of ε-lactones. The Baeyer–Villiger reaction is another common method for the synthesis of ε-lactones, perhaps best known to the wider community of organic chemists.

Diol Oxidation to give ε-Lactones (Sasaki)

Current methods for the synthesis of ε-lactones can be roughly divided into the four main categories of diol oxidation, Baeyer-Villiger oxidation of ketones, Yamaguchi. Finally, halolactonization has been used in the synthesis of ε-lactones, but has proven to be a far more challenging and less widely applicable reaction than the halolactonizations toward γ- and δ-lactones.

Baeyer-Villiger Ring Expansion to give Brassinolide (Elbert)

The Yamaguchi macrolactonization conditions are widely used in the synthesis of larger ring sizes than ε-lactones, but have also proven capable in the synthesis of ε-lactones (Scheme 24).26. Examples of halolactonizations to give ε-lactones are relatively rare, and tend to depend on electrophilic halogen species that can charitably be described as unusual.27 Rousseau and co-workers.

Yamaguchi Macrolactonization to give ε-Lactones (Urones)

The use of the Baeyer-Villiger reaction here is particularly impressive in light of the fact that no protecting groups were used on a complex steroid architecture (3f) and that a relatively high yield was still achieved. A final proof of the challenge inherent in the field can be seen by the fact that as recently as 2012, Yeung and co-workers published a catalytic bromolactonization in which the action of the catalyst acted solely to enhance reactivity, and no enantioselection in did not cause the product (Scheme 26). 29.

Bis(sym-collidine)iodine(I) Hexafluorophosphate Mediated Iodolactonization (Rousseau)

Organocatalyzed Bromolactonization to give ε-Lactones (Yeung)

This response and its revelation serve as an indication of the substantial challenges encountered against halolactonization toward larger ring sizes. Following the discovery of PIDA/KI as a competent oxidant system in combination with StilbPBAM catalysis to achieve asymmetric iodolactonization, efforts were made to develop an application of the system that would be truly unique.

The Discovery of an Enantioselective Iodolactonization to give ε-Lactones

Furthermore, the reactivity of the 7-membered iodolactonization was remarkably poor under the given conditions, yielding only 14% after 4 days of reaction time. Neglecting to flame dry the given glass container and using no other additive gave the best result of the three conditions tested in terms of yield and enantioselection.

Effect of Water on 7-Membered Iodolactonization

The results were meaningful if very dilute conditions (A. and B. in Scheme 30) gave even lower reactivity (so that pure compound could not be obtained to determine the enantioselectivity), while more concentrated conditions (D. and E .in Scheme 30) ) resulted in higher conversion but a significant decrease in enantioselection. Finally, it was found that the initial concentration (C. in Scheme 30) was superior to the alternatives, so it was set as a variable, and efforts were directed to other possible routes to improve the reaction.

Effect of Temperature on 7-Membered Iodolactonization

Effect of Concentration on 7-Membered Iodolactonization

The majority of the solvents analyzed gave no formation of product and are duly listed in Scheme 31. This discovery led to an investigation of different ratios of dichloromethane to toluene as solvent during the reaction.

Solvent Screen (Unsuccessful Solvents)

Holding other reaction variables constant, the relative proportions of dichloromethane and toluene were changed to see the effect on yield and enantioselection. The results showed a good trend, with the previous insight that dichloromethane confers higher reactivity and toluene greater selectivity.

Full Conversion under New Solvent Conditions

Interestingly, at this point it was observed that the solvent system of dichloromethane and toluene offered an additional advantage over toluene alone; namely, that the reaction with exclusively toluene appears to stall at about 20% yield even at prolonged reaction times, a problem not observed with the new solvent system (Scheme 32). To the author's surprise, this appeared to have a detrimental effect on the yield of the reaction and no effect on the enantioselectivity (Scheme 34).

NIS Shows Reactivity under New Solvent Conditions

Some enantioselection was even observed, but both reactivity and enantioselection were so unequivocally worse than the PIDA/AI system that no attempts were made to try to optimize the reaction under NIS conditions. In an attempt to further increase reactivity while also shortening the very long reaction times, the reaction was carried out under increased catalyst loading.

Results of Increased Catalyst Loading

Having exhausted some of the more obvious routes of reaction manipulation, efforts turned to an examination of various catalyst structures (Table 7). The most interesting observation was that the catalyst with anthracenyl backbone. 4h) appeared to reverse the enantioinduction of the reaction, but the yield and enantioselection were so poor that it was not pursued further.

Table 7. Examination of Catalyst Modifications

Results with I 2 and PIDA/I 2 Oxidant Systems

The only immediate drawback to this finding was that a significant amount of byproduct was also formed under these conditions (13% by 1H NMR). At the time, the byproduct was believed to be an iodolactone arising from an 8-endo cyclization (Scheme 36, 4t), as this structure appeared consistent with what little information could be gleaned from 1H NMR of the crude reaction mixture .

Initial Proposal for Byproduct Structure

Following the discovery of the PIDA/I2 oxidant system, efforts immediately focused on the optimization of the improved conditions, with little thought given to its mechanism, or the identity of the byproduct, which proved challenging to isolate. Nevertheless, the discussion is placed here in the hope that it may provide a better understanding of the response with which the rest of this text grapples, however inadequate.

Formation of Acetyl Hypoiodite from PIDA/I 2

It was mentioned earlier that the paper that inspired the testing of the PIDA/I2 oxidant system suggested that the active iodinizing species was acetyl hypoiodite (Scheme 37, 4u).30 Further review of the literature showed that the evidence for the formation of PIDA/I2 acetyl hypoiodite as an active species for iodination was quite powerful and widely accepted.31,32,33 In particular, the e-EROS article alerted us to the fact that the reagent system had been widely used in radical generation for decades under the nickname of the Suárez reagent. 33. During our investigations, it was also found that replacing the BAM catalyst with dimethylaminopyridine (DMAP) favored the formation of the side product over the formation of the lactone product 4d.

NIS and Acetyl Hypoiodite as Structural Analogies

Moreover, its structure matched remarkably well with that of NIS, being of course the electrophilic iodine species that was best placed to confer enantioselectivity in the 6-membered iodolactonization (Scheme 38). Armed with the ability to favor the elusive pathway, we were finally able to purify and characterize the byproduct, revealing that it was not the 8-endo lactone 4t but the iodoacetate 4v (Scheme 39).

The Elusive Byproduct Revealed

This revelation served as further evidence for the role of acetyl hypoiodite as the active iodine-forming species, as the byproduct 4v most likely results from the addition of acetate to the benzyl cation that results from iodonium formation. This discovery also highlighted the importance of the catalyst, not only in the induction of.

Effect of Temperature with PIDA/I 2 System

The reaction proceeded readily at this temperature in the absence of catalyst, and the disfavor of this background reaction at lower temperatures was thought to be the source of the significant enhancements observed after cooling the reaction to -50 °C. It should also be noted that the background reaction without any basic catalyst again gave a roughly 1:1 ratio of iodolactone 4d and by-product 4v.

Substantial Background Reaction Revealed

The PIDA 4x analog was used in an effort to increase the reactivity of PIDA in the reaction; unfortunately, it reduced the yield and completely eliminated the enantioselection, while forming a significant amount of the trichloroacetate analog of the side product 4v. Replacement of pyrrolidine rings with substituents of diverse electronics and (especially) sterics was also unsuccessful.

Table 11. Further Examination of Various Oxidant Systems

Final Result of the Asymmetric Iodolactonization towards ε-Lactones

Previous efforts to use direct analogues of PIDA have focused on increasing its reactivity by making the components of its acetate analogues relatively better leaving groups (see PIFA in Table 3 and 4x in Table 11). However, modifying the structure of eyeless acetate ligands to increase immediate reactivity has proven somewhat more fruitful.

A Brief Inquiry into PIDA Analogs

His results are in reasonable agreement with those observed for PIFA and 4x, in that increasing the reactivity of the active iodizing species decreases the enantioselectivity and yield (probably due to numerous side reactions) in proportion to the increase in reactivity. Like the observation that additions of acetic acid favor the formation of byproduct 4v (Table 14), this result was inexplicable until the identity of the byproduct was finally discovered, when it became apparent that the significantly more sterically demanding environment of the pivalate species was so ineffective , that the nucleophile with respect to the substrate-dependent carboxylic acid, that the formation of the corresponding iodopivalate was complete.

Synthesis of Salicylate-Derived Substrates 4aq and 4au

The ester 4ap was then saponified using potassium hydroxide to obtain the desired substrate acid 4aq in 97% yield. The ester 4at was then saponified using potassium hydroxide to obtain the desired substrate acid 4au in 56% yield.

Synthesis of Tosylamino-Linked Substrate 4bb

The methyl ester 4az was then alkylated (albeit in poor yield of 21%) with 4as and potassium carbonate, giving 4ba. Ester 4ba was readily saponified via lithium hydroxide, yielding the desired tosylamino acid substrate 4bb in 55% yield.

Synthesis of para-Methoxy Substrate 4be

The reaction mixture was poured over 1 M aqueous HCl, extracted with diethyl ether and washed with brine. The reaction mixture was stirred for three hours and then quenched by the addition of water, extracted with diethyl ether, dried (MgSO 4 ), filtered and concentrated.