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Home , Heptene, Hexene, Imine, Norbornene, Olefin metathesis, Pentene

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Part I: Carbonyl-

Chapter 1 – Metathesis Reactions of Double Bonds

Introduction

Double bond metathesis, shown conceptually in Figure 1, encompasses a wide variety of chemical transformations, most prominently olefin metathesis1 via transition metal catalysts, and the Wittig olefination2. In both of these cases, two reactive double bonds come together to form a

[2+2] cycloadduct. This cycloadduct then undergoes a [2+2] cycloreversion to release the metathesis products. These transformations are a powerful way to form -carbon double bonds and are used in a variety of industrial procedures, including drug development and material synthesis. The progress and importance of these reactions will be discussed in this chapter.

Figure 1. metathesis.

While these types of metathesis reactions are well developed and synthetically useful, carbonyl-olefin metathesis remains an underdeveloped platform, despite its potential to be very impactful. There exists a few limited cases in which carbonyl-olefin metathesis has been done in a step-wise fashion using transition metal alkylidenes,3 photochemistry,4 or Lewis acid activation.5 More recently catalytic processes have been developed using a Lewis acid catalyst.6

My colleagues in the Lambert lab have also established a carbonyl-olefin metathesis reaction using a catalyst.7 These reactions will also be discussed in this chapter. 2

Figure 2: Select Categories of Double Bond Metathesis Reactions

Olefin Metathesis

Olefin metathesis is a robust reaction which has transformed organic . It has myriad applications, and its utility and importance was recognized in 2005 when ,

Robert Grubbs, and Richard Schrock were awarded the . There are three major types of olefin metathesis, shown below in Figure 3. Ring-opening metathesis is frequently driven by ring-strain, and can be used to form polymers in a process known as ring opening metathesis (ROMP). Ring-closing metathesis is often driven by entropy from the release of a molecule of gas. Cross metathesis can be the most difficult type of metathesis to enact selectively because the reaction is in principle reversible. However, this can be mitigated by catalyst design, steric and electronic factors, and, in some reactions, the release of ethylene as a driving force.8 3

Figure 3. Major types of olefin metathesis reactions.

The earliest olefin metathesis reaction was observed in 1955 by Karl Ziegler.9 He was studying propylene polymerization and, instead of the expected polymer product, noticed the formation of 1- from certain aluminum and nickel catalysts. In 1960, DuPont reported the ring-opening polymerization of to polynorbornene using and lithium aluminum tetraheptyl, a process they called “coordination polymerization”.10 A few years later a group at the Phillips Company reported what they called “olefin ” with and catalysts.11 They were able to convert propylene to a mixture of 2-butene and ethylene and incorrectly proposed a cyclopropene-metal complex as a reaction intermediate. The term “olefin metathesis” was coined in 1967 by researchers at Goodyear Tire and Rubber Company. They observed that 2- quickly became a mixture of 2-pentene, 3-, and 2-butene upon exposure to a tungsten catalyst and an aluminum Lewis acid.12 In 1971, Chauvin proposed the mechanism for olefin metathesis that is widely accepted today.13 As shown below in Figure 4, a metal alkylidene coordinates to an olefin and then reacts to form a metallacyclobutane, which can then undergo a cycloreversion to produce a new olefin and a new alkylidene. The other olefin product is formed when the new 4 metal alkylidene reacts with a different olefin in the same process. The first transitional metal alkylidene discovered was a tungsten alkylidene observed by Fischer in 1964.14

Figure 4. Basic mechanism for the olefin metathesis reaction.

Catalysts that are significantly more stable and well-behaved than those early catalysts have been developed. Grubbs has developed a number of effective -based catalysts,15 and Hoyveda has built on that by incorporating a chelating for increased stability.16

Shrock has developed a series of molybdenum catalysts for metathesis.17 In general, the Shrock catalysts are more active (and thus more useful for sterically bulky substrates), while the Grubbs catalysts are more air-stable.8 These catalysts also have different compatibility, making them complementary: The molybdenum catalysts can tolerate exposed and , while the ruthenium catalysts can tolerate , carboxylic acids, and .

A few of the more widely used catalysts are shown below in Figure 5. All of these catalysts are commercially available.

Figure 5. Commonly used achiral olefin metathesis catalysts. 5

A variety of chiral olefin metathesis catalysts have been developed, such as molybdenum catalyst 418 and ruthenium catalyst 5.19 These chiral catalysts can promote ring-opening or ring- closing metatheses on pro-chiral substrates. Chiral metathesis catalysts can also perform kinetic resolutions by reacting with one enantiomer much faster than the other one. Additionally, while cross-metathesis products tend to be E-olefins, this selectivity can be reversed by sterically bulky catalyst 6 shown below.20

Figure 6. Chiral metathesis catalysts 4 and 5 and Z-selective catalyst 6.

These metathesis catalysts and many others have been used to enact a plethora of organic transformations, and have proven useful in both industrial and academic settings. A number of biologically active natural products have been synthesized using metathesis, including

Bistramide A,21 made using catalyst 2, Baconipyrone C,22 made using catalysts 3 and 6, and

Cylindrocyclophane F,23 made using catalyst 1. All three of these syntheses involve two key metathesis steps. Olefin metathesis has been used in the large scale production of pharmaceutical candidates, such as BILN 2061 ZW,24 active against hepatitis C. The key metathesis step, promoted by ruthenium catalyst 7, and eventual product are shown below. ROMP has proven to be a very effective method for producing polymeric compounds on a large scale and is used to 6 make polymers such as polynorbornene (Norsorex), polyoctenamer (Vestenamer) and polydicyclopentadiene, and also used to make block copolymers.25 ROMP is so robust that it is being incorporated into self-healing materials, where small amounts of the active monomer and metathesis catalyst are incorporated into a material and can react to form a dicyclopentadiene polymer plug when microcracking occurs.26

Figure 7. Large-scale synthesis of BILN 2061 ZW using olefin metathesis.

Wittig Reaction

Like olefin metathesis, the Wittig Olefination has had a tremendous impact on the field of organic chemistry, and was recognized with a Nobel Prize in 1979. Discovered by Georg Wittig in 1953, the is a reaction between a carbonyl and a phosphorus to produce an and oxide.27 The reaction proceeds as shown below in Figure 9. First, the ylide attacks the carbonyl to form betaine intermediate 8. The betaine intermediate then closes to form the oxaphosphetane 9 which eliminates to form triphenylphosphine oxide and the alkene product. The reaction is driven by the formation of the strong oxygen-phosphorus double bond.

The existence of betaine intermediate 9 is debated; there is evidence that carbonyls and phosphorus can react directly in a [2+2] fashion to form oxaphosphetane 8.28 7

Figure 8. The first report of the Wittig Reaction.

Figure 9. The mechanism of the Wittig Reaction.

The Wittig reaction with unstabilized ylides, as originally reported by Wittig, tends to be very selective for the Z-isomer. Reactions with stabilized ylides (where R3 in Figure 9 is an electron withdrawing group) are slower and produce more of the E-isomer. The Schlosser modification, which involves the addition of lithium salts at -78 °C, reverses the stereochemistry of the betaine to enable the selective synthesis of E-.29 The Horner-Wadsworth-Emmons reaction is a variation that uses -stabilized 10 instead of a phosphorus ylide and produces E-alkenes.30 These phosphonate-stabilized are more nucleophilic and less basic than their ylide counterparts. The salt byproduct can be easily removed by aqueous extraction, unlike triphenylphosphine oxide. The Still modification of the Horner-

Wadsworth-Emmons reaction allows for the synthesis of Z-alkenes. Here, phosphonate 10 has electron withdrawing groups on it (such as R1 = trifluoroethyl) and highly dissociative conditions are used.31 8

Figure 10. The Horner-Wadsworth-Emmons Reaction.

One of major downside of the Wittig reaction is the stoichiometric formation of phosphorus byproducts, which greatly hurts the reaction’s atom economy and can make purification difficult, especially on a large scale. To mitigate this, the phosphine oxide can be recycled,32 and a catalytic version of the Wittig reaction has also been developed.33 Here, the phosphine oxide is reduced in situ using diphenyl silane, and the resulting phosphine can be alkylated by an halide. After deprotonation of the phosphine salt the resulting ylide can react with an to form the desired alkene. Enantioselective versions of the Wittig reaction have also been developed in which a chiral phosphorus ylide desymmetrizes meso dicarbonyl compounds.34

Because the Wittig reaction is robust, diastereoselective, and well-behaved, it has tremendous utility in the field of organic chemistry. The Wittig reaction has been employed in the of a number of natural products including leukotriene C-1,35 Showdomycin,36 and prolycopene.37 Industrial production of Vitamin A by BASF was done using a large-scale

Wittig reaction, as shown below in Figure 11.38 A variety of other polyene natural products have also been industrially synthesized in a similar fashion.

Figure 11. BASF’s Industrial Synthesis of Vitamin A 9

Tebbe Olefination

The Tebbe reagent is used for the methylenation of carbonyl compounds, as shown below in Figure 12.39 Originally synthesized by Fred Tebbe at Dupont Central Research, the Tebbe reagent was the first compound to connect a transition metal to a main group metal using a . It is a red pyrophoric solid that needs to be handled under an inert atmosphere.

This reaction proceeds when a mild Lewis base (such as ) reacts with the Tebbe reagent to product the active titanium (IV) Schrock 11. The oxophilic titanium reacts with the carbonyl to form oxatitanocyclobutane 12 ring which immediately decomposes to release the desired alkene product.40 Similarly to the Wittig reaction, the formation of the titanium-oxygen bond provides the driving force this reaction, and its strength prevents turnover of the titanium.

Figure 12. The Tebbe olefination.

Figure 13. The mechanism of the Tebbe reaction.

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As discussed previously, olefination of carbonyls can also be done using a Wittig reaction; however, in certain cases the Tebbe reagent is more effective. The Tebbe reagent can react with more sterically hindered , and can also react with the carbonyl moiety of and to from and enol , respectively. It is non basic and so does not cause beta elimination. The Tebbe reagent can methylenate with stereochemistry at the alpha position without any racemization; this has proven very valuable in reactions of sugars where stereochemistry is crucial.41 A number of natural products have been synthesized using the

Tebbe olefination, including Okilactomycin,42 Aplysin,43 and Azadiractin.44 All three of those syntheses involved the methylenation of an and so would not have been possible using a

Wittig reagent.

The Tebbe olefination has had significant impact on organic chemistry and has proven to be a powerful method for olefinating carbonyl compounds. Considering the Tebbe reaction alongside olefin metathesis and the Wittig olefination, it is clear that double bond metathesis reactions have been tremendously useful. These reactions have had a transformative effect on organic chemistry and have changed the way chemists think about making and breaking chemical bonds.

Carbonyl-Olefin Metathesis

In contrast to the metathesis reactions previously mentioned, carbonyl-olefin metathesis has proven to be a much greater challenge and has received significantly less attention from the synthetic community, despite the fact that it would have tremendous utility. One could imagine three types of carbonyl-olefin metathesis, not unlike the three types of olefin metathesis shown above in Figure 3: ring opening, ring closing, and cross-metathesis. Ring opening metathesis 11 would provide a linear molecule with orthogonal functionality on either end. Cross metathesis could be seen as a catalytic alternative to the Wittig reaction, and it would avoid the selectivity problems sometimes seen in olefin cross metathesis by having two different functional groups reacting.

There have been a few isolated instances of carbonyl-olefin metathesis, most of which are very limited in scope, step-wise, and/or non-catalytic. Efforts have been made towards a transition metal-mediated carbonyl-olefin metathesis, such as the ring-closing metathesis shown below in Figure 14.45 These reactions attempt to use a strategy similar to the catalytic olefin metathesis reactions discussed previously; however, they are limited by the very strong metal- oxo bond which prevents the metal from re-entering the , and necessitates that this process be stoichiometric in transition metal. This reaction is similar in concept to the Tebbe reaction.

Figure 14. Metal-mediated carbonyl-olefin metathesis.

There have also been photochemical attempts at enacting carbonyl-olefin metathesis using the Paterno-Büchi reaction, such as the ring-opening metathesis shown below in Figure

15.46 Here, light enables the carbonyl and olefin to react in a [2+2] fashion to form the oxetane ring, which is then subject to pyrolysis conditions to form the metathesis product. Photochemical reactions can be difficult to control and perform, and are often inconsistent. The harsh pyrolysis conditions required to open the oxetane ring severely limits the potential scope of the reaction and results in low yields and decomposition. While there have been other attempts at opening the 12 ring using methods such as photoinduced electron transfer,47 this process remains operationally complex and ungeneralized.

Figure 15. Stepwise carbonyl-olefin metathesis using photochemistry.

A few examples of Lewis acid mediated carbonyl-olefin metathesis have also been reported. Most reports work on only a few specific substrates and require a super-stoichiometric amount of boron trifluoride diethyl etherate Lewis acid.48 A catalytic version of the reaction was recently published in 2015.49 As shown below in Figure 17, a trityl Lewis acid can catalyze carbonyl-olefin metathesis in moderate yield. This reaction built on previous work using EPZ-10, a clay-based Lewis acid,50 and produces exclusively the E-isomer. Unfortunately, the reactions take over 24 hours and are limited to aromatic aldehydes and tri-substituted alkenes. Attempts at using aliphatic aldehydes resulted in aldehyde decomposition and no product, likely due to undesired aldol-type processes catalyzed by the Lewis acid. Less substituted alkenes are ineffective due to the instability of the potential carbo-cation intermediate. For unclear reasons, tetra-substituted olefins were also completely unreactive.

Figure 16. Lewis acid mediated carbonyl-olefin metathesis

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Figure 17. Trityl Lewis acid catalyzed carbonyl-olefin metathesis.

Earlier this year, Schindler published an account of an iron-catalyzed Lewis acid carbonyl-olefin metathesis.51 Here, she shows ring-closing metathesis on a variety of ketones to produce and products. This could be done on trisubstituted alkenes as well as certain aryl-substituted alkenes and represents the most general carbonyl- olefin metathesis to date.

Figure 18. Iron(III)-catalyzed carbonyl-olefin metathesis.

The limitations of these methods make it clear that there is still ample room for growth in the field of carbonyl-olefin metathesis. One thing that all of these strategies have in common, along with the previously mentioned metathesis reactions, is that they rely on a [2+2]/retro [2+2] strategy. One of the major downsides of this paradigm is that [2+2] reactions are thermally forbidden, and so can only be done stepwise or photochemically. In 2012, my colleagues in the

Lambert lab published the first example of catalytic carbonyl-olefin metathesis.7 They moved away from the [2+2] paradigm and instead used a thermally allowed [3+2] strategy to enact the metathesis of cyclopropenes and aldehydes. The details of this strategy will be discussed further in chapter 2. 14

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Chapter 2 – Progress Towards Carbonyl-Olefin Metathesis of Norbornene

Introduction

As previously discussed, while many different strategies for carbonyl-olefin metathesis have been explored, there is no general strategy, and carbonyl-olefin metathesis remains a woefully underdeveloped field. All of the previously developed strategies rely on a [2+2] mechanism which is undesirable because it is thermally disallowed, and so must be done photochemically or in a step-wise fashion. Additionally, metal-oxo bonds are very strong and so, unlike with olefin metathesis, metal-mediated carbonyl-olefin metathesis requires a stoichiometric amount of transition metal. As a result, the Lambert lab hypothesized that a [3+2] cycloaddition/cycloreversion sequence could be used instead of the traditional [2+2] paradigm.

In 2012, my colleagues in the Lambert lab published the seminal paper on this topic, and the first example of catalytic carbonyl-olefin metathesis.52

Figure 19 a. The traditional [2+2] metathesis paradigm b. The new [3+2] paradigm.

In this chapter, the design and precedence of this new reaction, the proposed catalytic cycle, and the previous work done by my colleagues Christine Vanos and Allison Griffith on the metathesis of cyclopropene will be discussed. Theoretical evidence and work I have done 18 towards expanding the scope of the reaction from cyclopropene to norbornene will be elaborated along with a detailed discussion of the various factors affecting the cycloaddition and cycloreversion steps.

[3+2] Metathesis Paradigm

In thinking about moving to a new [3+2] metathesis paradigm, as shown above in Figure

19b, several criteria would need to be met. Firstly, the carbonyl metathesis partner would need to be easily interconverted into the reactive dipole. Secondly, this reactive intermediate would need to readily undergo a cycloaddition reaction. This cycloaddition reaction would produce a psuedosymmetric cyclic intermediate, akin to the psuedosymmetric 4-membered ring intermediate produced in the [2+2] paradigm. Thirdly, this 5-membered ring intermediate must be able to undergo a [3+2] cycloreversion in the orthogonal direction of the cycloaddition to produce the desired products. All of these criteria could be met with the use of a hydrazine catalyst, or X=N in Figure 19, as shown in Figure 20. Looking at the proposed catalytic cycle in

Figure 21, the hydrazine catalyst would first condense with an olefin to form an azomethine imine, which could then undergo a [3+2] cycloaddition to form the psuedosymmetric pyrazolidine intermediate. Following subsequent orthogonal [3+2] cycloreversion, the product olefin would be released along with a new azomethine imine, which could be hydrolyzed, releasing the carbonyl product and allowing the hydrazine to reenter the catalytic cycle. The reversible condensation between and olefins to form azomethine imines is well established, and there is precedence for the both the cycloaddition and cycloreversion steps, as will be discussed. This new catalytic cycle uses the same general idea from the [2+2] paradigm of having the reacting partners form a psuedosymmetric cyclic intermediate and then an 19 orthogonal retro-cycloaddition occurring to give the products; however, it uses a thermally allowed [3+2] cycloaddition instead of a thermally forbidden [2+2] reaction.

Figure 20. The new [3+2] metathesis plan

Figure 21. The proposed catalytic cycle using a hydrazine catalyst

Cycloaddition Precedence

There is ample precedence for 1,3-dipolar cycloadditions of azomethine imines and olefins53 dating back to extensive work done by Hüisgen in the 1960’s.54 Hüisgen explored a wide variety of cycloaddition reactions and was able to perform the first cycloaddition by combining azomethine imine 15 with a or 1- to readily form pyrazolidine cycloadduct 16 in good yield.55 For this early work on cycloadditions, he fully isolated the 20 azomethine imine starting material: in this case, by combining diazo fluorene 13 with diazocyanide 14 to produce the solid azomethine imine 15.

Figure 22. First example of an azomethine imine cycloaddition reaction.

Hüisgen showed that both acyclic and cyclic azomethine imines could react with all types of olefins except for those which were highly substituted, due to issues with steric bulk. He found these reactions to be facile and to occur at only mildly elevated temperatures with unactivated dipolarophiles such as styrene and norbornene. These 1,3-dipolar cycloaddition reactions are in part driven by the elimination of charge from the zwitterionic dipole during the course of the reaction, and additionally driven by the formation of new sigma bonds. This driving force is so powerful that these dipolar cycloadditions can even occur when the cycloaddition reaction breaks aromaticity (Figure 23), although those reactions tend to require activated dipolarophiles, such as methyl propiolate, due to the additional driving force required.56

Figure 23. 1,3-dipolar cycloaddition which breaks aromaticity.

While much of Hüisgen’s work on cycloadditions with azomethine imines was done with the azomethine imine preformed, he also noted that they could be formed in situ from the 21 condensation of an aldehyde and a hydrazine compound. He suggested that this might be a more general strategy for their formation and that, due to the strong driving force for the reaction, the cycloaddition would proceed even if only modest amounts of the azomethine imine were present at equilibrium.54 Indeed this can be seen in the cycloaddition reaction in Figure 24, where the cycloaddition occurs in refluxing without the need for dehydrative conditions.57 Here, the acid from the hydrazine salt proved necessary for the reaction.

Figure 24. Cycloaddition where the azomethine imine is formed in situ.

These cycloadditions are frequently extremely regioselective, often producing a single isomer via NMR analysis. This can sometimes be explained by frontier molecular orbital (FMO) theory.57 The LUMO of the azomethine imine dipole has a much large coefficient on the carbon atom than on the terminal atom. The reverse is true for the HOMO; the larger lobe is on the outside nitrogen atom. When the dipolarophile is activated with an electron withdrawing group, the LUMO of the dipolarophile interacts with the HOMO of the azomethine imine. In contrast, when the dipolarophile has only electron donating groups on it, the HOMO of the dipolarophile reacts with the LUMO of the dipole. These two cases produce differing regioisomers, since in both cases the larger lobe on the dipole is interacting with the terminal carbon on the alkene. Because of the concerted nature of the reaction is it also stereospecific and so cis and trans alkene dipolarophiles will produce different products. The steric bulk of the substituents on the reactants can sometimes be used to predict the relative stereochemistry of the product by examining the less hindered approach. 22

Figure 25. Use of FMO theory to explain regiochemistry

The above work clearly shows that cycloaddition reactions between azomethine imines and alkenes to form pyrazolidines are facile and can occur under fairly mild conditions. Said azomethine imines can be formed in situ via condensation between hydrazines and carbonyl compounds. This strongly suggests that the first two steps of the proposed catalytic cycle are valid and should occur readily.

Cycloreversion Precedence

In comparison to cycloaddition reactions, there is far less precedence for cycloreversion reactions. While cycloaddition reactions are driven by elimination of the charge separation from the dipole and the formation of new sigma bonds, cycloreversion reactions do not have an obvious general driving force. Conjugation gain and steric relief are the two most common driving forces for cycloreversion reactions.58 As a result there are only three previous examples of the retro cycloaddition of pyrazolidine in the literature and they are all specific and somewhat contrived. All of these examples require elevated temperatures and long reaction times.

The first example of a cycloreversion of a pyrazolidine is shown below in Figure 26 when azomethine imine 16 is heated with tetracyanoethylene to form pyrazolidine 17.59 The high 23 number of electron withdrawing groups and the steric strain renders pyrazolidine 17 unstable, and it undergoes an orthogonal cycloreversion. The cycloreversion goes towards products as opposed to back towards starting material because pyrazolidine 18 has two trifluoromethyl groups on the adjacent carbon helping to stabilize the negatively charged nitrogen atom, as opposed to the two methyl groups on pyrazolidine 16. This is the only example in the literature of a cycloreversion occurring orthogonally following a cycloaddition, as would be required for the proposed catalytic cycle to work; the other two examples are pyrazolidine cycloadducts reverting to starting material. While this example of metathesis is encouraging, it is clearly quite contrived and not synthetically useful.

Figure 26. Metathesis reaction via cycloaddition/cycloreversion sequence.

Conjugation in the dipole and dipolarophile products as a driving force can be seen in

Figure 27 below.60 Here, pyrazolidine 19 undergoes a cycloreversion reaction upon being refluxed in xylene for four days. The azomethine imine intermediate was trapped with norbornene to yield pyrazolidine 21 in moderate yield. Both the azomethine intermediate 20 and the cyclopentenone released from the cycloreversion include conjugation not present in pyrazolidine 19. This conjugation gain is crucial to the reaction; the reaction completely shuts down if the carbonyl on pyrazolidine 19 is protected as an . 24

Figure 27. Cycloreversion driven by conjugation.

The third example of a cycloreversion of a 1,3-dipolar cycloreversion of a pyrazolidine, shown below in Figure 28, is also driven by conjugation present in the alkene product.61 It is likely also driven by steric relief as pyrazolidine 22 is highly substituted. This reaction required 4 days of high temperatures and proceeds in only moderate yield. The azomethine imine product could also be trapped by other dipolarophiles.

Figure 28. Cycloreversion driven by conjugation gain and steric relief.

From these isolated examples it is clear that, although the [3+2] cycloreversion step of the proposed catalytic cycle is thermally allowed and has been done, it is not nearly as facile as the [3+2] cycloaddition step. The cycloaddition is general and can occur under mild conditions, while the cycloreversion requires longer reaction times, higher reaction temperatures, and very specific substrates.

Carbonyl-Olefin Metathesis of Cyclopropene 25

In 2012, my colleagues in the Lambert lab demonstrated this proposed catalytic cycle and reported the first example of catalytic carbonyl-olefin metathesis.52 Their initial work validated that the cycloreversion step was indeed the most challenging step of the catalytic cycle, as suggested by the literature precedent. To enact the cycloreversion reaction, and to ensure that the cycloreversion reaction was orthogonal to the cycloaddition reaction, they used cyclopropenes as the reactive olefins. The ring strain present in the cyclopropane ring moiety of the pyrazolidine intermediate provided the driving force for the cycloreversion. Bicyclic hydrazine catalyst 22 proved to be uniquely effective at enacting this transformation. The transformation is effective for a variety of aromatic aldehydes and several cyclopropene substrates.

Figure 29. Organocatalytic carbonyl-olefin metathesis.

A significant amount of evidence was found suggesting that this reaction does indeed proceed through the proposed catalytic cycle (Figure 21). Firstly, the products are exclusively formed as the E isomer. To produce the Z isomer, the cycloaddition step would have to occur via approach on the Z azomethine imine 23. While the Z azomethine imine is thermodynamically favored, interconversion between the Z and E hydrazoniums should be facile, and, as shown in

Figure 30a, this approach would lead to a high amount of steric clashing. Secondly, the hydrazonium salt from hydrazine 22 and benzaldehyde was isolated, recrystallized, and subject to an equivalent of cyclopropene 24 under reaction conditions. Hydrazonium 25 was observed by

NMR as would be expected from the cycloaddition/cycloreversion sequence; the final aldehyde product from the step was not observed due to the lack of water present in the 26 reaction. Although the cycloadduct was not observed at any point during the reaction, this evidence strongly suggests that the proposed catalytic cycle is in effect and that the cycloadduct intermediate is too short-lived to be detected.

Figure 30. Evidence for the proposed catalytic cycle.

Computational Work

Following the publication of this work, the Lambert lab engaged in a collaboration with the Houk group at UCLA and they performed a density functional theory (DFT) study of this reaction.62 They calculated the Gibbs free energies for the proposed catalytic cycle and corroborated its validity. Their results line up with the experimental evidence shown in Figure

30: the Z-hydrazonium is more stable than the E-hydrazonium, but the energy barrier for interconversion is only 3.3 kcal/mol and the energy barrier for cycloaddition is 3.4 kcal/mol higher for the Z-isomer than the E-isomer, leading to a predicted 1000:1 selectivity in favor of the E-product. The barrier for cycloaddition is also significantly higher than the energy barrier for cycloreversion, consistent with the fact that the cycloadduct intermediate was never observed.

27

While the reaction has been experimentally limited to cyclopropenes, the Houk group looked computationally at the cycloaddition and cycloreversion energy barriers for other olefin substrates, as shown in Table 1. These calculations provide insight as to why this reaction is currently only viable for cyclopropene substrates; cyclopropenes are the only substrate for which the cycloaddition energy barrier is significantly lower than that of the cycloreversion. While the cyclobutene cycloaddition and cycloreversion energy barriers are comparable and cyclobutenes might be usable substrates, they can be difficult to synthesize and would not represent a significant improvement in scope. All other substrates have much higher cycloreversion energy barriers. This also reinforces what the literature evidence suggests: the cycloreversion step is by far the most challenging step and the largest obstacle to overcome in generalizing this reaction.

While the energy barrier for the cycloaddition of unstrained olefins is still fairly low, the cycloreversion energy barrier increases significantly. There is a strong correlation (r2 = 0.89) between the ring strain released during the cycloreversion and the cycloreversion energy barrier, suggesting that the ring strain is indeed providing the driving force for the reaction. 28

Table 1. Calculated cycloaddition and cycloreversion barriers for various olefins.

Another report by Zhang detailing a DFT study on this carbonyl-olefin metathesis suggests that proton transfer is the rate determining step with the very high energy barrier of 30.9 kcal/mol.63 This contradicts other reports that proton transfer between amines is a low energy process,64 and opposes the fact that the pyrazolidium salt was never observed under experimental conditions. The Houk calculations support the fact that the cycloadduct was never observed.

All of this theoretical evidence suggests that moving to other olefins would be non-trivial and that new catalysts would likely need to be developed moving forward.

29

Carbonyl-Olefin Metathesis of Norbornene

When I joined the project my goal was to expand this metathesis reaction from cyclopropene to norbornene. The products of such a metathesis would be orthogonally functionalized cyclopentane rings, known to be synthetically useful compounds.65 Additionally,

ROMP of norbornene produces norsorex, a polymer important in industry.66

Figure 31. Ring opening metathesis of norbonene.

In thinking about expanding carbonyl-olefin metathesis from cyclopropene to norbornene, the challenging step is clearly going to be the cycloreversion step. Norbornene has significantly less ring strain than cyclopropene (54.5 vs. 27.2 kcal/mol), although there is still ring strain present to help facilitate the cycloreversion and to ensure that it is irreversible and in the correct direction. In looking at the theoretical work done by Houk, the cycloaddition energy barrier for cyclopropene and norbornene are very similar; only a modest increase is seen moving to the less strained norbornene.62 However, the cycloreversion energy barrier for the norbornene cycloadduct is nearly double that of the cyclopropene cycloadduct. While the cyclopropene cycloadduct was never isolated nor observed, we would expect the norbornene cycloadduct to be isolable, based on both the theoretical work and on previous research on cycloadditions.57 30

Figure 32. ΔGact for the metathesis of cyclopropene vs. norbornene

Due to these differences in activation energy, I decided to take a different approach to the carbonyl-olefin metathesis of norbornene. Rather than attempting to enact the metathesis in one- pot, like my colleagues did with cyclopropenes, I decided to first synthesize and isolate the pyrazolidine cycloadducts, and then investigate the conditions required to force the pyrazolidine ring to break open. Because the cycloreversion step has the highest energy barrier, determining how to lower that energy barrier should lower the energy barrier of the overall reaction. This would also provide valuable insight into the factors affecting pyrazolidine cycloreversion reactions, as there is limited research on this topic. By heating dimethylhydrazine dihydrochloride, benzaldehyde, and norbornene in refluxing methanol, the cycloadduct could be isolated in an unoptimized 50% yield.

Figure 33. Synthesis of norbornene cycloadduct.

31

With the cycloadduct in hand, a variety of conditions were screened to determine how to force the cycloreversion. The cycloadduct was heated up in a variety of different solvents under neutral conditions, as well as with Lewis and Brønsted acids. After extensive screening it was found that trace amounts of the product were produced with one equivalent of hydrochloric acid in refluxing ethylene glycol. Here, the product was protected in situ as the acetal, which enabled it to not fully decompose under the harsh reaction conditions.

Figure 34. First observation of ring-opening carbonyl-olefin metathesis of norbornene.

With a method for enacting this metathesis in hand, I was now able to explore what factors affect the cycloreversion, and in doing so hopefully raise the yield and work towards a catalytic strategy. We first considered the major factors which can affect cycloreversion reactions: steric strain, electronic factors, ring strain, and conformational flexibility.58 Moving from cyclopropene to norbornene the effect of lowering the ring strain is clear: less ring strain means a lower driving force for the reaction, and as a result I needed to use a much higher temperature. We decided to first explore how electronic factors could have an effect on the cycloreversion, and a variety of cycloadducts from para-substituted benzaldehydes were synthesized with the goal of making a Hammett plot. Unfortunately, while the cycloreversion product from these cycloadducts was observed, I was unable to obtain any consistent data. The harsh conditions required for the reaction meant that there was product decomposition, as well as decomposition of various internal standards, making it difficult to monitor the reactions.

Additionally, the very high temperature required for the reaction meant that the reactions could 32 not be done in an oil bath; instead, they were performed in a sand bath, rendering it extremely challenging to keep the temperature consistent. While it was gratifying to see that the cycloaddition worked with both electron rich and electron poor aldehydes, I realized at this point that I would need to figure out a way to perform the reactions at a lower temperature in order to conduct a meaningful investigation.

Figure 35. Investigation of electronic effects.

When my colleagues Christine Vanos and Allison Griffith were testing hydrazine catalysts for the metathesis of cyclopropene, they found that [2.2.1] bicyclic hydrazine catalyst

22 was by far the most effective catalyst. We believe this was due to two major factors. Firstly, the acyclic hydrazine catalysts were subject to catalyst degradation when chloride ions directly attacked the hydrazonium intermediate; in the hydrazonium derived from the bicyclic catalyst this pathway is blocked. While this degradation process would not have an effect on the cycloreversion step, it is important to consider when looking forward to an eventual catalytic process. Secondly, the bicyclic catalyst forces conformational rigidity into the cycloadduct intermediate. In order for the electrocyclic cycloreversion to occur, the central pyrazolidine ring needs to be planar and the lone pair orbitals on the nitrogen atoms need to be in a syn-periplanar alignment. In cycloadducts from dimethylhydrazine, the orbitals can achieve alignment but it is not the lowest energy conformation due to steric strain between the methyl groups. In contrast, in 33 the cycloadduct derived from the bicyclic hydrazine catalyst, the orbitals are forced into the syn- periplanar alignment required for the cycloreversion by the rigidity of the hydrazine structure.

Figure 36. Dimethyl hydrazine vs. [2.2.1] bicyclic hydrazine.

I formed a cycloadduct derived from the bicyclic hydrazine and subjected it to cycloreversion conditions. Excitingly, it showed reactivity as low at 130 °C. At this temperature, an oil bath could be used, and product decomposition was not observed, making it possible to monitor the reaction quantitatively. This lower temperature allowed for screening of a much wider range of solvents, but after extensive experimentation (1-butanol, butane diol, cyclohexanal, furfuyl , DCB, DMA, DMF, DMSO, ionic liquid, propane diol, propionic acid, mesitylene, and NMP were all tested) it was found that the only other solvent that could enact the reaction at all was propane diol, and it was significantly less effective than ethylene glycol. Screening was also done to examine the effects of adding different types and amounts of acid. These showed that the type and strength of the Brønsted acid present did not matter and that while a minimum of one equivalent of acid was optimal, more acid did not seem to have an impact. Thus I proceeded with one equivalent of hydrochloric acid for simplicity. Lastly, the 34 influence of water on the reaction was tested and it was found that the addition of 10% water as a co-solvent had a mild beneficial effect on the reaction. With these conditions in hand, a 2.6%

NMR yield was observed after 24 hours (compared to a standard added after the reaction). This

NMR yield and all other yields presented in this chapter represent an average of three consistent runs. While this yield is still quite low, it was gratifying to get consistent results and to have a firm starting point with which to examine the factors affecting the cycloreversion reaction.

Figure 37. Optimized cycloreversion reaction with the [2.2.1] bicyclic hydrazine.

With these conditions in hand, a series of cycloadducts were made with increasing steric demand on the aldehyde component to try to destabilize the central pyrazolidine ring. Moving from benzaldehyde to 2,4-dimethylbenzaldehyde resulted in a modest increase in NMR yield up to 4.2% in 24 hours. Further increase in the steric bulk to mesitylaldehyde caused a large jump in yield to 16%, a 6.2 fold increase from benzaldehyde. The cycloadduct from 2,6- dichlorobenzaldehyde was synthesized and also had a 16% NMR yield, demonstrating that this was a steric effect as the 2,6-dichlorobenzene and mesitylene are approximately the same size but are very different electronically. Lastly, the steric demand of the aldehyde component was increased to 9-anthraldehyde. Here, the reaction was complete in eight hours and the yield increased to 22%. At this point the central pyrazolidine ring was so destabilized that other undesirable decomposition pathways were occurring as well. This trend could be due to the weakening of the carbon-nitrogen bond that breaks during the cycloreversion reaction. 35

Table 2. The effects of increasing steric bulk of the aldehyde component on the efficacy of the cycloreversion.

Given that increasing the steric bulk on the aldehyde had a clear positive effect, I next set out to increase steric bulk on the hydrazine to see if the effect translated. This would hopefully move us closer to a general catalytic strategy. This proved difficult as the [2.2.1] bicyclic hydrazine is formed via a Diels-Alder reaction between and diazo compound

26, followed by and deprotection to produce hydrazine 22 (Figure 38a).

Cyclopentadiene compounds rearrange far faster than Diels-Alder reactions occur and so substituents tend to end up in the least-hindered position. While ideally we would have liked to install substitution at the bridgehead positions to increase the steric demand around the central pyrazolidine ring in the cycloadduct, this proved problematic. Known with a single tert ,67 a spiro cyclopropane ring,68 and a spiro cyclopentane ring69 were synthesized to produce hydrazines 27, 28, and 29 respectively (Figure 38b-d).

Pentamethylcyclopentadiene was also used as a dienophile and while the Diels-Alder reaction 36 could occur, one of the Boc groups fell off during the reaction and the resulting product could not be hydrogenated, leading to the synthesis of hydrazine 30 (Figure 38e).

Figure 38. Synthesis of [2.2.1] bicyclic hydrazines.

Hydrazines 27-30 were subject to cycloaddition conditions with benzaldehyde and norbornene and cycloadducts were created from hydrazines 27-29. Hydrazine 30 was too sterically hindered to undergo the cycloaddition reaction. The cycloadduct from hydrazine 27 had the same cycloreversion NMR yield in 24 hours as the parent cycloadduct; the tert-butyl group was too far away from the central pyrazolidine ring to have any effect on the 37 cycloreversion. Adding spiro-rings to the hydrazine proved detrimental to the cycloreversion: the cycloadducts from hydrazines 28 and 29 had only a 1.1% NMR yield in 24 hours.

Figure 39. 24 hour NMR yields of cycloadducts derived from substituted [2.2.1] bicyclic hydrazines.

Because of the limitations on the synthesis of substituted [2.2.1] bicyclic hydrazines, we turned our focus to forming substituted pyrazolidines. This would allow us to do a more systematic study on the connection between steric bulk on the hydrazine and cycloreversion efficacy. A series of hydrazines with increasing steric bulk on carbon three were synthesized using a condensation/cyclization reaction followed by reduction of the imine.70 I also synthesized a hydrazine with a spiro cyclopentane ring using a similar strategy.71 To form 3,3,5-trimethyl pyrazolidine a stronger reducing agent, “Superhydride” was necessary due to steric hindrance on the imine carbon.72 The use of this stronger reducing agent necessitated a protection/deprotection sequence due to the incompatibility of “Superhydride” with acidic protons. 38

Figure 40. Synthesis of substituted pyrazolidines.

Cycloadducts were synthesized from these pyrazolidines, benzaldehyde, and norbornene and subject to cycloreversion conditions. Unfortunately, these cycloadducts were not well- behaved. While the cycloreversion was observed with all of them, the yields were very inconsistent, ranging from 3-6%, and as a result no clear pattern could be discerned.

Figure 41. Cycloadducts synthesized from pyrazolidines.

One reason for these inconsistencies could relate back to the reason why the bicyclic hydrazine is more effective than acyclic hydrazines: orbital alignment. As a result we decided to return to looking at bicyclic hydrazine catalysts and I synthesized [2.2.2] bicyclic hydrazine 31. 39

Although 1,3-cyclohexadiene is a less powerful dienophile then cyclopentadiene, I was still able to synthesize this hydrazine using a Diels-Alder reaction followed by hydrogenation and deprotection. However, light was necessary to force dienophile 22 into the s-cis conformation required for the Diels-Alder reaction; in the absence of light the prevails.73

Figure 42. Synthesis of [2.2.2] bicyclic hydrazine 31.

The cycloadduct from hydrazine 31, benzaldehyde, and norbornene had a 22% NMR yield in 24 hours, a significant increase over the 2.6% NMR yield from the cycloadduct derived from [2.2.1] bicyclic hydrazine 22. We hypothesized that this could be due to the increased C-N-

N bond angle, as shown in Figure 43b. The larger bond angle would cause the nitrogen atoms to favor being in the sp2 hybridization, as they are in the product, as opposed to the sp3 hybridization, as they are in the cycloadduct. 40

Figure 43. The cycloadduct from the [2.2.2] bicyclic hydrazine has an increased cycloreversion yield due to the increased bond angle.

We tried to further widen the bond angle by synthesizing larger monocyclic hydrazines.

These monocyclic hydrazines were easily prepared via bis-alkylation of hydrazine with a dibromo followed by deprotection (Figure 44a).74 I also synthesized a bulky 3,6-dimethyl analogue of the 6 membered ring using a Diels-Alder reaction followed by hydrogenation and deprotection (Figure 44b).75 Unfortunately, the cycloadducts from these hydrazines, shown below in Figure 44c, did not show any product, likely because they are not in the proper conformation. The 7 and 8 membered ring hydrazines and resulting cycloadducts were synthesized by my former colleague Allison Griffith. 41

Figure 44a. and b. Synthesis of larger monocyclic hydrazines. c. Resulting cycloadducts which were not viable substrates for the cycloreversion.

Because this evidence suggested that using bicyclic hydrazines was essential for the cycloreversion, I tried to further increase the C-N-N bond angle by synthesizing larger bicycles.

Unfortunately, the synthetic pathway used to synthesize bicyclic hydrazines 22 and 31 was not viable for forming larger bicycles. Cycloheptadiene and cyclooctadiene are poor for the

Diels-Alder reaction and so did not react with dienophile 26. Instead, more reactive urazole dienophile 32, again followed by hydrogenation, was used to form [3.2.2] and [4.2.2] protected hydrazines.76 Previously, deprotection was facile because the Boc groups could be removed under acidic conditions and would crash out of dioxanes as the bis-HCl salt. Urazole groups are more difficult to deprotect and require basic conditions and elevated temperatures.77 A variety of conditions were screened but under all of them the urazole was oxidized in situ to the diazene; it appears that these hydrazines are unstable under deprotection conditions. One factor that could 42 come into play here is that the large bond angle desired to promote the cycloreversion reaction could be making this hydrazine more prone to oxidation.

Figure 45. Synthetic pathway to larger bicyclic hydrazines.

This work suggested that larger bicycles such as [3.2.2] and [4.2.2] were not feasible, and attempts and incorporating steric hindrance into the [2.2.2] catalyst were not successful.

However, the success of the [2.2.2] catalyst combined with the improvement seen when using sterically hindered aldehydes led me to attempt a one-pot carbonyl-olefin metathesis procedure.

With a 20% catalytic loading of bicyclic hydrazine 31, the carbonyl-olefin metathesis of 2,6- dichlorobenzaldehyde and norbornene was affected with an 8% NMR yield in 48 hours. The lack of turnover is likely due to the hydrazine’s instability under the harsh reaction conditions. This represents the first one-pot carbonyl-olefin metathesis of norbornene.

Figure 46. One-pot carbonyl-olefin metathesis of norbornene.

Conclusions

This chapter describes efforts towards expanding the Lambert lab’s [3+2] strategy for organocatalytic carbonyl-olefin metathesis from cyclopropene to norbornene. While this ultimately proved unsuccessful catalytically, the process proceeds in modest yields in 2-steps. 43

[3+2] cycloreversions of pyrazolidines are challenging and have been generally unexplored, and this research examined many of the factors affecting them. We found that steric factors seem to play a large role, with the reaction rate increasing with more hindered aldehydes, and that electronic factors seem to have little effect on the reaction. Orbital alignment was shown to play a key role in the reaction: the bicyclic catalysts were by far the most effective due to their structural rigidity. The effects of ring strain were shown in two ways. First, by showing that the cycloreversion is far more difficult with the less strained norbornene as opposed to cyclopropene, and second from the ring strain in the wider bond angles in the [2.2.2] hydrazine promoting the cycloreversion.

44

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Acknowledgements

I worked alongside Dr. Allison Griffith for some of the time while I was working on the metathesis of norbornene. She synthesized and tested the cycloadducts from the 7 and 8 member ring hydrazines and also did some work not discussed in this chapter. She and Dr. Christine

Miller (Vanos) did the work on the cycloreversion of cyclopropene that was key to the further work on norbornene. 47

Experimental Data for the Cycloreversion of Norbornene

General Information. All reactions were performed using oven-dried glassware under argon unless noted. Organic solutions were concentrated using a Buchi rotary evaporator. Aldehydes were distilled or recrystallized before use. All other commercial reagents were used as provided.

Flash column chromatography was performed employing 32-63 μm silica gel (Dynamic

Adsorbents Inc). Thin-layer chromatography (TLC) was performed on silica gel 60 F254 plates

(EMD).

1 13 H and C NMR were recorded in CDCl3 on Bruker DRX-300, DRX-400, and DRX-500 spectrometers as noted. Data for 1H NMR are reported as follows: chemical shift (δ ppm), multiplicity (s = singlet, brs = broad singlet, d = doublet, t = triplet, q = quartet, m = multiplet), coupling constant (Hz), integration, and assignment. Data for 13C NMR are reported in terms of chemical shift. Low- resolution mass spectra (LRMS) were acquired on a JEOL JMS-LCmate liquid chromatography mass spectrometer system using CI+ ionization technique.

Cycloreversion Reaction Method: The cycloadduct (0.1 mmol) was dissolved in an ethylene glycol/H2O solution (9:1, 1 mL, 0.1 M) which contained 1 equiv. of HCl. The solution was heated in a seal vial to 130 ºC for 24 hrs. Upon cooling, 1 equiv. of an NMR standard (benzyl ) was added as a solution in DCM. The mixture was further diluted with DCM and washed with 1 M NaOH followed by two H2O washes. The organic layer was separated, dried with

1 sodium sulfate and concentrated. Spectra were taken in CDCl3 to obtain an H-NMR yield.

48

(E)-2-(3-styrylcyclopentyl)-1,3-dioxolane: The compound was synthesized according to the cycloreversion method described above. Purified by column chromatography on Si to yield the

1 1 product as an oil (3% H NMR yield relative to standard). H NMR (400 MHz, CDCl3): 7.41-

7.23 (m, 4H, ArH), 7.23-7.13 (m, 1H, ArH), 6.45-6.32 (m, 1H, CH=CHAr), 6.25-6.12 (m, 1H,

RCH=CHAr), 4.76 (d, J = 5.4 Hz, 1H, HC(OCH2)2R), 4.08-3.94 (m, 2H, HC(OCH2)2R), 3.93-

3.79 (m, 2H, HC(OCH2)2R), 2.79-2.55 (m, 1H, RCHCH=CHAr), 2.43-2.19 (m, 1H,

13 HC(OCH2)2CHR), 2.08-1.31 (m, 6H, cyclopentylH). C NMR (101 MHz, CDCl3): 137.95,

135.03, 134.82, 128.62, 128.46, 126.96, 126.11, 107.55, 65.23, 65.19, 44.13, 43.14, 42.94, 42.07,

35.09, 34.09, 34.06, 33.71, 32.72, 29.84, 27.32, 26.65. LRMS (APCI+): exact mass calc’d for

+ C16H20O2 [M+1] requires m/z 245.15, found m/z 245.23.

(E)-2-(3-(2,6-dichlorostyryl)cyclopentyl)-1,3-dioxolane: The compound was synthesized according to the cycloreversion method described above. Purified by column chromatography on

Si to yield the product as an oil (16% 1H NMR yield relative to standard).1H NMR (400 MHz,

CDCl3): 7.28 (d, J = 8.1 Hz, 2H, ArH), 7.04 (t, J = 8.0 Hz, 1H, ArH), 6.49-6.28 (m, 1H,

CH=CHAr), 6.28-6.04 (m, 1H, RCH=CHAr), 4.78-4.76 (m, 1H, HC(OCH2)2R), 4.06-3.80 (m,

4H, HC(OCH2)2R), 2.89-2.62 (m, 1H, RCHCH=CHAr), 2.43-2.19 (m, 1H, HC(OCH2)2CHR),

13 2.12-1.36 (m, 6H, cyclopentylH). C NMR (101 MHz, CDCl3): 143.54, 134.48, 128.45, 127.68,

121.96, 107.49, 65.24, 65.20, 44.48, 43.47, 43.05, 41.98, 34.80, 33.67, 33.25, 32.37, 29.86, 49

+ 29.82, 27.20, 26.69. LRMS (APCI+): exact mass calc’d for C16H18Cl2O2 [M+1] requires m/z

313.07, found m/z 313.07.

(E)-2-(3-(2-(anthracen-9-yl)vinyl)cyclopentyl)-1,3-dioxolane: The compound was synthesized according to the cycloreversion method described above except this reaction was complete in 8 h. Purified by column chromatography on Si to yield the product as an oil (22% 1H NMR yield

1 relative to standard). H NMR (400 MHz, CDCl3): 8.38-8.26 (m, 3H, ArH), 8.03-7.95 (m, 2H,

ArH), 7.50-7.42 (m, 4H, ArH), 7.16-7.07 (m, 1H, CH=CHAr), 6.08-5.94 (m, 1H, RCH=CHAr),

4.90-4.78 (m, 1H, HC(OCH2)2R), 4.09-3.86 (m, 4H, HC(OCH2)2R), 3.11-2.93 (m, 1H,

13 RCHCH=CHAr), 2.49-1.53 (m, 7H, cyclopentylH). C NMR (101 MHz, CDCl3): 143.38,

143.24, 133.63, 133.60, 131.61, 129.70, 128.69, 126.30, 125.93, 125.25, 125.17, 123.94, 123.89,

107.63, 107.58, 65.31, 65.23, 44.76, 43.81, 43.10, 42.10, 35.29, 34.17, 33.83, 32.78, 27.42,

+ 26.80. LRMS (APCI+): exact mass calc’d for C24H24O2 [M+1] requires m/z 345.18, found m/z

344.96.

(E)-2-(3-(2,4-dimethylstyryl)cyclopentyl)-1,3-dioxolane: The compound was synthesized according to the cycloreversion method described above. Purified by column chromatography on

Si to yield the product as an oil (16% 1H NMR yield relative to standard). 1H NMR (400 MHz,

CDCl3): 7.31 (d, J = 7.8 Hz, 1H, ArH), 6.95 (d, J = 8.3 Hz, 2H, ArH), 6.53 (m, 1H, CH=CHAr),

6.08-5.95 (m, 1H, RCH=CHAr ), 4.78 (m, 1H, HC(OCH2)2R ), 4.04-3.84 (m, 4H, HC(OCH2)2R), 50

2.78-2.61 (m, 1H, HC(OCH2)2CHR), 2.29 (s, 6H, Ar(CH3)2), 2.06-1.30 (m, 7H, cyclopentylH).

13 C NMR (101 MHz, CDCl3): 136.52, 135.41, 135.25, 134.90, 131.06, 130.99, 126.84, 126.00,

125.96, 125.41, 107.63, 107.58, 65.24, 65.19, 44.44, 43.47, 42.98, 42.02, 35.27, 34.23, 33.90,

+ 32.87, 27.30, 26.66, 21.16, 19.90. LRMS (APCI+): exact mass calc’d for C18H24O2 [M+1] requires m/z 273.18, found m/z 273.21.

(E)-2-(3-(2,4,6-trimethylstyryl)cyclopentyl)-1,3-dioxolane: The above compound was synthesized according to the cycloreversion method described above. Purified by column chromatography on Si to yield the product as an oil (16% 1H NMR relative to standard). 1H

NMR (400 MHz, CDCl3): 6.84 (s, 2H, ArH), 6.30-6.25 (m, 1H, CH=CHAr), 5.64-5.56 (m, 1H,

RCH=CHAr ), 4.76 (m, 1H, HC(OCH2)2R ), 3.99-3.86 (m, 4H, HC(OCH2)2R), 2.79-2.55 (m, 1H,

HC(OCH2)2CHR), 2.25 (s, 3H, Ar(CH3)2), 2.24 (s, 6H, Ar(CH3)2), 2.05-1.26 (m, 7H,

13 cyclopentylH). C NMR (101 MHz, CDCl3) δ 139.39, 139.27, 135.79, 128.37, 125.45, 107.53,

65.04, 44.38, 43.32, 42.92, 41.89, 35.15, 33.99, 33.56, 32.61, 27.12, 26.53, 20.89. LRMS

+ (APCI+): exact mass calc’d for C19H26O2 [M+1] requires m/z 286.19, found m/z 286.21.

51

Cycloadduct Synthesis Method. The HCl salt of the hydrazine (1 equiv., 5 mmol), aldehyde (1 equiv., 5 mmol) and norbornene (10 equiv., 50 mmol) were combined in anhydrous MeOH (50 mL, 0.1 M) and heated to reflux overnight. The reaction was cooled to room temperature and diluted with CH2Cl2. (2 equiv., 10 mmol) was added to neutralize the compound.

The solution was washed with H2O twice. The organic layer was separated, dried with sodium sulfate and concentrated. The cycloadduct products were isolated by column chromatography.

N,N'-diazabicyclo[2.2.1]heptane-3,4-bicyclo[2.2.1]heptane-5-phenylpyrazolidine: The compound was synthesized as described above in the cycloaddition method. Purified by column

1 chromatography on Si to yield an oil. H NMR (400 MHz, CDCl3) major isomer: 7.58-7.21 (m,

5H, ArH), 4.27 (d, J = 8.4 Hz, 1H, 1), 3.50 (d, J = 3.6 Hz, 1H, 2), 2.85-2.76 (m, 2H, 3&4), 2.46-

13 2.20 (m, 3H, alkylH), 2.00-0.86 (m, 18H, alkylH). C NMR (101 MHz, CDCl3):143.17, 138.34,

129.44, 128.47, 128.26, 127.74, 127.63, 127.05, 78.30, 72.88, 72.82, 70.15, 66.23, 61.33, 61.04,

57.53, 55.98, 42.08, 40.23, 39.05, 37.02, 33.81, 33.36, 32.76, 31.28, 29.17, 28.27, 27.89, 27.57,

+ 27.42, 26.19. LRMS (APCI+): exact mass calc’d for C19H24N2 [M+1] requires m/z 281.19, found m/z 281.27.

52

N,N'-diazabicyclo[2.2.1]heptane-3,4-bicyclo[2.2.1]heptane-5-mesitylpyrazolidine: The compound was synthesized as described above in the cycloaddition method. Purified by column

1 chromatography on Si to yield an oil. H NMR (400 MHz, CDCl3): 6.93 (s, 1H, ArH), 6.86 (s,

1H, ArH), 4.46 (d, J = 9.1 Hz, 1H, 1), 3.56-3.50 (m, 1H, 2), 2.94-2.73 (m, 3H, alkylH), 2.52 (s,

3H, ArCH3), 2.46 (s, 3H, ArCH3), 2.30 (s, 3H, ArCH3), 2.26-2.21 (m, 1H, alkylH), 1.93-1.85 (m,

13 2H, 3&4), 1.72-0.98 (m, 11H, alkylH). C NMR (101 MHz, CDCl3): 140.84, 137.49, 136.75,

131.85, 131.08, 129.68, 100.09, 78.03, 68.46, 65.72, 57.39, 51.86, 41.90, 40.30, 33.91, 32.62,

28.30, 27.91, 26.21, 23.99, 21.80, 20.77. LRMS (APCI+): exact mass calc’d for C22H30N2

[M+1]+ requires m/z 323.24, found m/z 323.03.

N,N'-diazabicyclo[2.2.1]heptane-3,4-bicyclo[2.2.1]heptane-5-(2,4- dichlorophenyl)pyrazolidine: The compound was synthesized as described above in the cycloaddition method. Purified by column chromatography on Si to yield an oil. 1H NMR (300

MHz, CDCl3): 7.39 (dd, J = 7.9, 1.5 Hz, 1H, ArH), 7.31 (dd, J = 8.1, 1.4 Hz, 1H, ArH), 7.15 (t, J

= 8.0 Hz, 1H, ArH), 4.91 (d, J = 8.7 Hz, 1H, 1), 3.47 (d, J = 3.7 Hz, 1H, 2), 3.34 (td, J = 8.7, 1.3

Hz, 1H, alkyH), 2.90 (d, J = 2.3 Hz, 1H, alkyH), 2.82 (d, J = 8.6 Hz, 1H, alkyH), 2.21 (d, J = 4.1

13 Hz, 1H, alkyH), 1.96-1.35 (m, 13H, alkyH). C NMR (101 MHz, CDCl3): 139.63, 136.72, 53

133.51, 130.47, 129.26, 129.21, 78.18, 68.66, 65.56, 58.77, 50.57, 42.00, 40.37, 34.21, 32.75,

+ 32.44, 28.51, 27.84, 25.91. LRMS (APCI+): exact mass calc’d for C19H22Cl2N2 [M+1] requires m/z 349.12, found m/z 348.90.

N,N'-diazabicyclo[2.2.1]heptane-3,4-bicyclo[2.2.1]heptane-5-(9-anthracenyl)pyrazolidine:

The compound was synthesized as described above in the cycloaddition method. Purified by

1 column chromatography on Si to yield an oil. H NMR (400 MHz, CDCl3): 8.76 (d, J = 8.9 Hz,

1H, ArH), 8.48 (s, 1H, ArH), 8.35-8.30 (m, 1H, ArH), 8.11-8.06 (m, 1H, ArH), 8.04-8.00 (m,

1H, ArH), 7.59-7.45 (m, 4H, ArH), 5.40 (d, J = 8.6 Hz, 1H, 1), 3.71 (d, J = 3.8 Hz, 1H, 2), 3.26

(t, J = 8.6 Hz, 1H, 3), 3.13 (d, J = 8.5 Hz, 1H, 4), 3.00 (s, 1H, alkylH), 2.36 (d, J = 4.6 Hz, 1H, alkylH), 2.09 (d, J = 10.2 Hz, 1H, alkylH), 1.78-1.08 (m, 11H, alkylH). 13C NMR (101 MHz,

CDCl3): 133.76, 132.03, 131.68, 130.44, 129.96, 129.76, 128.68, 128.52, 126.41, 126.26,

126.22, 125.19, 124.66, 124.27, 77.82, 68.48, 65.39, 58.80, 54.78, 42.19, 41.00, 33.98, 32.85,

+ 32.75, 28.74, 27.94, 25.75. LRMS (APCI+): exact mass calc’d for C27H28N2 [M+1] requires m/z 381.23, found m/z 380.98.

54

N,N'-diazabicyclo[2.2.1]heptane-3,4-bicyclo[2.2.1]heptane-5-(2,4- dimethylphenyl)pyrazolidine: The compound was synthesized as described above in the cycloaddition method. Purified by column chromatography on Si to yield an oil. 1H NMR (400

MHz, CDCl3): 7.26 (d, J = 7.9 Hz, 1H, ArH), 7.11-7.07 (m, 1H, ArH), 7.06-7.02 (m, 1H, ArH),

4.38 (d, J = 8.4 Hz, 1H, 1), 3.50-3.43 (m, 1H, 2), 2.77 (d, J = 8.6 Hz, 1H, 3), 2.59 (s, 1H, 4), 2.48

(s, 3H, ArCH3), 2.35 (s, 3H, ArCH3), 2.26 (d, J = 3.4 Hz, 1H, alkylH), 1.97-1.92 (m, 1H, alkylH), 1.87 (dd, J = 10.5, 2.2 Hz, 1H, alkylH), 1.72-0.99 (m, 12H, alkylH). 13C NMR (101

MHz, CDCl3) ? 138.85, 137.00, 133.71, 131.74, 126.75, 126.21, 77.94, 68.71, 66.38, 57.60,

54.59, 42.33, 40.43, 33.28, 33.06, 31.36, 28.37, 27.73, 26.41, 21.00, 20.20. LRMS (APCI+):

+ exact mass calc’d for C21H28N2 [M+1] requires m/z 309.23, found m/z 309.02.

N,N'-diazacyclopentane-3,4-bicyclo[2.2.1]heptane-5-phenylpyrazolidine: The compound was synthesized as described above in the cycloaddition method. Purified by column chromatography

1 on Si to yield an oil. H NMR (300 MHz, CDCl3): 7.49-7.43 (m, 2H, ArH), 7.39-7.27 (m, 3H,

ArH), 3.92 (br m, 1H, 1), 3.27-3.13 (m, 1H, 2), 2.93-2.80 (m, 1H, alkylH), 2.73 (d, J = 8.0 Hz,

1H, alkylH), 2.54 (td, J = 9.3, 8.0, 1.4 Hz, 1H, alkylH), 2.40 (d, J = 8.3 Hz, 2H, alkylH), 2.23-

2.10 (m, 3H, alkylH), 2.02-1.92 (m, 2H, alkylH), 1.59-1.48 (m, 2H, alkylH), 1.16-0.98 (m, 3H,

13 alkylH). C NMR (101 MHz, CDCl3): 139.85, 128.34, 128.08, 127.16, 77.36, 72.17, 69.71,

50.48, 46.41, 40.06, 38.44, 33.12, 28.60, 26.24, 25.47. LRMS (APCI+): exact mass calc’d for

+ C17H22N2 [M+1] requires m/z 255.18, found m/z 255.05.

55

N,N'-diaza-3’-phenylcyclopentane-3,4-bicyclo[2.2.1]heptane-5-phenylpyrazolidine: The compound was synthesized as described above in the cycloaddition method. Purified by column

1 chromatography on Si to yield an oil. H NMR (400 MHz, CDCl3): 7.49-7.41 (m, 4H, ArH), 7.29

(dd, J = 28.8, 7.0 Hz, 6H, ArH), 3.68 (dd, J = 8.7, 6.9 Hz, 1H, 1), 3.22 (d, J = 7.8 Hz, 1H, 2),

2.83-2.61 (m, 3H, alkylH), 2.36 (d, J = 2.9 Hz, 2H, alkylH), 2.15-2.03 (m, 3H, alkylH), 1.55 (d,

J = 4.7 Hz, 1H, alkylH), 1.44-1.22 (m, 2H, alkylH), 1.01-0.79 (m, 3H, alkylH). 13C NMR (101

MHz, CDCl3): 143.75, 141.51, 128.49, 128.27, 127.92, 127.72, 127.28, 127.09, 70.34, 69.17,

65.47, 52.85, 47.42, 41.16, 39.23, 37.87, 33.44, 28.78, 25.03. LRMS (APCI+): exact mass calc’d

+ for C23H26N2 [M+1] requires m/z 331.21, found m/z 330.96.

N,N'-diazabicyclo[2.2.2]octane-3,4-bicyclo[2.2.1]heptane-5-phenylpyrazolidine: The compound was synthesized as described above in the cycloaddition method. Purified by column

1 chromatography on Si to yield an oil. H NMR (400 MHz, CDCl3): 7.41-7.36 (m, 2H, ArH),

7.33-7.19 (m, 3H, ArH), 3.39 (d, J = 7.3 Hz, 1H, 1), 2.95-2.86 (m, 2H, 2), 2.56-2.49 (m, 1H, alkylH), 2.30-2.21 (m, 1H, alkylH), 2.16-2.08 (m, 2H, alkylH), 2.08-1.74 (m, 5H, alkylH), 1.51-

13 1.23 (m, 6H, alkylH), 1.06-0.93 (m, 3H, alkylH). C NMR (101 MHz, CDCl3): 142.04, 128.35,

128.27, 127.03, 66.80, 65.82, 60.31, 50.13, 47.90, 39.14, 37.80, 33.39, 29.15, 28.54, 27.42,

+ 25.18, 22.74, 22.03. LRMS (APCI+): exact mass calc’d for C20H26N2 [M+1] requires m/z

295.21, found m/z 295.18. 56

N,N'-diazacyclohexane-3,4-bicyclo[2.2.1]heptane-5-phenylpyrazolidine: The compound was synthesized as described above in the cycloaddition method. Purified by column chromatography

1 on Si to yield an oil. H NMR (400 MHz, CDCl3): 7.39-7.20 (m, 5H, ArH), 3.14-3.04 (m, 1H, 1),

2.87 (d, J = 8.0 Hz, 1H, 2), 2.72 (dd, J = 10.9, 2.9 Hz, 1H, alkylH), 2.53-2.38 (m, 2H, alkylH),

2.12-2.08 (m, 2H, alkylH), 2.07-1.97 (m, 1H, alkylH), 1.93-1.84 (m, 2H, alkylH), 1.66-1.36 (m,

13 6H, alkylH), 1.09-0.89 (m, 3H, alkylH). C NMR (101 MHz, CDCl3): 141.97, 128.43, 128.17,

127.27, 74.41, 73.34, 56.86, 54.77, 52.88, 39.09, 37.64, 33.60, 28.68, 25.10, 24.72, 24.45. LRMS

+ (APCI+): exact mass calc’d for C18H24N2 [M+1] requires m/z 269.19, found m/z 269.44.

N,N'-diazacycloheptane-3,4-bicyclo[2.2.1]heptane-5-phenylpyrazolidine: The compound was synthesized as described above in the cycloaddition method. Purified by column chromatography

1 on Si to yield an oil. H NMR (300 MHz, CDCl3): 7.42-7.19 (m, 5H, ArH), 3.17-3.03 (m, 2H, 1 and alkylH), 2.80-2.62 (m, 2H, alkylH), 2.55 (d, J = 8.4 Hz, 1H, alkylH), 2.47-2.33 (m, 1H, alkylH), 2.14-2.05 (m, 2H, alkylH), 1.98-1.86 (m, 2H, alkylH), 1.83-1.35 (m, 8H, alkylH), 1.12-

13 0.87 (m, 3H, alkylH). C NMR (126 MHz, CDCl3): 143.38, 128.46, 127.98, 127.13, 76.41,

75.57, 59.79, 57.11, 55.73, 39.93, 38.50, 33.33, 28.32, 27.05, 26.55, 25.79, 25.16. LRMS

+ (APCI+): exact mass calc’d for C19H26N2 [M+1] requires m/z 283.21, found m/z 283.17.

57

N,N'-diazacyclooctane-3,4-bicyclo[2.2.1]heptane-5-phenylpyrazolidine: The compound was synthesized as described above in the cycloaddition method. Purified by column chromatography

1 on Si to yield an oil. H NMR (300 MHz, CDCl3): 7.44-7.18 (m, 5H, ArH), 3.19-2.95 (m, 3H, alkylH), 2.76-2.50 (m, 3H, alkylH), 2.10 (m, 2H, alkylH), 1.97-1.34 (m, 12H, alkylH), 1.12-0.87

13 (m, 3H, alkylH). C NMR (126 MHz, CDCl3): 143.73, 128.50, 128.21, 127.19, 74.97, 73.42,

56.72, 55.23, 53.10, 39.91, 38.71, 33.17, 28.34, 26.16, 26.05, 25.25, 24.73. LRMS (APCI+):

+ exact mass calc’d for C20H28N2 [M+1] requires m/z 297.23, found m/z 297.18.

N,N'-diazabicyclo[2.2.1]tertbutylheptane-3,4-bicyclo[2.2.1]heptane-5-phenylpyrazolidine:

The compound was synthesized as described above in the cycloaddition method. Purified by

1 column chromatography on Si to yield an oil. H NMR (400 MHz, CDCl3) major isomer: 7.43-

7.30 (m, 5H, ArH), 4.13 (d, J = 8.4 Hz, 1H, 1), 3.48 (d, J = 3.6 Hz, 1H, 2), 2.80-2.65 (m, 2H,

3&4), 2.40-2.21 (m, 2H, alkylH), 1.96 (s, 1H, alkylH), 1.79 (d, J = 10.0 Hz, 1H, alkylH), 1.60-

0.86 (m, 12H, alkylH), 0.80 (s, 9H, C(CH3)3). LRMS (APCI+): exact mass calc’d for C23H32N2

[M+1]+ requires m/z 337.26, found m/z 337.37.

58

N,N'-diazatricyclo[2.2.0.2]nonane-3,4-bicyclo[2.2.1]heptane-5-phenylpyrazolidine: The compound was synthesized as described above in the cycloaddition method. Purified by column

1 chromatography on Si to yield an oil. H NMR (400 MHz, CDCl3): 7.49 (d, J = 7.2 Hz, 2H,

ArH), 7.33 (t, J = 7.2 Hz, 2H, ArH), 7.26 (t, J = 7.2 Hz, 1H, ArH), 3.85 (d, J = 9.2 Hz, 1H, 1),

3.62 (d, J = 7.6 Hz, 1H, 2), 3.02 (s, 1H, alkylH), 2.72 (s, 1H, alkylH), 2.40-2.26 (m, 3H, alkylH),

+ 2.00-0.80 (m, 14H, alkylH). LRMS (APCI+): exact mass calc’d for C21H26N2 [M+1] requires m/z 307.21, found m/z 307.47.

N,N'-diazatricyclo[2.2.0.4]undecane-3,4-bicyclo[2.2.1]heptane-5-phenylpyrazolidine: The compound was synthesized as described above in the cycloaddition method. Purified by column

1 chromatography on Si to yield an oil. H NMR (400 MHz, CDCl3) major isomer: 7.48 (d, J =

7.2 Hz, 2H, ArH), 7.35 (t, J = 7.2 Hz, 2H, ArH), 7.26 (m, 1H, ArH), 4.21 (d, J = 8.8 Hz, 1H, 1),

3.41 (d, J = 8.4 Hz, 1H, 2), 2.98-2.74 (m, 2H, 3 4), 2.57 (s, 1H, alkylH), 2.40-2.20 (m, 2H,

+ alkylH), 2.15-1.00 (m, 18H, alkylH). LRMS (APCI+): exact mass calc’d for C23H30N2 [M+1] requires m/z 335.24, found m/z 335.48.

NMR Spectra for Cycloreversion of Norbornene

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Part II: Cyclopropenimine-Catalyzed Asymmetric Michael Reactions

Chapter 3 – Asymmetric with Chiral Brønsted Superbases

Introduction

Brønsted base deprotonation is a fundamental method of activation that can be used to enact a wide variety of synthetically useful transformations.1 These bases raise the HOMO of the pronucleophile enabling it to engage with a wider variety of electrophiles. In recent years there has been a focus on developing chiral Brønsted bases that can enact these transformations stereoselectively. Neutral organic bases hold many advantages over inorganic bases, such as increased solubility, milder and greener reaction conditions, and the lack of a metal cation

(which can result in a more “naked” and reactive anion). Despite the vast promise of chiral

Brønsted base catalysis, this area of is arguably undeveloped, although this is beginning to change.

Asymmetric Brønsted base catalysis dates back to 1912 when Bredig and Fiske formed cyanohydrins using simple cinchona alkaloid catalysts.2 While their enantioselectivities were low, this seminal study provided a proof-of-concept. During the late 1970’s, Wynberg developed cinchona alkaloid catalysis further,3 and since then a variety of groups have made a number of valuable contributions to this area.4 However, this field was restricted by the basicity of the cinchona alkaloids. Organic bases are inherently limited by pKa values: if the pKa of the substrate is too high relative to the base, no reaction will occur. As a result, much attention has been focused on developing stronger classes of bases, “superbases” that can activate a wider variety of pronucleophiles.

This chapter will provide an overview of Brønsted base catalysis in the “superbase” regime, with an emphasis on asymmetric transformations. The term superbase refers to bases 96 which synergistically combine two or more constituent bases to produce a highly basic species.5

This includes guanidines, phosphazenes, and proazaphosphatranes, all of which will be independently discussed in this chapter. Also included in this category are cyclopropenimines, which were recently developed by my former colleague Dr. Jeffrey Bandar in the Lambert group.

His work as well as the work of my former colleague Dr. Eric Nacsa will also be discussed in this chapter. I will also discuss higher-order analogues of these superbases.

Figure 1. Basicity scale of common organic Brønsted bases.

Guanidines

Guanidine bases consist of an imine with two additional nitrogen atoms bonded to the carbon atom. These additional nitrogen atoms stabilize the protonated form and give guanidines their increased basicity compared to simple amines and . The guanidine motif is biologically important: it is present in a wide range of natural products and most prominently in the arginine.6 Although it is usually protonated at a physiological pH, it is located in the active site of a number of enzymes and can facilitate enzymatic activity.7 The presence of 97 this functional group in nature inspired organic chemists to synthesize guanidines and utilize them for synthetic purposes.8 Guanidines are currently the most studied class of chiral organic superbases and a wide variety of reactions can be performed using guanidine superbases.

Figure 2. Guanidine bases are stabilized by three nitrogen atoms when protonated.

In 1981, D. H. Barton reported a series of sterically-hindered acyclic guanidines, now

9 called “Barton’s bases,” which have pKBH+ values of 23-24 in . The steric congestion at the imino-nitrogen rendered these guanidines poor nucleophiles, which suggested that they could be useful as bases. In 1985, Schwesinger reported the synthesis of cyclic guanidines TBD

10 and MTBD. He measured their pKBH+ values in acetonitrile as 26.0 and 25.5 respectively.

Figure 3. pKBH+ values for early guanidines that are still commonly used today.

The most commonly used synthetic pathway for creating guanidine bases, shown below in Figure 4, starts with reacting two equivalents of a secondary with phosgene or thiophosgene to create a or thiourea, respectively. The urea or thiourea is then activated, frequently with oxalyl chloride or phosgene, to form an imidoyl chloride intermediate. This intermediate is highly moisture sensitive and so must be formed and handled under strictly 98 anhydrous conditions. The guanidine hydrochloride salt is formed upon the addition of primary amine, and this salt can be deprotonated with strong base, commonly a hydroxide or .

These steps often proceed in good yield; however, optimization for each specific guanidine synthesis is normally required to determine whether to use the urea or thiourea pathway, and which activating agent is optimal.

Figure 4. Common synthetic pathway to guanidines.

The first asymmetric reaction catalyzed by chiral guanidines was a Henry reaction reported by Nájera in 1994.11 This reaction was chosen because of crystallographic and NMR evidence that guanidines bind tightly with nitroalkanes to form an ion-pair; it was speculated that this tight binding could lead to enantioinduction.12 She screened many guanidine catalysts and found that acyclic C2 symmetric catalyst 1 was best, affording enantioselectivities up to 54%.

While this yield and enantioselectivity are modest, this report sparked further research on chiral guanidine catalysis.

Figure 5. Asymmetric Henry reaction enacted with chiral guanidine catalysis.

99

In 1996, Lipton reported the first highly selective asymmetric guanidine catalyzed reaction.13 The use of dipeptide guanidine catalyst 2 enabled a Strecker reaction between cyanide and aryl aldimines in yields of up to 97% and enantioselectivities up to 99%. It should be noted that this result was called into question in 2005 when another group could not replicate the results.14 A few years later, Corey showed that this reaction could also be performed with C2 symmetric bicyclic chiral guanidine 3 with similar yields but reduced enantioselectivities.15 Bicyclic catalyst 3, unlike guanidine 2, was also able to achieve good enantioselectivity with aliphatic imines. This was the first report of high enantioselectivity with a

C2-symmetric bicyclic guanidine, and since this report the [3.3.0] bicyclic scaffold has become a privileged structure. Interestingly, Corey had developed a guanidine catalyst very similar to 3, in which the phenyl rings on 3 were instead cyclohexyl rings, 10 years earlier. However, while they recognized that it could have synthetic utility, they made no further reports about it, possibly due to its lengthy synthesis.16

Figure 6. Asymmetric guanidine-catalyzed Strecker Reactions.

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This [3.3.0] structure was used again by Tan in 2006 when he developed guanidine 4 to catalyze the highly asymmetric Diels-Alder reaction between anthrone and maleimide.17 He also synthesized the tert-butyl analogue, 5, which has been used with a variety of pronucleophiles including diarylphosphites, α-fluoromalonates, β-γ-unsaturated esters, and malonic acid half- esters.18 This structure allowed guanidine base catalysis to activate less acidic pronculeophiles such as β-γ-alkynoates.19 Tan also developed a simpler synthetic route to this structure involving the coupling of chiral .20

Figure 7. Examples of Tan’s reactions with [3.3.0] bicyclic guanidines.

Ishikawa, in 2001, expanded chiral guanidine catalysis to include glycinate benzophenone imine pronucleophiles.21 These substrates are less acidic than HCN and nitroalkanes which were previously used. He developed guanidine catalyst 6 which can catalyze highly enantioselective Michael reactions between tert-butyl glycinate benzophenone imine and electron deficient alkenes. While guanidine 6 had good reactivity neat, 101

its reactivity plummeted when used in solvent. Both the C2 symmetric backbone and the chiral top-piece were necessary for good enantioselectivity. Derivatives of catalyst 6 have been prepared and used with other pronucleophiles, but lower selectivities are generally observed when moving away from glycine imines.

Figure 8. Guanidine-Catalyzed Enantioselective Michael Addition.

Terada developed a new class of guanidine catalysts in 2006 with an axially chiral

BINOL skeleton.22 In contrast to the highly constrained catalysts 3 and 4, the guanidine moiety is in a relatively flexible nine-membered ring. As a result, increased steric bulk is required to obtain good enantioselectivities. Many steps are required to synthesize these guanidines, but they can often be recovered as their hydrochloride salts and recycled. Terada initially reported the asymmetric Michael addition of malonate pronucleophiles to nitroalkanes, but these bases have since been shown to induce high levels of enantioselectivity in a broad range of pronucleophiles, including lactones, α-keto esters, nitroalkanes, and phosphites.23 These guanidines are highly reactive; in one notable case, only 0.05% catalyst loading was required to achieve full conversion.23b 102

Figure 9. BINOL-derived guanidine catalysts and reactions they facilitate.

Terada also found that these bases could catalyze enantioselective [3+2] cycloaddition reactions between glycine imines and maleates.24 Pyrrolidine products were formed as a single diastereomer with moderate to high yields and enantioselectivities. Relevant to this thesis, they also performed control experiments with TMG and DBU and found that they catalyzed both the cycloaddition and the Michael reaction. With TMG, there was a 64% yield of the cycloadduct 103 and 35% yield of the Michael product; the selectivity flipped for DBU and only a 28% yield of the cycloadduct was obtained compared to a 66% yield of the Michael product.

Figure 10. Asymmetric cycloaddition reaction catalyzed by guanidine.

While open-chain guanidines are more synthetically accessible, their lack of rigidity often renders them poor at transferring chirality. However, in 2009 Feng developed a new guanidine catalyst with an intramolecular hydrogen bond.25 This hydrogen bond introduces structural rigidity around the guanidine moiety. Guanidine 9 is readily synthesized in high yields and was first used in an enantio- and diastereoselective Michael reaction between nitrosostyrenes and β- keto esters. It has since been used in a more complex domino reaction on azlactones to produce cis 3,4-diaminochromanones.

Figure 11. Michael reaction with Feng’s chiral guanidine catalyst.

Bifunctional guanidine catalysts with thiourea hydrogen-bond donors have also been developed. In these catalysts, the nucleophile is activated by the guanidine via Bronsted base activation while the electrophile is activated via hydrogen bonding to the thiourea. Nagasawa has 104

developed a series of C2 symmetric bifunctional guanidine/thiourea catalysts for use in a variety of reactions including enantioselective Michael reactions of phenols and Mannich reactions of dimethylmalonate26 and N-Boc aldimines.27 Here, the reaction will proceed without the thiourea moiety but produce only racemic product. The example below demonstrates the hydrogen bonding power of these catalysts; despite being very conformationally flexible they are able to achieve excellent enantioselectivity with only methyl groups on the chiral backbone.

Figure 12. Asymmetric with bifunctional guanidine catalyst.

Guanidines remain the best established area of Brønsted base catalysis. The highly stereoselective catalysts tend to use one of four method for transferring chirality. Catalysts such as 3, 4, and 5 have very rigid bicyclic structures. Catalysts 6 and 10 incorporate additional hydrogen bond components to interact with the electrophile. Terada’s BINOL-derived catalysts incorporate extremely bulky chiral backbones. And Feng’s guanidine catalysts use intramolecular hydrogen bonding to provide structural rigidity. Guanidine catalysts that do not incorporate one of these general ideas tend to be far less enantioselective; however, synthesis of these more involved catalysts is often challenging and remains a hindrance to this day.

105

Iminophosphoranes

Phosphazene bases, consisting of an iminophosphoric acid with three aminoalkyl groups on the phosphorus atom, were first developed by Schwesinger in 1987.28 Schwesinger’s bases consist of a central phosphorus atom with four amino groups bound to it. This allows for additional stabilization from three nitrogen atoms upon protonation, compared to only two nitrogen atoms for guanidine catalysts. There also exist iminophosphorane bases that consist of a central phosphorus atom bound to three aromatic rings and a nitrogen atom; these iminophosphoranes are less strong and generally include a hydrogen-bonding element for additional activation and enantioinduction.29

The most widely used class of chiral iminophosphoranes have [5,5]-P-spirocyclic scaffolds. These were first synthesized by Ooi in 2007 by reacting a valine-derived chiral diamine with phosphorus pentachloride to form the hydrochloride salt of the iminophosphorane base.30 These salts can be deprotonated in situ, usually by potassium tert-butoxide. It is important to note here that a key element of these bases is the chiral phosphorus atom; during synthesis, two diastereomers are formed but the desired isomer can be isolated via a combination of chromatography and recrystallization.

Figure 13. Synthesis of chiral iminophosphorane.

Ooi first used these iminophosphoranes to catalyze asymmetric Henry reactions, and later to enact asymmetric Pudovik reactions.31 He then synthesized a library of derivatives from 106 different amino acid precursors and also developed bases with additional substitution on some of the nitrogen atoms.32 The addition of alkyl groups on two of the nitrogen atoms renders the iminophosphoranes isolable in the free-base form and enabled a variety of new enantioselective transformations including aldol reactions, 1,6- and 1,8-conjugate additions of azlactones, and coupling reactions between isatins and aldehydes.32,33 Catalysts have also recently been synthesized from isoleucine with additional chiral centers and have been used in reactions such as asymmetric oxidation of N-sulfonyl imines to produce , and in Michael reactions of nitroalkanes.34

Figure 14. Enantioselective Reactions with [5.5] spirocyclic iminophosphoranes. 107

While the [5,5]-spiro structure has been the most prominent among chiral phosphazenes, in 2015 Wang developed a new class of [7,7]-P-spirocyclic iminophosphoranes derived from tartaric acid.35 These catalysts have been used for asymmetric chlorination reactions of oxindoles. They are far more air and moisture stable than the [5,5] catalysts, and they can be recovered via column chromatography and recycled up to six times without loss of enantioselectivity.

Figure 15. Enantioselective chlorination with [7,7]-P-spirocyclic iminophosphorane.

In 2013 Dixon developed a new type of iminophosphoranes with a thiourea hydrogen- bonding unit.36 These are synthesized via a Staudinger reaction between a β-azidothiourea with triaryl phosphine. The can be made in 4-6 steps from chiral 1,2-aminoalcohols. He was able to use base 15 in a highly enantioselective aza-Henry reaction and later in a sulfa-Michael addition.37 Dixon later developed an analogue that was supported on polystyrene and was used for Michael reactions of α-substituted dimethyl malonates and β-ketoamides.38 Polystyrene supported catalyst 15 could be easily recovered by simple filtration and reused up to eleven times without significant erosion of yield or enantioselectivity. In these catalysts, like in the guanidine- thiourea catalysts, the base portion serves to activate the pronucleophile while the thiourea hydrogen bonds to the electrophile to activate it and organize the transition state. 108

Figure 16. Synthesis and example reactions of iminophosphorane-thiourea bifunctional catalysts.

Proazaphosphatranes

Proazaphosphatranes were first reported by Verkade in 1977.39 Unlike guanidines or iminophosphoranes, they protonate on a phosphorus atom. These bases are extremely strong

(pKBH+ of 32-34 in MeCN) because, upon protonation, the axial nitrogen donates electron density into the protonated phosphorus. The distance between the phosphorus and the axial nitrogen shrinks from 3Å to 2Å upon protonation, evidence of this trans-annular stabilization.40 Because the base relies on stabilization from the axial nitrogen, derivatives must maintain a well-defined cage structure. This coupled with the fact that the base is protonated at the phosphorus atom has made the synthesis of effective chiral derivatives extremely challenging. 109

Figure 17. Trans-annular stabilization of Verkade’s base.

Proazaphosphatranes are synthesized from the cyclization of tris(ethylamino)amines and

40 ClP(NMe2)2, followed by the deprotonation of the hydrochloride salt with inorganic base.

These bases are most commonly C3 symmetric but derivatives with different R groups have been prepared. Chirality can be incorporated into the cage backbone, provided that it does not distort the cage structure, or by adding in chiral R groups.

Figure 18. Synthesis of proazaphosphatranes.

Yamamoto synthesized the first chiral C3 symmetric proazaphosphatrane 16 from proline.41 He was able to observe a small amount of asymmetric induction in the ethylation of benzaldehyde with , and no transfer of asymmetry in the silylation of benzylalcohol.

Verkade synthesized chiral proazaphosphatrane 17 and, while it was an effective Brønsted base, he could not observe any enantioinduction when inducing cyanation of benzaldehyde with

TMSCN.42 He also synthesized base 18 and similarly found it to be ineffective at transferring chirality in the formation of mandelonitrile.43 More recently, the first P-chirogenic proazaphosphatrane, 19, was synthesized.44 However, it was formed as two diastereomers that could not be fully separated and thus far it has not been used as a base. The synthesis of these 110 chiral proazaphosphatranes is long and challenging and thus far they have not been effective chiral Brønsted bases. In all cases, it is postulated that the reason for the lack of asymmetric induction is that the chiral centers are too far away from the phosphorus atom to have a significant effect.

Figure 19. Chiral proazaphosphatranes and enantioselective catalysis.

Cyclopropenimines

Organic Brønsted base catalysis has played a huge role in organic chemistry, as detailed above. There is increasing demand for new Brønsted base scaffolds which can enantioselectively activate less acidic pronucleophiles. Brønsted bases are inherently limited by the basicity of their core functional group (although this can be somewhat modulated with the addition of hydrogen bonding elements). While high levels of enantioselective catalysis have been observed with guanidines and iminophosphoranes, the synthesis of these bases are often lengthy and the bases tend not to be modular and thus not easily tunable. An ideal Brønsted base catalyst would be highly basic, easily synthesized and modified, and air-stable and easy to use. To address these 111 issues, the Lambert lab introduced cyclopropenimines as a new chiral Brønsted base platform in

2012.45

Cyclopropenimines were first synthesized by Paquette in 1967 when he reported their formation via the coupling of an with a cyclopropenone.46 In 1980, Weiss synthesized the first 2,3-amino substituted cyclopropenes from tetrachlorocyclopropene.47 Alcarazo reported the first application of cyclopropenimines in 2010, in which they were used as on metal complexes.48

Figure 20. Syntheses of Cyclopropenimines.

Cyclopropenimines are analogous to guanidine bases; however, they contain a cyclopropene core. In addition to stabilization from three nitrogen atoms, there is a latent cyclopropenium ion which provides additional aromatic stabilization upon protonation, as shown below in Figure 21. Cyclopropenimines had previously been theorized to be effective Brønsted bases, but their use as bases was not reported prior to the Lambert lab’s publication in 2012.49 In this paper my former colleague Jeffrey Bandar measured the basicity of Cyclopropenimine 20 to 112

be 26.9 in acetonitrile, over 3 pKBH+ units stronger than a roughly analogous guanidine base and around the same basicity of a P1 phosphazene base.

Figure 21. Cyclopropenimines are strong bases in part because the protonated cyclopropenimine is stabilized by aromaticity.

Dr. Bandar developed chiral cyclopropenimine base 21 which is a highly active and enantioselective promoter of Michael reactions of glycine imines. Catalyst 21 is far more active than analogous guanidine catalyst 6 which was previously shown in Figure 8: the Michael addition to methyl acrylate is finished in one hour in ethyl acetate with cyclopropenimine 21 but takes three days under neat conditions with guanidine 6.21, 45 He later showed that base 21 was also effective in enantioselectively promoting a Mannich reaction.50 113

Figure 22. Enantioselective Michael and Mannich reactions catalyzed by cyclopropenimines.

Jørgensen recently showed that cyclopropenimine base 20 is effective at promoting asymmetric [3+2] cycloadditions between 2- acyl cycloheptatrienes and azomethine ylides.51

Here, the cyclopropenimine exclusively promotes the [3+2] cycloaddition as opposed to the

[3+6] cycloaddition.

Figure 23. Enantioselective cyclopropenimine-promoted cycloaddition.

114

Cyclopropenimines are an emerging and increasingly relevant class of organic superbases. Further details on previous work including synthesis of cyclopropenimenes as well as my research on cyclopropenimines will be detailed in the following chapter.

Higher-order Superbases

The term superbases, as previously discussed, refers to bases which incorporate multiple basic constituents to create a stronger base. In the quest to create stronger superbases to access a wider range of substrates, some groups have furthered this superbase concept and extended it to combining multiple superbases to “higher-order superbases”. These higher-order superbases are even stronger than each of their superbase components and can thus achieve very high levels of basicity.

Schwesinger developed higher-order phosphazene bases in which some of the nitrogen atoms are double-bonded to additional tris-aminophosphorus substituents.52 These bases are named based on the number of phosphorus atoms they contain, and higher-order superbases ranging from P2 (two phosphorus atom) all the way up to P7 (seven phosphorus atoms) exist.

Going from P1 to P2 causes an increase of roughly 3-4 pKBH+ units; however, diminishing returns are seen with each additional phosphorus unit and P7 bases are often roughly the same strength as analogous P5 bases as a result. One of the most commonly used phosphazene base is the P4 superbase shown below, which has a pKBH+ of 42.7. These higher-order phosphazenes are synthesized in an analogous fashion to the P1 phosphazene bases. While these bases have been extremely useful in achiral Brønsted base catalysis, they have thus far not been utilized asymmetrically. 115

Figure 24. Synthesis of higher-order phosphazenes and pKBH+ of selected bases.

Chiral higher order bis(guanidine)iminophosphorane bases have also been synthesized.53

They are synthesized similarly to the P1 phosphazene bases by reacting an aminoguanidine with phosphorus pentachloride. These catalysts are stored as their hydrochloro salts and deprotonated in situ. They can asymmetrically promote reactions with less acidic pronucleophiles than chiral guanidine or chiral phosphazene bases such as in the electrophilic amination of 2-methyl tetralone shown below.

Figure 25. Amination with chiral bis(guanidine)iminophosphorane catalyst.

116

A variety of other higher-order guanidine bases have been synthesized and shown higher basicity than simple guanidine bases. Biguanidine 22, proton sponge/guanidine hybrid 23, and bis(imidazolyl)guanidine 24 are representative examples of these types of bases.54 Thus far, there have been no chiral derivatives of these substrates.

Figure 26. Selected higher-order superbases with guanidine components.

My former colleague Dr. Eric Nacsa built on this work with a systematic study of higher- order superbases with cyclopropenimine, guanidine, and phosphazene components.55 He studied how changing the core and subsistuent groups affected the pKBH+. He also developed a new nomenclature based on Schwesinger’s naming system for the higher-order phosphazenes. Here, the bases are classified first by their core and then by the substituents on the outside.

Representative examples of higher-order bases he synthesized are shown below. While he briefly attempted to synthesize some chiral anaogues of these bases, thus far asymmetric catalysis with higher-order superbases is limited to Terada’s bis(guanidine)phosphazenes. One of the limiting factors is that asymmetric catalysis with cyclopropenimines has thus far required a hydrogen bond donating element, which is incompatible with these stronger bases. 117

Figure 27. Selected higher-order superbases with cyclopropenimine components.

Summary

Brønsted bases are an important tool for organic chemists as they are able to enact myriad chemical transformation and possess many advantages over their inorganic base counterparts.

Advances have been made in guanidine, iminophosphorane, and proazaphosphorane catalysis and in developing higher-order analogues of these bases. Of the classes just listed, guanidine bases have been most widely used in asymmetric Brønsted base catalysis, but successful chiral iminophosphoranes have also been developed. Despite these significant achievements, there is still a need for more effective chiral Brønsted bases. To this end the Lambert lab developed chiral cyclopropenimine bases in 2012, and has continued to expand on this class of superbases.

The next chapter will provide more detail on cyclopropenimine catalysis and feature some of my contributions to this area.

118

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Chapter 4 – Asymmetric Michael Reactions with Cyclopropenimines

Introduction

Glycine imines have long been studied as nucleophiles because their products can be hydrolyzed to produce unnatural amino acids, as well as further functionalized to produce a variety of synthetically relevant natural products. Many methods exist for performing asymmetric alkylations, Michael additions, and other reactions using method such as phase- transfer catalysis and Brønsted base catalysis; alkylations of glycine imines are so well studied that they are often used to compare the efficacy of different phase-transfer catalysis.56 Michael additions on glycine imines produce protected amino acids with a functional group handle and can be derivativized into many different products.

Because of this, when the Lambert lab was first developing cyclopropenimines, my former colleague Jeffrey Bandar developed Michael and Mannich reactions with glycine imine pronucleophiles, as detailed in the previous chapter.57 While he was able to expand the electrophile scope easily, catalyst 20 proved to have lower levels of enantioselectivity and/or reactivity when different nucleophiles were used. As a result, I decided to move to more challenging nucleophiles that were still related to the glycine imine but far less studied. In this way, I could expand cyclopropenimine and Brønsted base catalysis while producing valuable enantioenriched products.

Cyclopropenimine Synthesis and Properties

As discussed in the previous chapter, cyclopropenimines are an emerging class of chiral

Brønsted bases, and they have many properties that make them worth developing further. They are strong bases due to the stabilization of three nitrogen lone pairs in addition to the aromatic 123 cyclopropenium core present in the protonated form. This increased basicity over analogous guanidines allows for increased activity and access to a wider range of nucleophiles. There are significantly more stable than phosphazene bases and can generally be used in open-air reactions and without the need for dry solvent. Additionally, they are easy and inexpensive to synthesize.

Cyclopropenimine 20•HCl can be synthesized as shown below on a multigram scale from an amino-acid derived primary amine, dicyclohexylamine, and pentachlorocyclopropane, and no purification is necessary. Pentachlorocyclopropane is commercially available but can easily be synthesized on scale in one step from commodity chemicals. In order to access the free base, a

DCM solution of the salt is washed with 1 M NaOH, then dried and concentrated to yield a solid which can be used as a catalyst without further purification.

Figure 28. Two step synthesis of cyclopropenimines.

While this synthesis can be done on a large scale from the pentachlorocyclopropane, it is modular in nature and the dichloro intermediate can be isolated and stored, allowing for easy diversification of the head group. Additionally, different secondary amines can easily be added instead of the dicyclohexylamino groups as 2,3 substituents. However, smaller groups will add in three times and produce a trisaminocyclopropenium salt. This salt must then be hydrolyzed with potassium hydroxide and activated with oxalyl chloride before it can be turned into the cyclopropenimine. The large steric bulk that prevents the dicyclohexylamine from adding into the pentachlorocyclopropane three times also proved to be crucial in enacting high 124 enantioselectivity.57a As a result, we opted to keep using dicyclohexylamino groups as 2, 3- substituents when moving forward to other pronucleophiles.

Base and conditions screening has shown that a hydrogen-bond donor, such as an alcohol, is crucial in the top piece for enantioselectivity. This alcohol is able to activate the electrophile and help to organize the transition state. This organization is disrupted and enantioselectivity drops if a hydrogen-bonding solvent is used; non-polar solvents have generally proven to be ideal in inducing enantioselectivity with cyclopropenimines. Extensive theoretical transition state analysis has provided insight as to the catalytic cycle and revealed an interesting intermolecular hydrogen bond in the catalyst between the alcohol and a hydrogen on the α- carbon of one of the cyclohexyl rings.58

In summary, cyclopropenimines are simple and inexpensive to synthesize, and their modular synthesis allows for the easy formation of a variety of derivatives. Their enantioselectivity has thus far depended on the presence of bulky 2,3-dicyclohexylamino groups and an alcohol in the chiral top piece. However, while much has been studied about their mechanism, they have only been used on a narrow range of pronucleophiles when they surely have the potential to access a far broader range of substrates.

3-Butenoates

While investigating which hydrogen bonds were necessary for enantioinduction, Dr.

Bandar synthesized glycine imine analogue 25 in which the nitrogen atom had been replaced with a carbon atom.59 He saw greatly reduced activity; however, it was surprising and encouraging that the reaction proceeded at all. Furthermore, he observed only a modest erosion of enantioselectivity, down to 70%. 125

Figure 29. Michael Reaction with a carbon analogue of glycine imine.

β-γ-unsaturated esters have had very little use as substrates in Michael additions, due to their lower acidities and the fact that the double bond is prone to isomerization to the α-β position. Their use has been limited to substrates with electron-withdrawing groups such as in the α-position to increase acidity.60 We thought that the increased activity of our catalyst and the encouraging initial result meant that we could target diaryl-3-butenoate type substrates.

These types of nucleophiles have, however, previously been used by Corey in phase- transfer alkylations.61 To achieve excellent enantioselectivity, it was necessary to add electron donating group to the aryl rings in order to lower the acidity of the α-proton, although this did cause decreasing reactivity. 126

Figure 30: Corey’s phase-transfer alkylation of β-γ-unsaturated esters.

Because of the low reactivity of substrate 25, I first set out to synthesize more acidic analogues by putting electron withdrawing groups on the phenyl rings. Substrate 26 was synthesized in a four-step sequence from 4-bromo benzylbromide as shown below.62

Unfortunately, my efforts to install trifluoromethyl or nitro substituents for even more acidity were unsuccessful; the acidic rearrangement from the to the aldehyde failed. 127

Figure 31. Synthetic pathway to dibromo-substrate 26.

With substrate 26 in hand I tested it under the conditions Dr. Jeffrey Bandar had developed and found that the reactivity had increased; I obtained a 75% yield after 24 hours.

There was a slight decrease in enatioselectivity compared to substrate 25, to 61%, but it was now in a useful range of reactivity.

Figure 32. Increased reactivity from addition of bromo-substituents.

A small solvent screen revealed as the best solvent, with a 53% conversion and

83% enantioselectivity in 24 hours. Increasing the concentration up to 0.5 M caused the conversion to jump to 90% with only a negligible decrease in enantioselectivity to 82%. Further 128 increase in concentration to 1 M saw a drop in enantioselectivity to 76%. However, when screening further I noticed a troubling lack of reproducibility in enantiomeric excess values, which could vary from 60% to 78% for seemingly the same reaction conditions. Furthermore, there was a puzzling slight decrease in enantioselectivity when performing the reaction at 5 °C as opposed to room temperature. Exclusion of water and inert atmosphere did not seem to have an obvious effect, so racemization was suspected. Diphenyl glycine imine substrates rarely undergo multiple addition or racemization events because of steric clashing that would occur between one of the phenyl rings and the α-substituent (shown later in this chapter in Figure 37b). However, this does not appear to the case with this carbon analogue, likely due to the slightly longer C=C bond relieving the steric crowding. Enoate 27 with 80% enantiomeric excess was subjected to catalyst 20 in toluene at 5 °C for 24 hours and it was found that the enantiomeric excess had decreased to 54%, evidence that the catalyst was racemizing the product.

Figure 33. Product racemization by cyclopropenimine catalyst.

This result called into question the validity of earlier solvent and concentration screens and necessitated screening both the enantioselectivity and the conversion of the reaction as it progressed. In order to ensure accurate enantioselectivites, the reactions were loaded directly onto a silica gel column (without warming to room temperature in the case of chilled reactions), and aliquots taken at time points were quickly diluted into CDCl3 for NMR analysis of 129 conversion and then loaded directly onto the column from the NMR tube. These actions resulted in reproducible results and allowed for a comprehensive screen of conditions.

Table 1. Solvent screen for optimization of Michael addition on substrate 26.

The solvent screen revealed that while TBME appeared to be the best solvent early on, it suffered from significant racemization compared to toluene and mesitylene. Temperature screening revealing that cooling the reaction down in TBME did not impede the racemization but did cause a drop in reactivity, so I opted to move forward with mesitylene and to screen different temperatures. 130

Table 2. Temperature screen on Michael addition with substrate 26.

A temperature screen revealed comparable reactivity and increased enantioselectivity as the reaction was cooled from room temperature to -20 °C and -40 °C. Importantly, the racemization reaction slowed down significantly -40 °C to the point where it was nearly unnoticeable over the course of the reaction. This result proved reproducible and an isolated yield of 91% was achieved upon letting it go without interruption for 8 hours at -40 °C. Similarly to previous reactions with cyclopropenimines, this reaction is done with unpurified mesitylene and under an atmosphere of air (the vial is sealed to prevent excessive condensation of water into the vial at cold temperatures).

Unfortunately, expanding this reaction to a broader range of nucleophiles was difficult given the dependence of the reaction on the precise electronics. Attempts at using substrates in which one of the aryl rings was replaced with a methyl groups were unsuccessful: the substrates were difficult to synthesize as a single isomer, and irreproducible results were obtained along with lower reactivities and/or enantioselectivities. In the case of glycine imines, the imine can be easily hydrolyzed to reveal a free amine and thus the specific substituents are irrelevant. 131

However, when that nitrogen is replaced with a carbon atom, further functionalization becomes non-trivial. Processes such as are possible but would result in poor atom economy.

While one could imagine performing coupling reactions on dibromo 27, it is hard to visualize significant use for Michael reactions performed on substrate 26, especially given that it is non- trivial to synthesize.

α-Substituted Glycine Imines

While Michael additions can be performed very effectively on unsubstituted glycine imines, there is currently no general effective method for performing them on glycine imines with substitution at the alpha position. However, these products would be enormously valuable.

Following hydrolysis they would be tetrasubstitued amino acids; more specifically, glutamic acids, which have been used as selective neurotransmitters.63 Libraries of these glumatic acids have been synthesized and some show selectivity for metabotropic glutamate receptors while others are selective antagonists for kinate receptors.64 Additionally, if these products could be lactamized upon work-up they would produce a pyroglutamate, derivatives of which are a structural motif that forms the core of a number of biologically active natural products, including

(−)-dysibetaine, salinosporamide A, and lactacystin.65 These natural products all include a tetrasubstituted sterocenter on the gamma-carbon, which is difficult to make in a stereoselective fashion. Additionally, pyroglutamic acids have frequently been used as starting materials in a variety of natural product syntheses, in part because of their two orthogonally reactive carbonyl groups.66 This makes them attractive synthetic intermediates for the synthesis of natural products containing a γ-lactam. 132

Figure 34. Biologically active natural products with pyroglutamate cores.

Stereoselective paths to pyroglutamates with further substitution on the γ-carbon are often lengthy and utilize chiral auxiliaries67 or resolutions.68 It is also possible to do an alkylation on a glutamate imine; however, this has yet to be demonstrated with high enantioselectivity.69 An

α-β-unsaturated analogue of this structure can be made via cinchona alkaloid coupling of an amine and a dihalogenated acrylic ester.70 Current methods for forming these racemically include alkylating and oxidizing a protected proline,71 radical cyclization,72 and alkylation followed by lactamization.73 133

Figure 35. Enantioselective pathways to γ-substituted pyroglutamates.

These lactams could also in theory be produced from a Michael addition on an azlactone followed by hydrolysis and lactamization. To date, Kobayashi has reported the only example of an asymmetric Michael addition of an azlactone and an acrylic ester.74 Using a chiral calcium complex he was able to achieve enantioselectivities of up to 84%.

134

Figure 36. Enantioselective Michael reaction of an azlactone.

As previously mentioned, α-substitued glycine imines are more challenging pronucleophiles because of their increased steric demand. In the case of these pronucleophiles, imines formed from benzophenone generally cannot be used due to steric crowding in the conjugate acid. This steric interaction is an A1,3 strain, and causes the acidity to decease by over four orders of magnitude in moving from a glycine benzophenone imine to an alanine benzophenone imine.75 However, this strain is relieved when the imine is formed from an aldehyde, most commonly 4-chlorobenzaldehyde. Here, there is only a modest increase in pKa when switching from the glycine imine to the alanine imine. 135

Figure 37. pKa values for various glycine imines and allylic strain rational for pKa differences.

As a result, there are only two reports to date on enantioselective Michael additions on α- substituted glycine imines, and both rely on phase-transfer catalysis. The first report uses D2- symmetric quaternary salt 30 to achieve an enantiomeric excess of 63% with an alanine imine.76 However, if further substitution is present enantiomeric excess plummets and the products are racemic or nearly racemic. A second report uses cesium chloride and BINOL- derived quaternary ammonium salt 31.77 Here, they are able to achieve 90% enantiomeric excess when using a very bulky di(tert-butyl)methyl ester alanine imine. Glycine imines with substitution other than methyl in the α-position were not reported. 136

Figure 38. Previous asymmetric Michael additions on α-substituted glycine imines.

Because cyclopropenimines showed high reactivity for reactions with glycine imines, we hypothesized that they might also be effective in inducing reactivity on these less reactive α- substituted glycine imines. I synthesized alanine imine 32 and subjected it to the conditions Dr.

Jeffrey Bandar had developed and achieved a 90% conversion of 33 in 24 hours with an extremely promising 84% enantiomeric excess. Unfortunately, unexpected cycloadduct side product 34 was also observed (33:34 ratio of 4:1), and I had difficulty purifying the imine product due to hydrolysis during column chromatography. Asymmetric cycloadditions on α- substituted substrates like 32 are known and can proceed enatioselectively with catalysts such as /silver(I) complexes, binamphos/copper(I).78 As discussed in the previous chapter, a similar cycloaddition in unsubstituted glycine imines has been catalyzed asymmetrically by a guanidine base (Figure 10), and earlier this year the first asymmetric 137 cycloaddition reaction with cyclopropenimine bases was reported on 2-acyl-cycloheptatrienes

(Figure 23).

Figure 39. Initial test reaction for Michael addition of α-substituted glycine imines.

Cyclopropenimine catalysts were screened to try to both increase the enantioselectivity and suppress the cycloaddition side product. I opted to vary only the top piece and to keep dicyclohexylamino groups on the bottom since their steric bulk had proven key for inducing high enantioselectivity. I had a large selection of catalysts on hand as a result of a collaboration with

Drs. Spencer Dreher and Alexander Buitrago-Santanilla from Merck in which they commissioned the synthesis of a library of catalysts. Through this collaboration, cyclopropenimine catalysts 35-41 (and many more catalysts) were synthesized by Ji Qi and coworkers in China. I designed the catalyst structures and helped communicate with the scientists in China regarding the synthetic procedure. While the catalysts were originally made for high-throughput screening and I was trained at Merck in HTE technology, this screen was done at Columbia in a traditional manner with samples of the catalysts mailed to us from Merck.

Dr. Jeffrey Bandar first synthesized catalysts 42 and 43. In selecting which catalysts to screen I chose some catalysts which were selective in a previous screen and other catalysts for their structural diversity. 138

Figure 40. Catalyst screen for Michael reaction on alanine imine.

The results of this screen clearly showed the need for an alcohol in the top piece; catalyst

36 without an H-bond donor and catalyst 42 with an H-bond donor were completely ineffective. Catalysts 38 and 41 demonstrated that the relative stereochemistry of the alcohol is 139 crucial in a constrained system; reactivity and enantioselectivity dramatically decreased in these cis-catalysts. I decided to move forward with catalyst 43. Although catalyst 39 had the same enantioselectivity but higher regioselectivity, its lower reactivity could make substrates beyond the alanine imine inaccessible. An additional benefit of catalyst 43 is that it is completely bench- stable in the deprotonated form.59 Dr. Jeffrey Bandar found that catalyst 20 had a half-life of 15 days at room temperature, while catalyst 43 is completely bench stable with a half-life of more than 5 years. The decomposition of catalyst 20 is also seen in solution, limiting reaction times and preventing its use at elevated temperatures.

Figure 41. Decomposition pathway of cyclopropenimine 20.

With a catalyst chosen, a solvent screen was performed. Diethyl ether was found to be the most effective solvent, increasing the enantioselectivity up to 93%. Solvent did appear to play a role in the ratio of Michael reaction to cycloaddition, with the lowest ratio of 2.5:1 observed in toluene. Following the solvent screen, a brief concentration screen showed that increasing concentration sped up the reaction at the expense of the enantioselectivity, while diluting the reaction slowed it down without increasing the enantioselectivity. Lastly, closer analysis showed that the reaction was complete in 16 hours; while I was using 24 hours as a convenient time point, the reaction was in fact complete overnight. 140

Table 3. Conditions screen for Michael reaction on alanine imine.

While changing the conditions had successfully raised the enantioselectivity, I still wanted to see if I could reduce or eliminate cycloadduct side product 34. We hypothesized that by increasing the steric bulk on the aromatic component of the substrate, we could suppress the cycloaddition and obtain only the Michael addition. Surprisingly, the opposite was true. Moving the chloro group from the para-position to the ortho-position caused the amount of cycloadduct to increase. Looking at imines derived from dichlorobenzaldehyde, the 2,4-substrate had a ratio of 1:2 while the 2,6-substrate only produced the cycloadduct with decreased reactivity. Bulking further up to a chloro-substituted ring completely shut the reaction down. This suggested that both electronic effects and steric effects play a role; however, there proved no good way to apply this to decreasing the amount of cycloadduct produced. Removing the chloro- 141 group or adding electron-donating groups to the aromatic ring would be too detrimental to the reactivity. While this cycloaddition reaction could be an interesting reaction to pursue in and of itself, the fact that it is only viable on sterically hindered electron-deficient imines would severely limit its utility. Additionally, I did not observe any enantiomeric excess in the cycloadduct derived from 2,6-dichlorobenzaldehyde.

Figure 42. Effect of varying the aromatic group on the ratio of products.

I next developed a work-up procedure for the reaction. While literature reports isolated the pure imine, I saw trace to moderate amounts of hydrolysis of the imine during column chromatography that were exacerbated upon scale-up, preventing me from obtaining a good isolated yield. Hydrolysis with citric acid allowed me to isolate the free amine in good, but not great purity, and it was difficult to purify further. Attempts to reduce the imine to the amine were unsuccessful. Lastly, the lactam product was formed. After hydrolysis of the crude reaction with

0.5 M citric acid, the acidic aqueous layer was basified with potassium carbonate and stirred for

3 hours. The lactam could be obtained after extraction with DCM, and purified by column chromatography. This procedure required a precise amount of potassium carbonate: if too little was added the lactamization was slow, but if too much was added the ester would be hydrolyzed 142 and the product lost in the aqueous layer. However, with this procedure I was able to obtain a good isolated yield of 72% for the lactam and 19% for the cycloadduct.

Figure 43. Lactamization procedure for isolation of Michael addition product.

I next expanded this procedure to include imines other than alanine imine; one major limitation of previous procedures was that they were unable to accommodate further steric bulk in the alpha-position. Expanding from a to an caused a drop in reactivity; now, even with a 20% catalyst loading and a 48 hour reaction time, the reaction only went to around 85% conversion. However, there was a slight increase in selectivity to 6:1

Michael:cycloadduct and I was able to achieve a 70% isolated yield of the lactam. There was also a loss in enantioselectivity, down to 87%. Further expansion to a resulted in roughly the same reactivity but a further drop in enantioselectivity to 82%. Increasing the chain to a butyl and hexyl group caused increasingly lowered reactivity, but roughly the same enantioselectivity. It is clear that increasing the steric bulk in the alpha position has a detrimental effect on the reaction.

143

Table 4: Expansion of substrate scope to simple straight-chain alkyl groups.

Next, the substrate scope was expanded to branched alkyl-groups. There was no reactivity with a bulky isopropyl group in the alpha–position, but the reaction was tolerant of an isobutyl group, which had roughly the same reactivity as an n-butyl group. However, there was a drop in enantioselectivity to 77%. I observed similarly lowered enantioselectivity with a , so I returned my focus to straight chains. Looking at unsaturation, there was 94% enantioselectivity with an and 88% enantioselectivity with a propargyl group, both higher than that of the parent propyl group, possibly due to a combination of their smaller size, lower degree of conformational freedom, and/or secondary orbital overlap. I also looked at substrates with chains containing heteroatoms and found an 84% enantioselectivity from a methionine-derived substrate. Unfortunately, adding a on the end of the chain caused a drastic drop in enantioselectivity. It is possible that the nitrile is participating in a detrimental hydrogen-bond. Interestingly, both of these heteroatom-containing substrates showed much 144 higher reactivity than the analagous straight-chain alkyl substrates; the reactions were complete in 16 hours with just 10% catalyst loading.

Table 5. Further expansion of substrate scope.

This procedure is far more effective than the methods previously reported in the literature. One previous method did not report substrates other than the alanine imine,77 while the other saw a drop in enantioselectivity from 63% to 9% when a phenylalanine imine was used instead of an alanine imine, possibly partially due to the increase in temperature required to induce reactivity on the more hindered substrate (Figure 38).76 While there is still room for improvement in yield and enantioselectivity, this work represents a step forward over previous methods. 145

Additionally, this is the first example of a Brønsted base engaging asymmetrically with an α-substituted glycine imine. As mentioned previously, cyclopropenimines have increased reactivity over analogous guanidine bases due to the latent aromatic core. Here, the benefit can be clearly seen: while guanidine bases can barely activate glycine imines, cyclopropenimines can easily engage them and can also activate more challenging substituted derivatives.

Conclusions

This chapter describes my efforts to expand cyclopropenimine catalysis to include more challenge glycine imine derivatives. I was able to successfully develop conditions to perform

Michael additions using a glycine imine in which the nitrogen atom has been replaced with a carbon, and on glycine imines with further substitution at the alpha position. The yields and enantiomeric excesses for these processes ranged from moderate to excellent and represent the state of the art for these substrates and the first example of their use with Brønsted base catalysis.

146

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Acknowledgements: I would like to acknowledge Dr. Jeffrey Bander for his pioneering work in developing cyclopropenimine catalysis. He developed catalysts 20, 42, and 43 which were discussed in this section. I would also like to acknowledge Drs. Spencer Dreher and Alexander Buitrago-

Santanilla from Merck for providing the synthesis of catalysts 33-41 which were also used in this section.

149

Experimental Data for Michael Reaction with Cyclopropenimines

General Information. Organic solutions were concentrated using a Buchi rotary evaporator.

Commercial reagents were used as provided. Flash column chromatography was performed employing 32-63 μm silica gel (Dynamic Adsorbents Inc). Thin-layer chromatography (TLC) was performed on silica gel 60 F254 plates (EMD).

1 13 1 H and C NMR were recorded in CDCl3 on Bruker DRX-400 spectrometers. Data for H

NMR are reported as follows: chemical shift (δ ppm), multiplicity (s = singlet, brs = broad singlet, d = doublet, t = triplet, q = quartet, m = multiplet), coupling constant (Hz), integration, and assignment. Data for 13C NMR are reported in terms of chemical shift. Low- resolution mass spectra (LRMS) were acquired on a JEOL JMS-LCmate liquid chromatography mass spectrometer system using CI+ ionization technique.

Methyl 4,4-bis(p-bromophenyl)but-3-enoate (26) was synthesized according to the following sequence:

150

trans-4,4’-Dibromostilbene: Based on the method of Peng and Deng1, sodium p- toluenesulfinate (1.78 g, 10 mmol, 0.5 equiv.), potassium hydroxide (1.65 g, 30 mmol, 1.5 equiv.), 4-bromobenzyl bromide and dimethylsulfoxide were added to a 500 mL round bottom flask equipped with a magnetic stir bar. The reaction was heated to 100 °C and stirred for 16 hours at this temperature. Upon cooling to room temperature the reaction was diluted with dichloromethane (500 mL) and water (500 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (100 mL). The combined organic layers were washed water

(5 x 500mL), brine (500 mL), dried over anhydrous sodium sulfate, and concentrated to provide the title product as a pale yellow solid. The crude product was used without purification.

Spectroscopic data was identical to the literature.1

trans-4,4’-Dibromostilbene oxide: Crude trans-4,4’-dibromostilbene from the previous step was dissolved in dichloromethane (125 mL) in a 250 mL round bottom flask equipped with a stirbar. mCBPA (5.1 g, 22 mmol, 2.2 equiv.) was added and the reaction was stirred until it was complete, as determined by 1H NMR. The reaction was washed with saturated sodium bicarbonate (2 x 100 mL), brine (1 x 100 mL), dried over anhydrous sodium sulfate and concentrated to form a yellow solid. The crude product was purified by flash chromatography

1 Zhao, F.;Luo, J.; Tan, Q.; Liao, Y.; Peng, S.; Deng, G.-J.Adv. Synth. Catal., 2012, 354, 1914-1918. 151

(5% ethyl acetate/) on silica gel afforded the title product a white solid (2.26 g, 64% yield over 2 steps). Spectroscopic data was identical to the literature.2

2,2-bis(p-bromophenyl): As described by Nangia,3 trans-4,4’-dibromostilbene oxide (3.85 g, 10.9 mmol, 1 equiv.) was dissolved in DCM (109 mL) in a 250 mL round bottom flask. The solution was cooled to 0 °C. Boron trifluoride diethyl etherate (0.67 mL, 5.4 mmol,

0.5 equiv.) was added and the mixture was stirred for 30 minutes. After quenching with water at

0 °C, the solution was warmed to room temperature, extracted with water (100 mL), brine (100 mL), dried over anhydrous magnesium sulfate and concentrated. The crude material was purified by flash chromatography (5% ethyl acetate/hexanes) to yield the title compound as a yellow oil

(2.58 g, 67%). Spectroscopic data was identical to the literature.4

4,4-bis(p-bromophenyl)but-3-enoic acid: Following the procedure of Brown5 with 2,2-bis(p- bromophenyl)acetaldehyde, after purification by flash chromatography (5%-50% ethyl acetate/hexanes), the title compound was obtained as a white solid (1.96 g, 75%). 1H NMR (400

MHz, CDCl3) δ 7.53 (d, J = 8.4 Hz, 2H, ArH), 7.40 (d, J = 8.6 Hz, 2H, ArH), 7.09 (d, J = 8.6 Hz,

2H, ArH), 7.04 (d, J = 8.4 Hz, 2H, ArH), 6.23 (t, J = 7.5 Hz, 1H, HC=C), 3.17 (d, J = 7.5 Hz,

2 Okazaki, Y.; Ando, F.; Jugo Koketsu, J. Bull. Chem. Soc. Jpn., 2003, 76, 2155–2165 . 3 Roy, S.; Banerjee, R.; Nangia, A.; Kruger, G. J. Chem. Eur. J. 2006, 12, 3777 – 3788. 4 Chen, C.-C.; Chen, L.-Y.; Lin, R.-Y.; Chu, C.-Y.; Dai, S. A. Heterocycles, 2009, 78, 2979-2992. 5 Hudgens, D. P.; Taylor, C.; Batts, T. W.; Patel, M. K.; Brown, M. L. Bioorg. Med. Chem., 2006, 14, 8366-8378. 152

13 2H, CH2COOH). C NMR (101 MHz, CDCl3) δ 177.59, 143.41, 140.27, 137.46, 131.97,

131.54, 131.47, 129.12, 122.16, 122.07, 120.64, 35.19. LRMS (APCI+): exact mass calc’d for

+ C16H12Br2O2 [M+1] requires m/z 396.92, found m/z 396.69.

Methyl 4,4-bis(p-bromophenyl)but-3-enoate: Following the procedure of Armesto6 with 4,4- bis(p-bromophenyl)but-3-enoic acid, after purification by flash chromatography (2% ethyl acetate/hexanes) the title compound was obtained as a white solid (0.810 g, 74%). 1H NMR (400

MHz, CDCl3) δ 7.51 (d, J = 8.4 Hz, 2H, ArH), 7.39 (d, J = 8.6 Hz, 2H, ArH), 7.08 (d, J = 8.6 Hz,

2H, ArH), 7.04 (d, J = 8.4 Hz, 2H, ArH), 6.24 (t, J = 7.5 Hz, 1H, HC=C), 3.70 (s, 3H, CO2CH3),

13 3.13 (d, J = 7.5 Hz, 2H, CH2CO2Me). C NMR (101 MHz, CDCl3) δ 171.88, 142.80, 140.41,

137.59, 131.85, 131.50, 131.46, 129.09, 121.97, 121.87, 121.54, 52.11, 35.29. LRMS (APCI+):

+ exact mass calc’d for C17H14Br2O2 [M+1] requires m/z 408.94, found m/z 408.36.

1, 5 dimethyl 2-[2,2-bis(p-bromophenyl)ethenyl]pentanedioate: Enoate 26 (41 mg, 0.1 mmol,

1 equiv.), and cyclopropenimine 20 (5.5 mg, 0.01 mmol, 0.1 equiv.) were dissolved in mesitylene (0.2 mmol, 0.5 M) and cooled to -40 °C. Methyl acrylate (27 μL, 0.03 mmol, 3 equiv.) was added and the solution was stirred at -40 °C for eight hours. The chilled solution was loaded directly onto a silica gel column and the title compound was isolated as a clear oil (44.9

6 Armesto, D.; Ortiz, M. J.; Agarrabeitia, A. R.; Aparicio-Lara, S. Synthesis, 2001, 8, 1149-1158. 153

1 mg, 91% yield). H NMR (400 MHz, CDCl3) δ 7.53 (d, J = 8.8 Hz, 2H, ArH), 7.39 (d, J = 8.8

Hz, 2H, ArH), 7.05 (dd, J = 8.8 Hz, 1.2 Hz, 4H, ArH), 6.02 (d, J = 10.2 Hz, 1H, HC=C), 3.70 (s,

3H, CO2CH3), 3.58 (s, 3H, CO2CH3), 3.25-3.15 (m, 1H, CHCO2Me), 2.28-2.21 (m, 2H,

13 CH2CO2Me), 2.15-2.05 (m, 1H, AlkylH), 1.99-1.87 (m, 1H, AlkylH). C NMR (101 MHz,

CDCl3) δ 173.69, 173.11, 143.03, 140.12, 137.52, 131.91, 131.58, 131.55, 129.03, 126.60,

122.14, 122.10, 52.29, 51.80, 45.42, 31.41, 27.78. HPLC analysis: Chiralpak OD-H (Hex/iPrOH

= 98/2, 0.8 mL/min, 254 nm), 9.7 min (major), 12.1 min (minor), 89% ee.

Synthesis of Cycloadducts and Lactams:

A vial was charged with cyclopropenimine catalyst (0.1-0.2 eq), and imine (0.2 mmol, 1 eq.), ether (0.8 mL, 0.25M), and methyl acrylate (0.054 mL, 0.6 mmol, 3 eq.) were added. The vial was parafilmed shut and stirred for 16-48 hours at room temperature. At that time the mixture was concentrated and redissolved in 2 mL THF and 2 mL 0.5 M aqueous citric acid. After stirring for one hour the mixture was diluted with water (20 mL) and extracted twice with ether

(2x20mL). The ether layers were combined, dried and concentrated to reveal the crude cycloadduct, which was purified on Si. Potassium carbonate (414 mg, 3 mmol, 30 eq.) was added to the aqueous layer and it was stirred for 3 hours. It was extracted with DCM (3x20 mL) and the combined organic layers were dried and concentrated. After purification on Si the pure lactams were isolated. Enantiomeric excess was determined by HPLC of the imine, HPLC of the lactam product, or addition of Europium(III) tris[3-(heptafluoropropylhydroxymethylene)-d- camphorate] (chiral shift reagent) to the lactam. Racemates were made using an achiral cyclopropenimine. 154

Procedure for determination of enantiomeric excess via use of chiral shift reagent Eu(hfc)3: Prior to use, CDCl3 was dried with sodium sulfate and filtered through a silica plug. 0.5- 2 mg of lactam was dissolved in 0.6 mL CDCl3 under Ar. Approximately 5 mg of Eu(hfc)3 was added as a solution in CDCl3 (this solution was around 50 mg/mL and was filtered through a syringe filter to remove insoluble paramagnetic impurities). A 1H NMR was taken. If the peaks were not sufficiently separated more Eu(hfc)3 was added until separation occurred. Enantiomeric excess was determined by the methyl ester peaks, which were shifted downfield and cleanly separated.

NMR spectra are provided of both the racemic mixture and chiral substrate; however, the peaks are not always at the exact same chemical shift due to slightly differing ratios of substrate to

Eu(hfc)3.

Methyl 2-methyl-5-oxopyrrolidine-2-carboxylate: This compound was synthesized as

1 described above and isolated in 73% yield as a clear oil. H NMR (400 MHz, CDCl3): 5.9 (br s,

1H, NH), 3.76 (s, 3H, CO2CH3), 2.50-2.57 (m, 1H, alkylH), 2.41 (t, J= 7.6 Hz, 2H, C(O)CH2),

13 1.99-2.07 (m, 1H, alkylH), 1.52 (s, 3H, CCH3). C NMR (101 MHz, CDCl3) δ 176.62, 174.33,

+ 62.05, 52.77, 32.20, 29.83, 25.89. LRMS (APCI+): exact mass calc’d for C7H12NO3 [M+1] requires m/z 158.07, found m/z 157.91. HPLC analysis (performed on the imine intermediate):

Chiralpak OJ-H (Hex/iPrOH = 90/10, 1 mL/min, 254 nm), 11.5 min (major), 19.6 min (minor),

93% ee.

155

2,4-dimethyl 2-methyl-5-(4-chlorophenyl)pyrrolidine-2,4-dicarboxylate: This compound was synthesized similar to above; however, it remained in the aqueous layer after the ether extraction of the citric acid mixture and so was isolated following lactamization. It was isolated as a white

1 solid in 19% yield. H NMR (400 MHz, CDCl3): 7.30-7.22 (m, 4H, ArH), 4.68 (d, J =7.6 Hz,

1H, ArCH), 3.83 (s, 3H, CO2CH3), 3.40-3.33 (m, 1H, MeCO2CH), 3.26 (s, 3H, CO2CH3), 2.73

(dd, J = 13.6 Hz, 5.2 Hz, 1H, CH2), 2.07 (dd, J = 13.6 Hz, 7.6 Hz, 1H, CH2), 1.517 (s, 3H, CH3).

13 C NMR (101 MHz, CDCl3) 176.36, 172.75, 137.63, 133.40, 128.39, 128.19, 65.82, 64.15,

+ 52.65, 51.37, 50.15, 40.07, 27.35. LRMS (APCI+): exact mass calc’d for C15H18ClNO4 [M+1] requires m/z 312.09, found m/z 312.17.

Methyl 2-iso-butyl-5-oxopyrrolidine-2-carboxylate: This compound was synthesized as described above with a 20% catalyst loading and 48 hr reaction time. It was isolated as a white

1 solid in 62% yield. H NMR (400 MHz, CDCl3): 6.15 (br s, 1H, NH), 3.78 (s, 3H, CO2CH3),

2.56-2.46 (m, 1H, alkylH), 2.40-2.34 (m, 2H, alkylH), 2.13-2.04 (m, 1H, alkylH), 1.91-1.84 (m,

1H, alkylH), 1.73-1.61 (m, 2H, alkylH), 0.95 (d, J = 6.4 Hz, 3H, CH3), 0.90 (d, J = 6.4Hz, 3H,

13 CH3). C NMR (101 MHz, CDCl3) δ 176.74, 174.33, 65.25, 52.57, 48.07, 32.24, 29.40, 24.90,

+ 23.82, 23.00. LRMS (APCI+): exact mass calc’d for C10H17NO3 [M+1] requires m/z 200.12, found m/z 200.18. HPLC analysis: Chiralpak OD-H (Hex/iPrOH = 97/3, 1 mL/min, 210 nm),

25.5 min (major), 29.8 min (minor), 77% ee. 156

2,4-dimethyl 2-iso-butyl-5-(4-chlorophenyl)pyrrolidine-2,4-dicarboxylate: This compound was synthesized as described above with a 20% catalyst loading and 48 hr reaction time. It was

1 isolated as a clear oil in 10% yield. H NMR (400 MHz, CDCl3): 7.29-7.22 (m, 4H, ArH), 4.56

(d, J = 7.6 Hz, 1H, ArCH), 3.81 (s, 3H, CO2CH3), 3.34 – 3.26 (m, 1H, MeCO2CH), 3.24 (s, 3H,

CO2CH3), 2.97 (br s, 1H, NH), 2.64 (dd, J = 13.7, 5.2 Hz, 1H, alkylH), 2.04 (dd, J = 13.6, 7.6

Hz, 1H, alkylH), 1.85 – 1.69 (m, 2H, alkylH), 1.59 (dd, J = 13.2, 4.9 Hz, 1H, alkylH), 0.95 (d, J

13 = 6.5 Hz, 3H, CH3), 0.84 (d, J = 6.4 Hz, 3H, CH3). C NMR (101 MHz, CDCl3) δ 176.54,

172.98, 138.13, 133.24, 128.32, 128.23, 68.99, 64.53, 52.27, 51.30, 49.94, 48.94, 40.90, 25.28,

+ 24.29, 22.85. LRMS (APCI+): exact mass calc’d for C18H24ClNO4 [M+1] requires m/z 354.14, found m/z 354.19.

Methyl 2-benzyl-5-oxopyrrolidine-2-carboxylate: This compound was synthesized as described above with a 15% catalyst loading and 48 hr reaction time. It was isolated as a white

1 solid in a 77% yield. H NMR (400 MHz, CDCl3): 7.36-7.28 (m, 3H, ArH), 7.17-7.13 (m, 2H,

ArH), 5.89 (br s, 1H, NH), 3.74 (s, 3H, CO2CH3), 3.30 (d, J = 13.6 Hz, 1H, PhCH2), 2.93 (d, J =

13 13.6 Hz, 1H, PhCH2), 2.54-2.45 (m, 1H, alkylH), 2.39-2.15 (m, 3H, alkylH). C NMR (101

MHz, CDCl3) δ 176.40, 173.56, 134.78, 129.66, 128.77, 127.57, 66.37, 52.60, 45.21, 30.91,

+ 29.60. LRMS (APCI+): exact mass calc’d for C13H15NO3 [M+1] requires m/z 234.11, found m/z 157

233.97. HPLC analysis: Chiralpak AD-H (Hex/iPrOH = 90/10, 1 mL/min, 210 nm), 11.3 min

(major), 21.5 min (minor), 75% ee.

2,4-dimethyl 2-benzyl-5-(4-chlorophenyl)pyrrolidine-2,4-dicarboxylate: This compound was synthesized as described above with a 15% catalyst loading and 48 hr reaction time. It was

1 isolated as a white solid in 21% yield. H NMR (400 MHz, CDCl3): 7.30-7.18 (m, 9H, ArH),

4.49 (d, J =7.6 Hz, 1H, ArCH), 3.75 (s, 3H, CO2CH3), 3.23 (s, 3H, CO2CH3), 3.19-3.15 (m, 1H,

MeCO2CH), 3.12 (d, J = 13.2 Hz, 1H, PhCH2), 2.93 (d, J = 13.2 Hz, 1H, PhCH2), 2.84 (br s, 1H,

13 NH), 2.74 (dd, J = 14.0 Hz, 5.6 Hz, 1H, CH2), 2.20 (dd, J = 14.0 Hz, 7.6 Hz, 1H, CH2). C

NMR (101 MHz, CDCl3) δ 175.60, 172.69, 138.43, 136.75, 133.25, 130.09, 128.27, 128.16,

126.89, 70.28, 64.26, 52.29, 51.30, 49.80, 45.82, 38.28. LRMS (APCI+): exact mass calc’d for

+ C21H22ClNO4 [M+1] requires m/z 388.12, found m/z 388.33.

Methyl 2-propyl-5-oxopyrrolidine-2-carboxylate: This compound was synthesized as described above with a 20% catalyst loading and 48 hr reaction time. It was isolated as a white

1 solid in 67% yield. H NMR (400 MHz, CDCl3): 6.04 (br s, 1H, NH), 3.76 (s, 3H, CO2CH3),

2.53-2.44 (m, 1H, alkylH), 2.40-2.33 (m, 2H, alkylH), 2.13-2.04 (m, 1H, alkylH), 1.88-1.78 (m,

1H, alkylH), 1.76-1.66 (m, 1H, alkylH), 1.35-1.20 (m, 1H, CH2CH3) 0.93 (t, J = 7.6 Hz, 3H,

13 CH3). C NMR (101 MHz, CDCl3) δ 176.64, 174.00, 65.58, 52.61, 41.61, 30.72, 29.62, 17.57, 158

+ 14.02. LRMS (APCI+): exact mass calc’d for C9H15NO3 [M+1] requires m/z 186.11, found m/z

186.18. Enantiometric excess (82% ee) was determined by the addition of chiral shift reagent.

2,4-dimethyl 2-propyl-5-(4-chlorophenyl)pyrrolidine-2,4-dicarboxylate: This compound was synthesized as described above with a 20% catalyst loading and 48 hr reaction time. It was

1 isolated as a white solid in 13% yield. H NMR (400 MHz, CDCl3): 7.29-7.21 (m, 4H, ArH),

4.56 (d, J =7.2 Hz, 1H, ArCH), 3.81 (s, 3H, CO2CH3), 3.25 (s, 3H, CO2CH3), 3.30-3.23 (m, 1H,

MeCO2CH), 3.01 (br s, 1H, NH), 2.70 (dd, J = 13.6 Hz, 4.8 Hz, 1H, CH2), 2.06 (dd, J = 13.6 Hz,

7.6 Hz, 1H, CH2), 1.87-1.76 (m, 1H, CH2CH2CH3), 1.66-1.55 (m, 1H, CH2CH2CH3), 1.52-1.41

13 (m, 1H, CH2CH3), 1.22-1.10 (m, 1H, CH2CH3), 0.91 (t, J= 7.2Hz, 3H, CH2CH3). C NMR (101

MHz, CDCl3) δ 176.25, 172.99, 137.88, 133.29, 128.36, 128.13, 69.52, 64.76, 52.39, 51.29,

+ 50.21, 43.28, 39.66, 18.43, 14.20. LRMS (APCI+): exact mass calc’d for C17H22ClNO4 [M+1] requires m/z 340.12, found m/z 340.25.

Methyl 2-methylthioethyl-5-oxopyrrolidine-2-carboxylate: This compound was synthesized as described above with a 10% catalyst loading and 16 hr reaction time. It was isolated as a white

1 1 solid in 76% yield. H NMR (400 MHz, CDCl3): H NMR (400 MHz, CDCl3): 6.51 (br s, 1H,

NH), 3.78 (s, 3H, CO2CH3), 2.53-2.42 (m, 3H, alkylH), 2.40-2.34 (m, 2H, alkylH), 2.27-2.17 (m,

13 1H, alkylH), 2.14-2.06 (m, 1H, alkylH), 2.10 (s, 3H, SCH3) 2.06-1.97 (m, 1H, alkylH). C 159

NMR (101 MHz, CDCl3) δ 176.84, 173.58, 65.24, 52.85, 38.26, 31.27, 29.36, 28.95, 15.58.

+ LRMS (APCI+): exact mass calc’d for C9H15NO3S [M+1] requires m/z 218.08, found m/z

218.18. Enantiometric excess (84% ee) was determined by the addition of chiral shift reagent.

2,4-dimethyl 2-methylthioethyl-5-(4-chlorophenyl)pyrrolidine-2,4-dicarboxylate: This compound was synthesized as described above with a 10% catalyst loading and 16 hr reaction

1 time. It was isolated as a white solid in 19% yield. H NMR (400 MHz, CDCl3): 7.31-7.19 (m,

4H, ArH), 4.54 (d, J =7.2 Hz, 1H, ArCH), 3.83 (s, 3H, CO2CH3), 3.26 (s, 3H, CO2CH3), 3.35-

3.25 (m, 1H, MeCO2CH), 3.09 (br s, 1H, NH), 2.75-2.60 (m, 2H, CH2), 2.40-2.30 (m, 1H, CH2),

13 2.21-2.03 (m, 3H, CH2), 2.10 (s, 3H, SCH3), 1.93-1.84 (m, 2H, CH2). C NMR (101 MHz,

CDCl3) δ 175.56, 172.90, 137.54, 133.42, 128.44, 128.08, 69.17, 64.84, 52.64, 51.36, 50.19,

+ 40.12, 29.71, 15.69. LRMS (APCI+): exact mass calc’d for C17H22ClNO4S [M+1] requires m/z

372.10, found m/z 372.23.

Methyl 2-allyl-5-oxopyrrolidine-2-carboxylate: This compound was synthesized as described above with a 10% catalyst loading and 48 hr reaction time. It was isolated as a white solid in

1 1 69% yield. H NMR (400 MHz, CDCl3): H NMR (400 MHz, CDCl3): 5.97 (br s, 1H, NH), 5.73-

5.61 (m, 1H, C=CH), 5.22-5.13 (m, 2H, C=CH), 3.76 (s, 3H, CO2CH3), 2.70-2.62 (m, 2H, 160

13 alkylH), 2.50-2.35 (m, 4H, alkylH) 2.16-2.08 (m, 1H, alkylH). C NMR (101 MHz, CDCl3) δ

176.57, 173.56, 130.96, 120.68, 65.13, 52.70, 43.53, 30.26, 29.66. LRMS (APCI+): exact mass

+ calc’d for C9H13NO3 [M+1] requires m/z 184.09, found m/z 184.15. Enantiometric excess (94% ee) was determined by the addition of chiral shift reagent.

2,4-dimethyl 2-allyl-5-(4-chlorophenyl)pyrrolidine-2,4-dicarboxylate: This compound was synthesized as described above with a 10% catalyst loading and 48 hr reaction time. It was

1 isolated as a white solid in 23% yield. H NMR (400 MHz, CDCl3): 7.32-7.25 (m, 4H, ArH),

5.92-5.79 (m, 1H, CH=CH2), 5.17 (s, 1H, CH=CH2), 5.15 (d, J = 3.6 Hz, 1H, CH=CH2), 4.62 (d,

J =7.6 Hz, 1H, ArCH), 3.84 (s, 3H, CO2CH3), 3.36-3.28 (m, 1H, MeCO2CH), 3.28 (s, 3H,

CO2CH3), 3.00 (br s, 1H, NH), 2.74 (dd, J = 13.6 Hz, 4.8 Hz, 1H, CH2), 2.60 (dd, J = 13.6, 7.6

Hz, 1H, CH2CH=CH2), 2.45 (dd, J = 13.6, 7.6 Hz, 1H, CH2CH=CH2), 2.14 (dd, J = 13.6 Hz, 7.6

13 Hz, 1H, CH2). C NMR (101 MHz, CDCl3) δ 175.68, 172.76, 138.02, 133.50, 133.30, 128.34,

128.18, 118.70, 69.31, 64.52, 52.44, 51.32, 50.09, 44.89, 38.34. LRMS (APCI+): exact mass

+ calc’d for C17H20ClNO4 [M+1] requires m/z 338.11, found m/z 338.27.

161

Methyl 2-(3-cyanopropyl)-5-oxopyrrolidine-2-carboxylate: This compound was synthesized as described above with a 10% catalyst loading and a 16 hr reaction time. It was isolated as a

1 1 white solid in 75% yield. H NMR (400 MHz, CDCl3): H NMR (400 MHz, CDCl3): 5.96 (br s,

1H, NH), 3.79 (s, 3H, CO2CH3), 2.57-2.47 (m, 1H, alkylH), 2.43-2.37 (m, 4H, alkylH), 2.13-1.87

13 (m, 3H, alkylH), 1.72-1.58 (m, 2H, alkylH). C NMR (101 MHz, CDCl3) δ 176.61, 173.28,

118.60, 64.79, 53.00, 38.03, 30.52, 29.47, 20.37, 17.22. LRMS (APCI+): exact mass calc’d for

+ C18H21ClN2O4 [M+1] requires m/z 211.10, found m/z 211.14. Enantiometric excess (16% ee) was determined by the addition of chiral shift reagent.

Dimethyl 5-(4-chlorophenyl)-2-(3-cyanopropyl)pyrrolidine-2,4-dicarboxylate: This compound was synthesized as described above with a 10% catalyst loading and a 16 hr reaction time. It was isolated as a white solid in 16% yield (9:1 mixture of 2 isomers). 1H NMR (400

MHz, CDCl3) (major isomer): 7.32-7.25 (m, 4H, ArH), 4.62 (d, J = 8.8 Hz, 1H, ArCH), 3.81 (s,

3H, CO2CH3), 3.25 (q, 1H, J = 8.0 Hz, MeCO2CH), 3.19 (s, 3H, CO2CH3), 2.85 (br s, 1H, NH),

2.55-2.32 (m, 4H, alkyl), 2.15-2.02 (m, 2H, alkyl), 1.90-1.80 (m, 1H, alkyl), 1.79-1.65 (m,

13 1H,alkyl). C NMR (101 MHz, CDCl3) δ 176.79, 172.47, 138.92, 133.22, 128.68, 128.04,

119.27, 68.37, 62.83, 52.70, 51.34, 48.48, 37.88, 36.21, 21.23, 17.47. LRMS (APCI+): exact

+ mass calc’d for C18H21ClN2O4 [M+1] requires m/z 365.12, found m/z 365.42.

162

Methyl 2-ethyl-5-oxopyrrolidine-2-carboxylate: This compound was synthesized as described above with a 20% catalyst loading and 48 hr reaction time. It was isolated as a white solid in

1 1 70% yield. H NMR (400 MHz, CDCl3): H NMR (400 MHz, CDCl3): 6.15 (br s, 1H, NH), 3.76

(s, 3H, CO2CH3), 2.54-2.44 (m, 1H, alkylH), 2.38 (t, J = 8.0 Hz, 2H, alkylH), 2.12-2.02 (m, 1H,

13 alkylH), 1.95-1.85 (m, 1H, alkylH), 1.85-1.76 (m, 1H, alkylH), 0.90 (t, J = 7.5 Hz, 3H, CH3). C

NMR (101 MHz, CDCl3) δ 176.75, 173.92, 66.10, 52.60, 32.27, 30.11, 29.72, 8.38. LRMS

+ (APCI+): exact mass calc’d for C8H13NO3 [M+1] requires m/z 172.09, found m/z 172.22.

Enantiometric excess (87% ee) was determined by the addition of chiral shift reagent.

2,4-dimethyl 2-ethyl-5-(4-chlorophenyl)pyrrolidine-2,4-dicarboxylate: This compound was synthesized as described above with a 20% catalyst loading and 48 hr reaction time. It was

1 isolated as a white solid in 11% yield. H NMR (400 MHz, CDCl3): 7.25 (q, J = 8.7 Hz, 4H,

ArH), 4.55 (d, J =7.2 Hz, 1H, ArCH), 3.82 (s, 3H, CO2CH3), 3.25 (s, 3H, CO2CH3), 3.30-3.23

(m, 1H, MeCO2CH), 2.70 (dd, J = 13.7 Hz, 4.6 Hz, 1H, CH2), 2.06 (dd, J = 13.7 Hz, 7.5 Hz, 1H,

CH2), 1.94-1.79 (m, 1H, CH2CH3), 1.75-1.62 (m, 1H, CH2CH3), 0.91 (t, J= 7.4Hz, 3H,

13 CH2CH3). C NMR (101 MHz, CDCl3) δ 176.09, 172.99, 137.90, 133.29, 128.37, 128.12, 70.04,

64.69, 52.39, 51.30, 50.25, 39.27, 33.74, 9.39. LRMS (APCI+): exact mass calc’d for

+ C16H20ClNO4 [M+1] requires m/z 326.11, found m/z 326.20.

163

Methyl 2-butyl-5-oxopyrrolidine-2-carboxylate: This compound was synthesized as described above with a 20% catalyst loading and 48 hr reaction time. It was isolated as a clear oil in 54%

1 yield. H NMR (400 MHz, CDCl3): 6.12 (br s, 1H, NH), 3.78 (s, 3H, CO2CH3), 2.55-2.45 (m,

1H, alkylH), 2.42-2.36 (m, 2H, alkylH), 2.15-2.05 (m, 1H, alkylH), 1.91-1.83 (m, 1H, alkylH),

13 1.79-1.69 (m, 1H, alkylH), 1.40-1.15 (m, 4H, alkylH) 0.92 (t, J = 7.6 Hz, 3H, CH3). C NMR

(101 MHz, CDCl3) δ 176.68, 174.03, 65.60, 52.60, 39.14, 30.65, 29.65, 26.23, 22.62, 13.80.

+ LRMS (APCI+): exact mass calc’d for C10H17NO3 [M+1] requires m/z 200.12, found m/z

200.40. Enantiometric excess (82% ee) was determined by the addition of chiral shift reagent.

2,4-dimethyl 2-butyl-5-(4-chlorophenyl)pyrrolidine-2,4-dicarboxylate: This compound was synthesized as described above with a 20% catalyst loading and 48 hr reaction time. It was

1 isolated as a white solid in 11% yield. H NMR (400 MHz, CDCl3): 7.25 (q, J = 8.7 Hz, 4H,

ArH), 4.56 (d, J =7.2 Hz, 1H, ArCH), 3.82 (s, 3H, CO2CH3), 3.25 (s, 3H, CO2CH3), 3.30-3.23

(m, 1H, MeCO2CH), 3.03 (br s, 1H, NH), 2.70 (dd, J = 13.7 Hz, 4.5 Hz, 1H, CH2), 2.06 (dd, J =

13.8 Hz, 7.5 Hz, 1H, CH2), 1.89-1.80 (m, 1H, alkylH), 1.67-1.56 (m, 1H, alkylH), 1.50-1.38 (m,

1H, alkylH), 1.35-1.25 (m, 2H, alkylH), 1.15-1.03 (m, 1H, alkylH), 0.89 (t, J= 7.4Hz, 3H,

13 CH2CH3). C NMR (101 MHz, CDCl3) δ 176.27, 173.00, 137.87, 133.29, 128.36, 128.13, 69.52,

64.75, 52.41, 51.30, 50.23, 40.81, 39.65, 27.29, 22.89, 13.98. LRMS (APCI+): exact mass calc’d

+ for C18H24ClNO4 [M+1] requires m/z 354.13, found m/z 354.19.

164

Methyl 2-hexyl-5-oxopyrrolidine-2-carboxylate: This compound was synthesized as described above with a 20% catalyst loading and 48 hr reaction time. It was isolated as a clear oil in 46%

1 yield. H NMR (400 MHz, CDCl3): 6.01 (br s, 1H, NH), 3.76 (s, 3H, CO2CH3), 2.53-2.43 (m,

1H, alkylH), 2.40-2.35 (m, 2H, alkylH), 2.12-2.02 (m, 1H, alkylH), 1.89-1.80 (m, 1H, alkylH),

13 1.76-1.68 (m, 1H, alkylH), 1.35-1.16 (m, 8H, alkylH) 0.88 (t, J = 7.6 Hz, 3H, CH3). C NMR

(101 MHz, CDCl3) δ 176.62, 174.02, 65.60, 52.60, 39.42, 31.48, 30.66, 29.63, 29.14, 24.06,

+ 22.46, 13.96. LRMS (APCI+): exact mass calc’d for C12H21NO3 [M+1] requires m/z 228.15, found m/z 228.44. Enantiometric excess (80% ee) was determined by the addition of chiral shift reagent.

2,4-dimethyl 2-hexyl-5-(4-chlorophenyl)pyrrolidine-2,4-dicarboxylate: This compound was synthesized as described above with a 20% catalyst loading and 48 hr reaction time. It was

1 isolated as a white solid in 9% yield. H NMR (400 MHz, CDCl3): 7.25 (q, J = 8.7 Hz, 4H,

ArH), 4.56 (d, J =7.2 Hz, 1H, ArCH), 3.82 (s, 3H, CO2CH3), 3.25 (s, 3H, CO2CH3), 3.30-3.23

(m, 1H, MeCO2CH), 3.00 (br s, 1H, NH), 2.70 (dd, J = 13.7 Hz, 4.5 Hz, 1H, CH2), 2.06 (dd, J =

13.8 Hz, 7.5 Hz, 1H, CH2), 1.94-1.79 (m, 1H, alkylH), 1.67-1.57 (m, 1H, alkylH), 1.50-1.35 (m,

1H, alkylH), 1.35-1.15 (m, 6H, alkylH), 1.15-1.03 (m, 1H, alkylH), 0.87 (t, J= 7.4Hz, 3H,

13 CH2CH3). C NMR (101 MHz, CDCl3) δ 176.24, 172.96, 137.95, 133.27, 128.35, 128.14, 69.53, 165

64.72, 52.37, 51.27, 50.21, 41.05, 39.60, 31.69, 29.44, 25.07, 22.57, 14.02. LRMS (APCI+):

+ exact mass calc’d for C20H28ClNO4 [M+1] requires m/z 382.17, found m/z 382.34.

Methyl 5-oxo-2-(prop-2-yn-1-yl)pyrrolidine-2-carboxylate: This compound was synthesized as described above with a 10% catalyst loading and 16 hr reaction time. It was isolated as a white

1 solid in 64% yield. H NMR (400 MHz, CDCl3): 5.99 (br s, 1H, NH), 3.80 (s, 3H, CO2CH3),

2.82 (dd, J = 16.6, 2.6 Hz, 1H, CH2 ≡CH), 2.60 (dd, J = 16.6, 2.6 Hz, 1H, CH2 ≡CH), 2.55 – 2.36

13 (m, 3H, alkylH), 2.29 – 2.13 (m, 1H, alkylH), 2.08 (t, J = 2.6 Hz, 1H, CH2 ≡CH). C NMR (101

MHz, CDCl3) δ 176.41, 172.67, 77.84, 72.20, 64.48, 53.07, 30.22, 29.68, 29.43. LRMS

+ (APCI+): exact mass calc’d for C9H11NO3 [M+1] requires m/z 182.07, found m/z 182.39.

Enantiometric excess (88% ee) was determined by the addition of chiral shift reagent.

Dimethyl 5-(4-chlorophenyl)-2-(prop-2-yn-1-yl)pyrrolidine-2,4-dicarboxylate: This compound was synthesized as described above with a 10% catalyst loading and 16 hr reaction

1 time. It was isolated as a white solid in 20% yield. H NMR (400 MHz, CDCl3) 7.37 – 7.19 (m,

4H, ArH), 4.74 (d, J = 7.5 Hz, 1H, ArCH), 3.86 (s, 3H, CO2CH3), 3.42-3.33 (m, 1H,

MeCO2CH), 3.25 (s, 3H, CO2CH3), 3.11 (br s, 1H, NH), 2.84 – 2.68 (m, 2H, CH2 ≡CH and CH2),

2.63 (dd, J = 16.4, 2.6 Hz, 1H, CH2 ≡CH), 2.24 (dd, J = 13.8, 7.5 Hz, 1H, CH2), 2.06 (t, J = 2.6

13 Hz, 1H, CH2 ≡CH). C NMR (101 MHz, CDCl3) δ 174.73, 172.48, 138.03, 133.40, 128.35, 166

128.24, 79.95, 71.00, 68.64, 64.77, 52.85, 51.39, 50.13, 37.80, 30.71. LRMS (APCI+): exact

+ mass calc’d for C20H28ClNO4 [M+1] requires m/z 336.09, found m/z 336.01.

2,4-dimethyl 2-methyl-5-(2,6-dichlorophenyl)pyrrolidine-2,4-dicarboxylate: This compound was synthesized as described above with a 10% catalyst loading and 48 hr reaction time. It was

1 isolated as a white solid in a 69% yield. H NMR (400 MHz, CDCl3): 7.30 (d, J = 8.0 Hz, 2H,

ArH), 7.13 (t, J = 8.0 Hz, 1H, ArH), 5.22 (d, J = 8.0 Hz, 1H, ArCH), 4.53 (br s, 1H, NH), 3.84

(s, 3H, CO2CH3), 3.50-3.41 (m, 1H, MeCO2CH), 3.38 (s, 3H, CO2CH3), 2.82 (dd, J = 13.6 Hz,

13 5.2 Hz, 1H, CH2), 2.05 (dd, J = 13.6 Hz, 7.6 Hz, 1 H, CH2). C NMR (101 MHz, CDCl3) δ

175.90, 172.64, 135.55, 132.49, 129.40, 128.91, 65.92, 62.09, 52.58, 51.80, 48.24, 40.47, 26.13.

+ LRMS (APCI+): exact mass calc’d for C15H17Cl2NO4 [M+1] requires m/z 346.05, found m/z

346.18. HPLC analysis: Chiralpak AD-H (Hex/iPrOH = 90/10, 1 mL/min, 254 nm), 6.7 min, 7.4 min, 0% ee.

Synthesis of Imines

Method A

According to the method of Wang et. al.,7 the racemic amino acid methyl ester hydrogen

7 Wang, C. J.; Liang, G.; Xue, Z. Y.; Gao, F. J. Am. Chem. Soc. 2008, 130, 17250. 167 chloride (6 mmol, 1.2 eq.) and magnesium sulfate (960 mg, 8 mmol, 1.6 eq.) were dissolved in

DCM (10 mL) and triethylamine (1 mL). After stirring for one hour at room temperature, aldehyde (5 mmol, 1 eq.) was added and the mixture was stirred overnight. The mixture was filtered and washed with twice with water and with brine. The organic layer was dried with sodium sulfate and concentrated to reveal the product which was used without further purification.

Method B

Glycine benzophenone imine (2.02 g, 8 mmol, 1 eq), tetrabutyl ammonium bromide (258 mg, 0.8 mmol, 0.1 eq) and potassium carbonate (1.1 g, 8 mmol, 1 eq) were dissolved in acetonitrile (20 mL). The mixture was stirred for 15 minutes at room temperature at which point alkyl bromide

(9.6 mmol, 1.2 eq) was added. The mixture was heated to reflux and stirred overnight at reflux.

Upon cooling it was filtered, concentrated and purified on Si.

The benzophenone imine (3 mmol) was dissolved in THF (30 mL) and 0.5 M citric acid (30 mL). After stirring for three hours the THF was removed by rotary evaporation and the remaining aqueous layer was extracted five times with ether. The aqueous layer was basified with saturated sodium bicarbonate and extracted three times with DCM. The combined organic layers were dried and concentrated to reveal the free amine, which was dissolved in DCM (0.25

M) with molecular sieves. Aldehyde (1 eq, based on the mass of the free amine) was added and the mixture was stirred at room temperature overnight. The mixture was filtered, dried with sodium sulfate, and concentrated to produce the imine which was used without further purification. 168

Methyl (E)-2-[(4-chloro-benzylidene)-amino]-propanoate: Synthesized according to method

A as a pale yellow oil in 91% yield. Spectral data was consistent with that previously reported in the literature.8

Methyl (E)-2-[(2-chloro-benzylidene)-amino]-propanoate: Synthesized according to method

A as a pale yellow oil in 71% yield. Spectral data was consistent with that previously reported in the literature.8

Methyl (E)-2-[(2,4-dichloro-benzylidene)-amino]-propanoate: Synthesized according to

1 method A as a pale yellow oil in 70% yield. H NMR (400 MHz, CDCl3): 8.71 (s, 1H, N=CH),

8.09 (d, J = 8.8 Hz, 1H, ArH), 7.5-7.25 (m, 2H, ArH), 4.25 (q, J = 6.8 Hz, 1H, CHCH3), 3.79 (s,

13 3H, CO2CH3), 1.56 (d, J = 6.8 Hz, 3 H, CHCH3). C NMR (101 MHz, CDCl3) δ 172.42, 158.39,

137.30, 135.77, 131.33, 129.54, 129.38, 127.45, 67.83, 52.15, 19.36. LRMS (APCI+): exact

+ mass calc’d for C11H11Cl2NO2 [M+1] requires m/z 260.02, found m/z 260.25.

8 Achard, T.; Belokon, Y.N.; Fuentes, J. A.; North, M.; Parsons, T. Tetrahedron 2004, 60, 5919. 169

Methyl (E)-2-[(2,6-dichloro-benzylidene)-amino]-propanoate: Synthesized according to

1 method A as a white solid in 61% yield. H NMR (400 MHz, CDCl3): 8.47 (s, 1H, N=CH), 7.34

(d, J = 7.6 Hz, 2H, ArH), 7.23 (t, J = 7.6 Hz, 1H, ArH), 4.27 (q, J = 6.8 Hz, 1H, CHCH3), 3.78

13 (s, 3H, CO2CH3), 1.59 (d, J = 6.8 Hz, 3 H, CHCH3). C NMR (101 MHz, CDCl3) δ 172.29,

158.85, 134.66, 132.84, 130.52, 128.54, 68.51, 52.30, 19.34. LRMS (APCI+): exact mass calc’d

+ for C11H11Cl2NO2 [M+1] requires m/z 260.02, found m/z 260.10.

Methyl (E)-2-[(4-chloro-benzylidene)-amino]-butanoate: Synthesized according to method A as a pale yellow oil in 90% yield. Spectral data was consistent with that previously reported in the literature.9

Methyl (E)-2-[(4-chloro-benzylidene)-amino]-pentanoate: Synthesized according to method A

1 as a yellow oil in 88% yield. H NMR (400 MHz, CDCl3): 8.23 (s, 1H, N=CH), 7.72 (d, J = 8.4

Hz, 2H, ArH), 7.39 (d, J = 8.4 Hz, 2H, ArH), 3.99 (dd, J = 8.0 Hz, 4.8 Hz, 1H, CHPr), 3.74 (s,

3H, CO2CH3), 2.04-1.81 (m, 1H, CH2CH2CH3), 1.31-1.17 (m, 1H, CH2CH3), 1.93 (t, J = 7.2 Hz,

9 Belokon, Y. N.; Bhave, D.; D’addario, D.; Groaz, E.; North, M.; Tagliazucca, V. Tetrahedron 2004, 60, 1849. 170

13 CH2CH3). C NMR (101 MHz, CDCl3) δ 172.31, 161.61, 136.88, 134.17, 129.63, 128.72, 72.93,

+ 51.90, 35.34, 19.04, 13.60. LRMS (APCI+): exact mass calc’d for C13H16ClNO2 [M+1] requires m/z 254.09, found m/z 254.18.

Methyl (E)-2-[(4-chloro-benzylidene)-amino]-hexanoate: Synthesized according to method A

1 as a brown oil in 85% yield. H NMR (400 MHz, CDCl3): 8.25 (s, 1H, N=CH), 7.74 (d, J = 8.4

Hz, 2H, ArH), 7.42 (d, J = 8.4 Hz, 2H, ArH), 3.99 (dd, J = 8.3, 5.4 Hz, 1H), 3.77 (s, 3H,

CO2CH3), 2.13 – 1.78 (m, 2H, alkylH), 1.45 – 1.12 (m, 4H, alkylH), 0.92 (t, J = 7.1 Hz, 3H,

13 CH2CH3). C NMR (101 MHz, CDCl3) δ 172.58, 161.72, 137.09, 134.17, 129.72, 128.86, 73.46,

+ 52.12, 33.12, 28.07, 22.33, 13.91. LRMS (APCI+): exact mass calc’d for C14H18ClNO2 [M+1] requires m/z 268.10, found m/z 268.11.

Methyl (E)-2-[(4-chloro-benzylidene)-amino]-octanoate: Synthesized according to method A

1 1 as a brown oil in 82% yield. H NMR (400 MHz, CDCl3): . H NMR (400 MHz, CDCl3): 8.23 (s,

1H, N=CH), 7.72 (d, J = 8.4 Hz, 2H, ArH), 7.39 (d, J = 8.4 Hz, 2H, ArH), 3.97 (dd, J = 8.3, 5.4

Hz, 1H), 3.74 (s, 3H, CO2CH3), 2.08 – 1.81 (m, 2H, alkylH), 1.35 – 1.18 (m, 8H, alkylH), 0.86

13 (t, J = 6.7 Hz, 3H, CH2CH3). C NMR (101 MHz, CDCl3) δ 172.56, 161.70, 137.07, 134.17,

129.70, 128.85, 73.44, 52.09, 33.39, 31.59, 28.87, 25.84, 22.53, 14.01. LRMS (APCI+): exact

+ mass calc’d for C16H22ClNO2 [M+1] requires m/z 296.13, found m/z 296.18. 171

Methyl (E)-2-[(4-chloro-benzylidene)-amino]-3-phenyl-propanoate: Synthesized according to method A as a white solid in 86% yield. Spectral data was consistent with that previously reported in the literature.9

Methyl (E)-2-[(4-chloro-benzylidene)-amino]-4-methyl-pentanoate: Synthesized according to method A as a pale yellow oil in 84% yield. Spectral data was consistent with that previously reported in the literature.9

Methyl (E)-2-[(4-chloro-benzylidene)-amino]-3-methyl-butanoate: Synthesized according to method A as a pale yellow oil in 75% yield. Spectral data was consistent with that previously reported in the literature.9

Methyl (E)-2-[(4-chloro-benzylidene)-amino]-but-3-enoate: Synthesized according to method

B as a pale yellow oil in 53% yield from the allyl benzophenone glycine imine. Spectral data was 172 consistent with that previously reported in the literature.9

Methyl (E)-2-((4-chlorobenzylidene)amino)pent-4-ynoate: Synthesized according to method

B as a pale yellow oil in 23% yield from the propargyl benzophenone glycine imine. 1H NMR

(400 MHz, CDCl3): 8.31 (s, 1H, N=CH), 7.73 (d, J = 8.5 Hz, 2H, ArH), 7.40 (d, J = 8.5 Hz, 2H,

ArH), 4.12 (dd, J = 8.5, 5.2 Hz, 1H, CHCO2CH3), 3.77 (s, 3H, CO2CH3), 2.94 (ddd, J = 16.8,

5.2, 2.6 Hz, 1H, CH2 ≡CH), 2.75 (ddd, J = 16.8, 8.5, 2.6 Hz, 1H, CH2 ≡CH), 2.00 (t, J = 2.6 Hz,

13 1H, CH2 ≡CH). C NMR (101 MHz, CDCl3) δ 170.73, 163.36, 137.43, 133.87, 129.91, 128.92,

+ 80.09, 71.57, 71.02, 52.54, 23.30. LRMS (APCI+): exact mass calc’d for C13H12ClNO2 [M+1] requires m/z 250.06, found m/z 250.37.

Methyl (E)-2-[(4-chloro-benzylidene)-amino]-4-(methylthio)butanoate: Synthesized

1 according to method A as an orange oil in 90% yield. H NMR (400 MHz, CDCl3): 8.28 (s, 1H,

N=CH), 7.72 (d, J = 8.4 Hz, 2H, ArH), 7.40 (d, J = 8.4 Hz, 2H, ArH), 4.21 (dd, J = 8.4 Hz, 5.2

Hz, 1H, CHCO2CH3), 3.75 (s, 3H, CO2CH3), 2.64-2.54 (m, 1H, CHCH2), 2.50-2.39 (m, 1H,

13 CHCH2), 2.33-2.17 (m, 2H, CH2S), 2.09 (s, 3H, SCH3). C NMR (101 MHz, CDCl3) δ 171.82,

162.85, 137.06, 134.01, 129.71, 128.79, 70.93, 52.15, 31.90, 30.14, 15.08. LRMS (APCI+):

+ exact mass calc’d for C13H16ClNO2S [M+1] requires m/z 286.06, found m/z 286.07.

173

Methyl 5-cyano-2-[(diphenylmethylene)amino]pentanoate: Synthesized according to method

1 B as a white solid in 43% yield. H NMR (400 MHz, CDCl3): 7.64 (d, J = 7.2, 2H, ArH), 7.51-

7.76 (m, 4H, ArH), 7.34 (t, J = 8.2 Hz, 2H, ArH), 7.21 – 7.13 (m, 2H, ArH), 4.10 (dd, J = 7.4,

5.1 Hz, 1H, CHCO2CH3), 3.72 (s, 3H, CO2CH3), 2.37 – 2.22 (m, 2H, alkylH), 2.12 – 1.96 (m,

13 2H, alkylH), 1.67 (m, 2H, alkylH). C NMR (101 MHz, CDCl3) δ 172.07, 171.20, 139.14,

136.07, 130.62, 128.88, 128.83, 128.72, 128.15, 127.68, 119.37, 64.25, 52.26, 32.48, 22.10,

+ 17.08. LRMS (APCI+): exact mass calc’d for C20H20N2O2 [M+1] requires m/z 321.15, found m/z 321.11.

Methyl (E)-2-[(4-chlorobenzylidene)amino]-5-cyanopentanoate: Synthesized according to

1 method B as a pale yellow oil in 45% yield. H NMR (400 MHz, CDCl3): 8.27 (s, 1H, N=CH),

7.72 (d, J = 8.4 Hz, 2H, ArH), 7.41 (d, J = 8.4 Hz, 2H, ArH), 4.03 (dd, J = 7.4, 5.6 Hz, 1H,

CHCO2Me), 3.76 (s, 3H, CO2Me), 2.41 (t, J = 7.1 Hz, 2H, CH2CN), 2.18 – 2.01 (m, 2H, alkylH),

13 1.73 (m, 2H, alkylH). C NMR (101 MHz, CDCl3) δ 171.53, 162.85, 137.47, 133.84, 129.78,

128.98, 119.25, 71.98, 52.39, 32.19, 22.01, 17.09. LRMS (APCI+): exact mass calc’d for

+ C14H15ClN2O2 [M+1] requires m/z 279.08, found m/z 279.34.

NMR Spectra for Michael Reaction with Cyclopropenimines

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Chiral HPLC Traces

Note: For each entry the top HPLC trace is a racemic sample that was prepared using an achiral cyclopropenimine

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