hydroamination of cycloalkanes in enantioselective synthesis

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Introduction 1 1. Introduction Humans have come a long way on the path of drug synthesis from using natural products derived from plants and animals to modern synthetically produced drugs such as aspirin in the late 1900s (Center for Drug Discovery, 2013). Along this path, both the efficiency and effectiveness of drugs have been improved and one method of doing this was accomplished through changing the shape of the drug (conformation) which directly affects its function. Two molecules of the same drug can have different shapes (enantiomers) and therefore different effects just like how puzzle pieces with different shapes do not fit in the same spot. This research explores using a novel reaction to promote one particular enantiomer of a drug over the other. To understand why this increases the efficacy of the drug, we first have to understand what enantiomers are and their importance to drug synthesis. Enantiomers are two mirror images of the same compound. This is based on the fact that there are certain carbon atoms in organic molecules with four groups attached in such a way that their rearrangement causes a conformation to be obtained which cannot just be obtained by rotating or transposing the original orientation. This principle is also true of your right and left hands and is known as chirality. If you look at your hands, you can see that although your hands are identical, there is no way to rotate or transpose your right hand so it sits perfectly on top of your left. Molecules behave the same way and enantiomers of two molecules occur when every chiral center has been flipped to give you the perfect mirror image. Although they only involve a small conformational change, enantiomers can have very different properties. This is very similar to enzymes in biology. A certain enzyme can only bind to certain substrates because of its shape, similar to how a key can only fit in its corresponding

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A short research paper about the hydroamination of cycloalkanes for use in enantioselective drug synthesis. Work was done in a lab at Duke University in the chemistry department and the research paper was submitted to several competitions including Siemens and Intel and won several research awards. In this research, we successfully designed a reaction mechanism to enantioselectively synthesize cycloalkane derivatives of drug molecules.

TRANSCRIPT

  • Introduction

    1

    1. Introduction

    Humans have come a long way on the path of drug synthesis from using natural products

    derived from plants and animals to modern synthetically produced drugs such as aspirin in the

    late 1900s (Center for Drug Discovery, 2013). Along this path, both the efficiency and

    effectiveness of drugs have been improved and one method of doing this was accomplished

    through changing the shape of the drug (conformation) which directly affects its function. Two

    molecules of the same drug can have different shapes (enantiomers) and therefore different

    effects just like how puzzle pieces with different shapes do not fit in the same spot. This

    research explores using a novel reaction to promote one particular enantiomer of a drug over the

    other. To understand why this increases the efficacy of the drug, we first have to understand

    what enantiomers are and their importance to drug synthesis.

    Enantiomers are two mirror images of the same compound. This is based on the fact that

    there are certain carbon atoms in organic molecules with four groups attached in such a way that

    their rearrangement causes a conformation to be obtained which cannot just be obtained by

    rotating or transposing the original orientation. This principle is also true of your right and left

    hands and is known as chirality. If you look at your hands, you can see that although your hands

    are identical, there is no way to rotate or transpose your right hand so it sits perfectly on top of

    your left. Molecules behave the same way and enantiomers of two molecules occur when every

    chiral center has been flipped to give you the perfect mirror image.

    Although they only involve a small conformational change, enantiomers can have very

    different properties. This is very similar to enzymes in biology. A certain enzyme can only bind

    to certain substrates because of its shape, similar to how a key can only fit in its corresponding

  • Introduction

    2

    lock. Enantiomers behave similarly which makes certain enantiomers of a drug more effective

    than others.1 An extreme example of how enantiomers can be the difference between life and

    death is the drug thalidomide. Used to treat morning sickness, it was later discovered that

    thalidomide was caused serious birth deformities (teratogenic). Recently though, research

    elucidated that only the S-enantiomer of thalidomide was teratogenic in mice and rats while the

    R-enantiomer was truly useful in treating diseases.2 Although this example is an extreme case

    where enantioselectivity is a matter of life and death, most drugs (even common ones like

    ibuprofen) have an ineffective and effective enantiomer.1 The majority of drugs are also sold as

    racemic mixtures (equal amounts of each enantiomer), so taking 100 mg of ibuprofen would

    have the same effect as taking 50 mg of the S-enantiomer (the effective enantiomer). Therefore,

    being able to synthesize or isolate a specific enantiomer of a drug greatly improves efficiency.

    The challenge with obtaining a specific enantiomer of a drug lies in the fact that

    enantiomers are so similar to one another. Since only their spatial conformations are different,

    enantiomers have the same physical properties such as boiling point and Rf (retardation factor),

    making them impossible to separate through conventional methods such as distillation or column

    chromatography. Thus it is easier to synthesize drugs enantioselectively rather than isolate

    enantiomers from racemic mixtures. By changing on the location and method nucleophiles

    attack molecules, researchers can obtain certain enantiomers over the other. However,

    increasing the enantioselectivity of reactions is very difficult since we do not fully understand the

    reaction mechanisms of most reactions and cannot fully predict how nucleophiles will attack

    molecules. Thus, enantioselective synthesis has been and will remain a major focus of 21st

    century research.

  • Introduction

    3

    An unique new method developed

    by Yamaguchi et al in 2008 to tackle this

    problem proposed using cyclopropane

    groups to restrict the conformation of

    drug molecules.3 Since a cyclopropane is

    a relatively small group, the researchers

    found that it did not significantly affect

    the chemical properties of the drug and

    could significantly restrict conformation

    to obtain the correct enantiomer. This

    reaction works in a very simple way. A

    cyclopropane ring essentially forces the

    two substituents attached to each carbon

    in the ring into a cis position (either both

    position A or B on Figure 1) or a trans

    position (position A on one carbon and B

    on the other). However, if the two

    substituents are in the cis position,

    potential energy is much greater than if they are in the trans position, so the trans position is

    favored. Furthermore, the cyclopropane structure forces the carbons into an eclipsed state,

    further increasing the force, termed cyclopropylic strain, between each substituent. This strain

    affects conformation because any carbon center adjacent to the cyclopropane would prefer an

    orientation in which the smallest substituent (least bulky) is closest to the R-group (Figure 2a.)

    Figure 2 (from Yamaguchi et al.3) Effect of the

    cyclopropane ring on the conformation of adjacent carbons

    Figure 1 - Geometry of a cyclopropane ring

    Figure 4 Proposed novel reaction to produce cyclopropane analogs

    Figure 3 - Reaction from previous literature used to create cyclopropane analogs

  • Introduction

    4

    Figure 5 3-D structure of synthesized compound showing the cyclopropyllic strain and resulting conformationally restricted product. If hydrogens A and B were replaced with functional groups, the bulkier group would replace hydrogen A because that position is furthest away from any other substituents.

    A

    B

    and the largest substituent is furthest away.7 This is illustrated in Figure 2 as both compounds

    tend to be restricted towards conformation B. Cyclopropylic strain creates a valuable tool in the

    creation of conformationally restricted drugs and researchers demonstrated the efficacy of this

    technique in the synthesis of various enantiomers of analogs of the drug haloperidol which

    displayed increased biological activity. Yamaguchi et al accomplished synthesis of

    cyclopropane derivatives using the JohnsonCoreyChaykovsky reaction with a Weinreb amine

    which simply adds an extra carbon to form the conformationally restricted cyclopropane analog

    (Figure 3).3 In this research, another reaction mechanism was found using a reaction called

    hydroamination where a portion of the drug structure was added directly to the cyclopropane

    group (Figure 4), efficiently producing the

    conformationally-restricted cyclopropane derivative

    of the drug shown in Figure 5, a product

    synthesized in this research restricted so that the

    imdazolidinone ring is as far away from the phenyl

    ring as possible.

    1.1 Hydroamination

    The hydroamination reaction is classified under an umbrella of reactions collectively

    called hydrofunctionalization reactions, which involve the addition of functional groups and a

    hydrogen across double and triple bonds. In particular, this research focused on

    hydroaminations, the addition of amines across C-C multiple bonds. This process is a more

    atom-economical and efficient way to add the N-H bond of an amine across the C=C bonds of

    various molecules. Preliminary research into the mechanism of the reaction showed that

    thermodynamically, the reaction had a high activation energy and a negative entropy, making it

  • Introduction

    5

    very unlikely to take place at high temperatures.4 This means that the reaction requires a

    catalyst to proceed. Early progress has already been made on synthesizing catalysts for this

    reaction which involve the use of alkali metal amides, lanthanide metallocene complexes, acidic

    zeolites, or Ru(II)/Rh(III)/Pt(II) metal complexes.5, 6

    The hydroamination reactions run in this

    experiment used a novel gold catalyst synthesized by other members of the lab.

    Although gold catalysts have been used before in hydroaminations to good effect, the

    results in this report show that the novel catalyst incorporating a new N-heterocyclic carbene

    ligand performs better than the standard gold catalyst system for this particular reaction. Typical

    gold catalyst systems use a gold catalyst with an electron-rich ligand in conjunction with a silver

    co-catalyst. The reaction mechanism will be discussed later in this report, but examples of these

    catalyst systems from past literature include variants of PPh3AuCl as the gold catalyst and

    AgSbF6, AgOTf, and AgBF4 as co catalysts.3,4,8,9,10

    A common problem with hydroamination

    and many other reactions is that there is not a single set of catalysts that will work for all

    hydroamination reactions; there are a large number of different variables which can all affect the

    effectiveness of a catalyst. Therefore, there are many different combinations of factors which

    can all impact the reaction differently.

    A catalyst system for gold-catalyzed hydroamination typically has two components: a

    gold catalyst and a silver co-catalyst. The purpose of the silver co-catalyst is twofold. First,

    since the gold catalyst is in the form of a chloride salt, the silver from the co-catalyst works to

    precipitate the chloride ion so that it does not interfere with the rest of the reaction. Second, the

    anion of the silver salt then forms a gold catalyst complex which binds to the substrate and

    completes the reaction.4 The gold catalyst itself is made up of two more components, the gold

    center and the ligand attached to the gold. After the hydroamination reaction mechanism was

  • Introduction

    6

    elucidated by Kovacs et al, researchers began to focus on developing electron rich ligands since

    they were found to be the most effective in catalyzing the reaction.4 Later on, new classes of

    more complicated ligands were developed: N-heterocyclic carbene ligands (NHC), like the

    catalyst used in this research, and cyclic alkyl amino carbene ligands (CAAC).16

    Since there are

    so many factors that influence the reaction, a small change in the type of catalyst system used

    can have a large effect on how that system catalyzes the reaction. The reactions in this research

    were first run with standard gold catalysts and then changed for this reason.

    2. Methods and Procedures

    2-phenyl-1-methylene-cyclopropane was synthesized and used it as the starting material

    for several intermolecular hydroamination reactions. The procedures used were adapted from

    existing literature and procedures used by the lab. While I performed all of these procedures, my

    PI and the grad student supervising me helped me run and interpret my NMR samples and

    provided me with the materials, including their novel gold catalyst, used in the experiment.

    2.1 Synthesis of 2-phenyl-1-methylenecyclopropane7 (Adapted from previous literature)

    First, 2.2 equivalence of sodium bis(trimethylsilyl)amide and 1.1 equivalence of anhydrous

    styrene and 48 mL of toluene were mixed in a 50 mL two-neck round bottom flask with a three-

    Figure 6 Reaction mechanism to form starting material adapted from previous literature.7

  • Methods and Procedures

    7

    Figure 8 Column used to separate products

    way stopcock under a nitrogen atmosphere (5.3 g sodium

    bis(trimethylsilyl)amide, 28.8 mmol and 1.5 g of styrene, 14.4

    mmol)

    Next, 1.0 equivalence of 1,1-dibromoethane (2.44 g of 1,1-

    dibromoethane, 13 mmol) was added dropwise in an ice bath

    at 0C and the mixture was stirred at 25C for 24 hours. After

    the reaction was completed, the reaction mixture was quenched

    using NH4Cl solution and washed with water. The organic

    layer was extracted using a separatory funnel and diethyl ether

    as the organic solvent. Then the organic layers were washed using brine to remove the entire

    aqueous layer. The final organic layer was dried over anhydrous CaSO4 desiccant to remove any

    remaining water. The mixture was then purified using flash column chromatography and pure

    hexane as the eluent to obtain 1-bromo-1-methyl-2-phenylcyclopropane. Using this as starting

    material 1 equivalence of 1-bromo-1-methyl-2-

    phenylcyclopropane was added dropwise to a solution

    of potassium tert-butoxide and DMSO solvent under a

    nitrogen atmosphere at 0C (1.02 g of 1-bromo-1-

    methyl-2-phenylcyclopropane, 4.84 mmol and 600 mg

    potassium tert-butoxide, 5.35 mmol). The reaction

    mixture was stirred at 25C for 24 hours and extracted

    using the same technique previously used to obtain the

    final product 2-phenyl-1-methylenecyclopropane.

    Figure 7 oil bath with microwave tube running reaction

  • Methods and Procedures

    8

    Figure 10 Rotovapor machine used to remove solvent from sample

    Figure 9 TLC plates used to separate fractions based on products.

    2.2 Hydroamination Procedure (using silver salt)

    A microwave tube was flame dried and placed in a

    desiccator. After the tube cooled, 0.05 equivalence

    of (tBu2-o-biphenyl)PAuCl catalyst and 1.1

    equivalence of 1-methyl-2-imdazolidinone were

    added (In this experiment, 5.4 mg of AuCl (0.01

    mmol) and 26 mg of imidazolidinone (0.21 mmol) were used). In a glove box, 0.05 equivalence

    of AgSBF6 was measured out and added to the microwave tube with AuCl catalyst and

    imidazolidinone (3.4 mg of AgSbF6, 0.01 mmol). Using a microsyringe, 1.0 equivalence of 2-

    phenyl-1-methylene-cyclopropane was added (29.1 L, 0.21 mmol). The microwave tube was

    sealed and 1 mL of dioxane was added. The reaction proceeded in an oil bath of experimental

    temperature (Figure 7), monitored every hour using gas chromatography (GC). After reaction

    was completed, flash column chromatography was run (Figure 8) using 300mL EtOAc/Hexanes

    (4:1). Each fraction was spotted from the column onto TLC plates and run using pure EtOAc as

    solvent (Figure 9). Spots were observed under UV light to make sure there are no impurities,

    (since none of the products were UV active, any spots under UV light would be impurities). The

    TLC plates were then stained using CAM stain and heated using

    heat gun for 1 minute. The spots that showed up after heating

    were marked and fractions containing each different product

    visible from the TLC were mixed so all fractions with the same

    product (same Rf) were collected together. A Rotovap machine

    (Figure 10) was used on the solutions to remove excess solvent

  • Methods and Procedures

    9

    and isolate the products. The product was weighed out and yields were calculated

    2.3 Hydroamination Procedure (without silver salt)

    A microwave tube was flame dried and placed in a desiccator. After the tube cooled, 0.05

    equivalence of MeCnAuP(Cy2-o-biphenyl)AgSbF6 catalyst and 1.1 equivalence of 1-methyl-2-

    imdazolidinone (7.4 mg of gold catalyst (0.009 mmol), 19.8 mg of imidazolidinone (0.180

    mmol)) were added. Using a microsyringe, 1.0 equivalence of 2-phenyl-1-methylene-

    cyclopropane was added (25 L, 0.180 mmol). The rest of the procedure was completed

    according to the hydroamination procedure with a silver salt.

    3. Results

    3.1 Raw Data

    To confirm the identity of the products, H-NMR spectra was run on the samples and

    TLC/GC were used to monitor reactions. The raw data from these analytical techniques are

    displayed below:

    Figure 11 H-NMR of starting material confirms the identity of 2-phenyl-1-methylenecyclopropane with minimal impurities. Some residual tBuOH remained which was then removed by evaporation under the house vacuum.

  • Data Analysis 10

    Figure 12 GC printout of 80 MeCnAuP(Cy2-o-biphenyl)AgSbF6-catalyzed reaction mixture at 2 hours. Reaction took 3 hours to complete and there is a 1-phenyl-2-methylenecyclopropane peak at 4.241 and product peaks (2 major 1 minor) at 9.477, 9.862, and 10.055. Peaks at around 5-6 are probably impurities or the other starting materials

    Figure 13 TLC plate from same reaction showing 3 products with 3 different Rfs. A stained plate is shown on the right from a different reaction which shows product spots more clearly.

    Product A Product B Product C

  • Data Analysis 11

    Figure 14 H-NMR of product A, the minor product. Around 5-5.7 ppm, we can see the peaks that are the result of vinyl hydrogens, hydrogens attached to sp carbons (double bonds). We can see two distinct signals, a singlet and a doublet of doublets (singlet at 5.6 ppm and dd at 5 ppm) which suggests the structure shown above since there are 2 distinct hydrogen signals on the double bond as opposed to what well see in product B. We can also see phenyl peaks >7 ppm and peaks from the imidazolidinone at 3 ppm and

  • Data Analysis 12

    3.2 Data Analysis

    After synthesizing and verifying the structure of the starting material through H-NMR as

    shown above, test reactions were run using the standard catalyst and procedure 1 from above.

    Based on the mechanism for hydroamination that will be elucidated later in this paper, it was

    expected that the amine group on the 1-methyl-2-imdazolidinone would add across the

    cyclopropane and form compounds A and B as the major products, but flash column

    chromatography and TLC results show three products. These products were run through a GC

    and determined that of the three products A, B, and C (A had the highest Rf and C had the

    lowest), B and C were the major products and A was a minor product (Figure 17). NMR data

    Figure 16 H-NMR of product C which shows a space where vinyl peaks on previous products were. This means that there is not double bond which then supports the structure above since the only way to lose the vinyl hydrogens is for the nucleophile to add across the double bond and keep the cyclopropane ring. This reasoning is supported because we can also see peaks from 1-2 ppm which suggests the cyclopropane ring is still intact.

  • Data Analysis 13

    showed unexpected results (Figure 16). Although it was initially thought that the two major

    products were isomers or diastereomers of when the amine group added across different carbons

    in the cyclopropane ring, what was found instead was that even though

    one of the major products did open up the ring, the other major product

    added across the double bond (Figures 14-16). This addition was very

    intriguing since in previous literature, Zhang et al used gold catalysts for

    a similar reaction reaction in a ring-opening synthesis of pyrrolidines.11

    Using standard gold catalysts very similar to the one used in this

    research (previous literature used Ph3PAuCl/AgOTf) as well as

    palladium catalysts, previous research showed the opening of the

    cyclopropane ring and addition across the ring as opposed to the alkylene

    which was observed in this research.12

    In the beginning, yields for this reaction were relatively low (Entry

    5, Table 1) specifically the yields for product C, the desired product. The ratio between the two

    major products was also undesirable at 2:1 in favor of product B, the one predicted by previous

    literature where the ring was opened. However, by changing the catalyst, temperature, and

    nucleophile (since catalyst systems have such a large effect on hydroamination reactions) the

    reaction yields and ratios were improved. The first variable changed was the gold catalyst (Entry

    1). Although the ratio remained biased towards product B, changing the catalyst from a standard

    gold catalyst to a novel silver-free NHC-ligand catalyst synthesized by the lab more than doubled

    the yields. The second variable tested was more successful in biasing the reaction towards the

    desired product. The reaction was run at two lower temperatures and at each temeprature, the

    ratios of products C:B improved (at 80C and 60C respectively, the ratios of products C:B were

    Figure 17 From top to bottom: Products A, B, and C

  • Data Analysis 14

    Entry Catalyst System Reaction Condition Yield B Yield C Time

    1 MeCnAuP(Cy2-o-biphenyl)SbF6 100 57.5% 28.6% 30 minutes

    2 MeCnAuP(Cy2-o-biphenyl)SbF6 80 28.7% 19.1% 3 hours

    3 MeCnAuP(Cy2-o-biphenyl)SbF6 60 38.3% 57.2% 6 hours

    4 MeCnAuP(Cy2-o-biphenyl)SbF6 rt 0.0% 0.0% NA

    5 (t-Bu2-o-biphenyl)PAuCl/AgSbF6 100 24.7% 14.3% 5 hours

    6 MeCnAuP(Cy2-o-biphenyl)SbF6 100 35.7% 11.5% 12 hours

    7 MeCnAuP(Cy2-o-biphenyl)SbF6 100 0.0% 0.0% NA

    Table 1 All reactions were done under nitrogen atmosphere using dioxane as solvent. 2-phenyl-1-methylenecyclopropane was used as the alkene and a 5% catalyst loading was used. For entries 1-5, 1-methyl-2-imidazolidinone was used as the nucleophile, benzyl carbamate was used in entry 6, and aniline was used in entry 7.

    1:1.5 and 1.5:1). Although decreasing the temperature increased the reaction time, the increase

    was small enough that the reaction is still useful at lower temperature. Reaction times for other

    gold-catalyzed intermolecular hydroaminations found in previous literature were typically

    around 24 hours, showing that reaction time is not a problem.5 After testing the 60 C reaction,

    another reaction was run at room temperature (Entry 4) but unfortunately, the reaction did not

    run to completion. Based on GC data, the products decayed back into the alkene and the reaction

    was stopped after 72 hours because all the gold catalyst had been consumed. The third factor

    tested was the effect of the nucleophile on the reaction; specifically whether or not this reaction

    would continue to produce the desired product using a less reactive nuclephile. To test this, two

    new nucelophiles were used: benzyl carbamate and anniline. The difference between these two

    new nucleophiles and 1-methyl-2-imidazolidinone is that the new nucleophiles contain primary

    amines which are less likely to undergo hydroamination. The benzyl carbamate reaction

    proceeded in a similar fashion as the previous reactions using 1-methyl-2-imidazolidinone and

    produced slightly higher yields, but only a 1:3 ratio between product C and B and took

    significantly longer (12 hours) to complete. While the primary amine in the benzyl carbamate

    underwent the reaction, the primary amine in aniline was completely unreactive. This is

    important because the goal of this research is to find a reaction that can be used with a large

    variety of nucleophiles.

  • Discussion

    15

    1

    2

    4

    3

    Figure 18 Potential positions where nucleophiles could attack the alkene

    4. Discussion

    The goal of this research was to create cyclopropane derivatives to restrict the

    conformation of molecules. Although only one product maintained the cyclopropane ring, this

    research shows promise because product C only appeared in one enantiomer, showing that

    cyclopropane derivatives can indeed restrict conformation and aid in enantioselective synthesis.

    From the data, it can be seen that the optimal temperature using this particular catalyst system

    and other reaction conditions was 60 C. Since other systems and even nucleophiles will have

    different optimal conditions, these conditions will need to be optimized for each set of reaction

    conditions. Another important observation was that these reactions were very fast. As

    previously noted, a similar reaction using the same catalyst ((t-Bu2-o-biphenyl)PAuCl and

    AgSbF6) and same nucleophile (1-methyl-2-imidazolidinone) took significantly longer to

    complete.5 The high reaction rate of this reaction is advantageous, giving the reaction good

    commercial value since it can yield more product in less time.

    Although the yields are rather low, this reaction is very promising due to the unexpected

    result. While it seems more intutitve for the amine bond to add across the cyclopropane group

    because of the torsional strain and the energy that would be released with the breaking of the

    ring, the unexpected addition can be explained by the reaction mechanism of hydroamination.

    This reaction mechanism is a three part mechanism in which the

    gold center of the catalyst first adds across a bond and breaks it,

    forming a temporary catalyst substrate complex. This bonding

    then causes a carbocation to be formed on an adjacent carbon

    which the nucleophile attacks and bonds to. The final stage

  • Discussion

    16

    transfers the hydrogen that the nucleophile loses to the substrate to the gold catalyst which then

    kicks off the gold catalyst and allows the process to repeat.4 In the case of the hydroamination of

    methylene cyclopropanes, the most likely location to attack would be the carbon at position 1

    (Figure 18) since the most stable carbocation would be formed there. After the gold bonds to

    carbon 1, either the ring or the double bond can be broken based on where the nucleophile

    attacks. If the nucleophile attacks position 2 or 3, the ring will be opened and product A and

    product B are formed respectively. On the other hand, if the nucleophile attacts position 4 and

    adds across the double bond, the ring will be maintained and it will form product C instead. This

    position of attack has not been observed before for this specific reaction and more research will

    be needed to understand why product C forms and why lowering the temperature increases the

    its yields.

    Looking back at our original goal of finding a way to enantioselectively syntheisze drugs,

    we can see that the hydroamination of methylene cyclopropanes provides an unexpected, yet

    viable way to achieve this. However, this reaction could also have implications in fields other

    than drug synthesis as many important chemical and biological molecules used to study various

    fields are sensitive to the enantiomer used. For example,

    pactamycin (Figure 19) is only useful to biochemists in the

    form shown and by the addition to cyclopropane derivatives

    found in this research, these conformations could be locked

    and a cyclopropane derivative of pactamycin can be made.

    Although current selectivities are not optimal, there are

    many other reaction conditions that could be changed which

    may increase the yield of the desired product. For example,

    Figure 19 Pactamycin, a natural product that has been the goal of many synthesis experiments. It is a useful biochemical molecule and is isolated naturally to study ribosomes and other cellular functions.

  • Discussion

    17

    by experimenting with more catalysts, the reaction can be further biased towards product C and

    yields can be increased. There is another limitation to this reaction which is evident in the failure

    of the anniline reaction. Since 1-methyl-2-imidazolidinone contains a secondary amine, it is

    more easily deprotonated (in the third stage of the hydroamination reaction mechanism, the

    hydrogen on the nucleophile leaves the nucleophile and bonds to the gold) than a primary amine

    such as those present in benzyl carbamate and aniline. The reason benzyl carbamate still reacts

    is the high electronegativity of the carbamate group which contains two oxygen atoms that

    deprotect the hydrogens. Aniline has no groups that cause a downshift in the hydrogen, so

    deprotonation is considerably less likely (pKa values support these explanations: pKa of

    imidazolidinone < 15, pKa(benzyl carbamate) = 23.0, pKa(anniline) = 30.6; pKa values from

    values found by Bordwell et al. in DMSO)13

    Therefore, a major goal for future reactions is to

    expand them to encompass more functional groups. This goal goes hand in hand with increasing

    yields as changing the catalyst system will also have an effect on which nucleophiles can be

    used. On the other hand the fact that benzyl carbamate followed the same pattern as 1-methyl-2-

    imdazolidinone shows that the reaction is not specific to the imdazolidinone and can be used

    with a variety of nucleophiles.

    5. Conclusion

    In conclusion, this research discovered an atom-efficient way to add amines to

    cyclopropane derivatives. The ultimate goal would be to be able to expand this reaction to more

    functional groups and eventually find a way to add any functional group to a cyclopropane

    without opening the ring. Thus the logical first step is to use the same catalyst system for

    different functional groups similar to what was done with the benzyl carbamate reaction. The

    next step would be optimizing the catalyst and conditions for each type of nucleophile since each

  • Conclusions 18

    functional group responds differently to the catalysts. More reactions can be run using different

    catalyst systems and solvents which can further optimize yields and the ratio between the desired

    and undesired product. Aniline, for example, has been successfully used as the nucleophile in

    intermolecular hydroaminations in previous literature using the silver co-catalyst AgNTf2, so it is

    possible to find a suitable catalyst system for this reaction.15

    The final step is compiling all these

    results so that future researchers can have a set of optimal reaction conditions for the addition of

    any functional group to cyclopropane derivatives.

    Although data from this research demonstrates the formation of an unexpected product

    from this reaction, the procedures should be repeated to confirm that the cyclopropane ring is

    indeed unopened in a major product and for data replication. This is especially important since

    previous research has never shown this particular product being formed during the reaction.11

    Perhaps the most important data that still needs to be collected is the effectiveness of this

    technique in synthesizing known cyclopropane derivatives of

    drugs, the enantioselectivity of that process, and the efficacy

    of the final products. The most useful future work in this

    reaction would be the synthesis of usable drugs like Figure 20,

    a conformationally restricted product found to be effective in treatment of diseases that are the

    result of calcium imbalances, instead of compounds synthesized just to show the efficacy of this

    reaction like the compounds made in this research.14

    Although several issues must be addressed (low yields and compatibility with other

    functional groups) and results must be replicated, this reaction can be useful as an efficient

    method to add functional groups to cyclopropane derivatives to synthesize conformationally

    restricted drug analogs as well as many other enantioselective products.

    Figure 20 1-(1-(3-Methoxyphenyl)-N-methylethanamine))-2-phenyl-cyclopropane made by researchers as a possible drug analog.

    3

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