research paper for enantioselective drug synthesis

8/10/2019 Research Paper for enantioselective drug synthesis

1/21

Page|1

1Introduction

Hydroamination of Methylene Cyclopropanes in Enantioselective Drug Synthesis

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


2/21

Page|2

2Introduction

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

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 asracemic 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.


3/21

Page|3

3Introduction

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 conformationto 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 transposition, 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 theR-group (Figure 2a.)

Figure2(fromYamaguchietal.3)Effectofthe

cyclopropanering

on

the

conformation

of

adjacent

carbons

Figure1 Geometryofa

cyclopropanering

Figure4Proposednovelreactiontoproduce

cyclopropaneanalogs

Figure3 Reactionfrompreviousliteratureusedto

createcyclopropaneanalogs


4/21

Page|4

4Introduction

Figure53Dstructureofsynthesizedcompound

showingthecyclopropyllicstrainandresulting

conformationallyrestrictedproduct. IfhydrogensAand

Bwerereplacedwithfunctionalgroups,thebulkier

groupwouldreplacehydrogenAbecausethatposition

isfurthestawayfromanyothersubstituents.

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 cyclopropanegroup (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


5/21

Page|5

5Introduction

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.4The 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


6/21

Page|6

6Introduction

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.

Materials 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-

Figure6

Reaction

mechanism

to

form

starting

material

adapted

from

previous

literature.7


7/21

Page|7

7ExperimentandMethods

Figure8Columnusedtoseparateproducts

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 CaSO4desiccant 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.

Figure7oilbathwithmicrowavetube

runningreaction


8/21

Page|8


Figure10Rotovapormachineused

toremovesolventfromsample

Figure9 TLCplatesusedtoseparatefractionsbased

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


9/21

Page|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:

Figure11HNMRofstartingmaterialconfirmstheidentityof2phenyl1methylenecyclopropane

withminimalimpurities. SomeresidualtBuOHremainedwhichwasthenremovedbyevaporation


10/21

Page|10

10DataAnalysis

Figure12GCprintoutof80MeCnAuP(Cy2obiphenyl)AgSbF6catalyzedreactionmixtureat2hours. Reactiontook3hours

tocompleteandthereisa1phenyl2methylenecyclopropanepeakat4.241andproductpeaks(2major1minor)at9.477,

9.862,and10.055. Peaksataround56areprobablyimpuritiesortheotherstartingmaterials

Figure13TLCplatefromsamereactionshowing3productswith3

differentRfs. Astainedplateisshownontherightfromadifferent

reactionwhichshowsproductspotsmoreclearly.

ProductA ProductB ProductC


11/21

Page|11

11DataAnalysis

Figure14HNMRofproductA,theminorproduct. Around55.7ppm,wecanseethepeaksthataretheresultofvinyl

hydrogens,hydrogensattachedtospcarbons(doublebonds). Wecanseetwodistinctsignals,asingletandadoubletof

doublets(singletat5.6ppmandddat5ppm)whichsuggeststhestructureshownabovesincethereare2distincthydrogen

signalsonthedoublebondasopposedtowhatwellseeinproductB. Wecanalsoseephenylpeaks>7ppmandpeaksfrom

theimidazolidinoneat3ppmand


12/21


13/21

Page|13

13DataAnalysis

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 aspalladium 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

Figure17Fromtopto

bottom:ProductsA,B,

andC


14/21

Page|14

14DataAnalysis

Entry CatalystSystem ReactionCondition YieldB YieldC Time

1 MeCnAuP(Cy2obiphenyl)SbF6 100 57.5% 28.6% 30minutes

2 MeCnAuP(Cy2obiphenyl)SbF6 80 28.7% 19.1% 3hours

3 MeCnAuP(Cy2obiphenyl)SbF6 60 38.3% 57.2% 6

hours

4 MeCnAuP(Cy2obiphenyl)SbF6 rt 0.0% 0.0% NA

5 (tBu2obiphenyl)PAuCl/AgSbF6 100 24.7% 14.3% 5hours

6 MeCnAuP(Cy2obiphenyl)SbF6 100 35.7% 11.5% 12hours

7 MeCnAuP(Cy2obiphenyl)SbF6 100 0.0% 0.0% NA

Table1Allreactionsweredoneundernitrogenatmosphereusingdioxaneassolvent. 2phenyl1methylenecyclopropanewas

usedasthealkeneanda5%catalystloadingwasused. Forentries15,1methyl2imidazolidinonewasusedasthenucleophile,

benzylcarbamatewasusedinentry6,andanilinewasusedinentry7.

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, twonew 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.


15/21

Page|15

15Discussion

1

2

4

3

Figure18Potentialpositionswhere

nucleophilescouldattackthealkene

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


16/21

Page|16

16Discussion

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 2or 3, the ring will be opened and product A and

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

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 willbe 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,

Figure19Pactamycin,anaturalproduct

thathasbeenthegoalofmanysynthesis

experiments. Itisausefulbiochemical

moleculeandisisolatednaturallytostudy

ribosomesandothercellularfunctions.


17/21

Page|17

17Discussion

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 ofimidazolidinone < 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


18/21


19/21

Page|19

19WorksCited

6. Works Cited

[1] McConathy, J., & Owens, M. J. (2003). Stereochemistry in Drug Action. Primary care

companion to the Journal of clinical psychiatry, 5(2), 7073. Retrieved from

http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=353039&tool=pmcentrez&re

ndertype=abstract

[2] Eriksson, T., Bjurkman, S., Roth, B., Fyge, . and Huglund, P. (1995), Stereospecific

determination, chiral inversion in vitro and pharmacokinetics in humans of the

enantiomers of thalidomide. Chirality, 7: 4452. doi: 10.1002/chir.530070109

[3] Yamaguchi, K., Kazuta, Y., Hirano, K., Yamada, S., Matsuda, A., & Shuto, S. (2008).

Synthesis of 1-arylpiperazyl-2-phenylcyclopropanes designed as antidopaminergic

agents: cyclopropane-based conformationally restricted analogs of haloperidol.

Bioorganic & medicinal chemistry, 16(19), 887581. doi:10.1016/j.bmc.2008.08.061

[4] Kovcs, G., Ujaque, G., & Lleds, A. (2008). The reaction mechanism of the

hydroamination of alkenes catalyzed by gold(I)-phosphine: the role of the counterion and

the N-nucleophile substituents in the proton-transfer step.Journal of the American

Chemical Society, 130(3), 85364. doi:10.1021/ja073578i

[5] Zhang, Z., Lee, S. Du, & Widenhoefer, R. a. (2009). Intermolecular hydroamination of

ethylene and 1-alkenes with cyclic ureas catalyzed by achiral and chiral gold(I)

complexes.Journal of the American Chemical Society, 131(15), 53723.

doi:10.1021/ja9001162


20/21

Page|20

20WorksCited

[6] Roesky, P. W., & Mller, T. E. (2003). Enantioselective catalytic hydroamination of alkenes.

Angewandte Chemie (International ed. in English), 42(24), 270810.

doi:10.1002/anie.200301637

[7] Kippo, T., Hamaoka, K., & Ryu, I. (2012). Bromine Radical-Mediated Sequential Radical

Rearrangement and Addition Reaction of Alkylidenecyclopropanes.Journal of the

American Chemical

[8] LaLonde, R. L., Sherry, B. D., Kang, E. J., & Toste, F. D. (2007). Gold(I)-catalyzed

enantioselective intramolecular hydroamination of allenes.Journal of the American

Chemical Society, 129(9), 24523. doi:10.1021/ja068819l

[9] Butler, K. L., Tragni, M., & Widenhoefer, R. a. (2012). Gold(I)-catalyzed stereoconvergent,

intermolecular enantioselective hydroamination of allenes.Angewandte Chemie

(International ed. in English), 51(21), 51758. doi:10.1002/anie.201201584

[10] Li, H., Lee, S. Du, & Widenhoefer, R. a. (2011). Gold(I)-Catalyzed Enantioselective

Intramolecular Hydroamination of Allenes with Ureas.Journal of organometallic

chemistry, 696(1), 316320. doi:10.1016/j.jorganchem.2010.09.045

[11] Zhang, D.-H., Du, K., & Shi, M. (2012). Gold(I)-catalyzed intramolecular hydroamination

and ring-opening of sulfonamide-substituted 2-(arylmethylene)cyclopropylcarbinols.

Organic & biomolecular chemistry, 10(18), 37636. doi:10.1039/c2ob25512j

[12] Nakamura, I., & Itagaki, H. (1998). Ring Opening in the Hydroamination of

Methylenecyclopropanes Catalyzed by Palladium, 3263(10), 64586459.


21/21

Page|21

21WorksCited

[13] Bordwell, F. (1988). Equilibrium acidities in dimethyl sulfoxide solution.Accounts of

Chemical Research, 2(10), 33053312. Retrieved from

http://pubs.acs.org/doi/abs/10.1021/ar00156a004

[14] Cohen, Judith H., Donald W. Combs, and Phillip J. Rybczynski. "1,2-disubstituted

Cyclopropanes." (n.d.): n. pag. Web.

.

[15] Zhang, X., Yang, B., Li, G., Shu, X., Mungra, D., & Zhu, J. (2012). Highly Regioselective

AgNTf2-Catalyzed Intermolecular Hydroamination of Alkynes with Anilines. Synlett,

23(04), 622626. doi:10.1055/s-0031-1290341

[16] Hashmi, A. S. K., & Lothschtz, C. (2010). Triazolate Counter Ions in Au I Complexes:

Catalysts with Improved Thermal Stability. ChemCatChem, 2(2), 133134.

doi:10.1002/cctc.20090028

[17] "Center for Drug Discovery."History and Background of Drug Discovery. University of

Georgia, n.d. Web. 20 Sept. 2013.

research paper for enantioselective drug synthesis

Documents