research paper for enantioselective drug synthesis
TRANSCRIPT
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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
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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.
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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
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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
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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
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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
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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
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8ExperimentandMethods
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
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9ExperimentandMethods
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
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10DataAnalysis
Figure12GCprintoutof80MeCnAuP(Cy2obiphenyl)AgSbF6catalyzedreactionmixtureat2hours. Reactiontook3hours
tocompleteandthereisa1phenyl2methylenecyclopropanepeakat4.241andproductpeaks(2major1minor)at9.477,
9.862,and10.055. Peaksataround56areprobablyimpuritiesortheotherstartingmaterials
Figure13TLCplatefromsamereactionshowing3productswith3
differentRfs. Astainedplateisshownontherightfromadifferent
reactionwhichshowsproductspotsmoreclearly.
ProductA ProductB ProductC
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11DataAnalysis
Figure14HNMRofproductA,theminorproduct. Around55.7ppm,wecanseethepeaksthataretheresultofvinyl
hydrogens,hydrogensattachedtospcarbons(doublebonds). Wecanseetwodistinctsignals,asingletandadoubletof
doublets(singletat5.6ppmandddat5ppm)whichsuggeststhestructureshownabovesincethereare2distincthydrogen
signalsonthedoublebondasopposedtowhatwellseeinproductB. Wecanalsoseephenylpeaks>7ppmandpeaksfrom
theimidazolidinoneat3ppmand
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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
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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.
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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
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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.
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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
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19WorksCited
6. Works Cited
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[2] Eriksson, T., Bjurkman, S., Roth, B., Fyge, . and Huglund, P. (1995), Stereospecific
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20WorksCited
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