2. 1
A Literature Review of
Organocatalytic Domino
Reactions from 2011 - 2014
University Of Southampton
Faculty of Natural and Environmental Sciences
Chemistry
Benjamin Arthur Hughes
Student ID: 25498738
Year of study: Third
Degree program: F100
Supervisor: Ramon Rios-Torres
Total Word Count: 5876
Revised Word Count: 5063
4. Introduction:
Organocatalysis:
Brief History of Organocatalysis:
The term organocatalysis is believed to
originally come from the German term
‘Organische Katalysatoren’. Friedrich
Wilhelm Ostwald better known for his
happiness formula (4) and his Nobel Prize in
1909 (5), used the term in 1904 to describe
catalysed reactions by small organic
molecules. .
However there are many examples of
organocatalysis occurring before this, chief
amongst them is an organocatalyzed
Benzoin reaction by Friedrich Wöhler and
Justus von Liebig in 1832 (Scheme 1, Eqn
1) (6). Some 28 years later in 1860, Justus
von Liebig synthesised oxamide using
dicyanogen and water with an acetaldehyde
catalyst (Scheme 1, Eqn 2) (7). A further 36
years year on in 1896, Emil Knoevenagel
catalysed a Knoevenagel condensation
using piperidine. (8) .
Scheme 1: Early examples of organocatalytic reactions
(i) Two equivalents of benzaldehyde reacted in the
presence of cyanide (KOH and HCN) to generate the α-
hydroxyl ketone.
(ii)Dicyanogen and water with acetaldehyde catalyst to
generate the oxamide.
In the 20th century more organocatalysis
was reported such as the N - heterocyclic
carbine organocatalysis by Sheehan et al. in
1966. (9) In addition to the Hajos – Parrish –
Eder – Sauer - Wiechert reaction (Scheme
2) in the early 1970’s which used L- Proline
to catalyse an aldol condensation of 5 to
form a Wieland-Miescher ketone 6. (10) The
ketones were usually used as intermediates
for the synthesis of steroids however this
was the last major organocatalytic
breakthrough of the 20th century.
Scheme 2: Wieland - Miescher ketone (Proline catalyzed)
(i) Proline, Acetonitrile or DMF at room temperature
At the dawn of the 21st century the field
was revitalised by List et al. and MacMillan
et al. List et al. revisited the Hajos – Parrish
– Eder – Sauer - Wiechert reaction leading
to the first published S-Proline catalysed
asymmetric intermolecular aldol reaction of
branched/ aromatic aldehydes (Scheme 3).
(11) These S-proline reactions were highly
enantiostereoselective which opened up
vast amounts of organocatalytic reactions
which were previously unheard of.
However it was the paper later that same
year by MacMillan et al. that had a
complementary activation mode known as
iminium activation that allowed great
enantiostereoselectivities in Diel-Alder
reactions of enals. The LUMO - Lowering
strategy by use of a catalysis got quick
acceptance amongst the scientific
community of organic chemists and broke
the thought that many of the reactions for
effective asymmetric synthesis could only
be done by metal catalysts, but instead
organocatalysts could also do them. (12)
Scheme 3: Reacting 4 - Nitrobenzaldehyde with acetone in
the presence of Proline.
Other advances in the 21st century have
led to three main fields of organocatalysis
being formed: The first being, formation of
5. 1
covalent bonds such as seen in the enamine
and iminium catalyst routes. The second is
formation of Hydrogen bonds which use
BrØnsted acids or phosphoryl triflylamides.
(1) The Third being Electrostatic/Ion Pairs
which is a concept established by List et
al. known as asymmetric counteranion
directed catalysis (ACDC). The counter-
anion causes enantio-induction of products,
this method also works with transition
metal catalysis. (2) (3) This literature review
will be looking predominately at the first
two fields in domino organocatalytic
reactions.
Domino reactions:
Domino reactions otherwise known as
cascade reactions or tandem reactions are a
type of reaction that takes multiple
components and reacts them in a minimum
number of separate reactions, which, if
possible being one reaction. A good
example of an organocatalytic domino
reaction is the Enders Triple cascade
(scheme 4). (13) Through only the one
catalyst being needed the reaction can
progress in one pot as the four steps are on
a catalytic cycle making a continuous
reaction. These continuous reactions are a
lot cheaper to run and usually have a higher
yield with chosen stereospecificity which
makes them very important for organic
chemists.
Scheme 4: Enders catalytic cycle
Domino reactions are quite often very
versatile allowing different catalysts and
components/reagents to be used to create
novel compounds as will be talked about
later on. Obviously changing the catalyst(s)
and solvent(s) will change yield… etc and
so optimum conditions are usually found
for individual reaction sets. Never the less
the flexibility of being able to change
components/reagents means that floors
with the synthesis such as, can’t proceed in
acid solvents can often be navigated
around, allowing many more reactions to
come into the schemes scope.
Literature reviews
Enantioselective multicomponent
domino reactions using hydrogen
bonding catalysis:
In recent years the utility of hydrogen
bond catalysis has multiplied and so more
research is being aimed towards hydrogen
bonding catalysed domino reactions. The
high versatility and ability to build complex
molecular structures akin to nature’s
biological catalysis of reactions being the
main reason for this focus.
The research done by Nicola Kielland et
al in 2013 on borane – isocyanide
multicomponent reactions are a clear
example as not many multicomponent
reactions currently use boron species.
Nicola Kielland et al. redesigned the 1960’s
synthesis of oxazolidines using iso-
cyanides, aldehydes and boranes by Hesse.
(14) The incorporation of dipolarophiles
allowing aziridines and pyrrolidines to be
synthesised as well. (15) The reaction has an
azomethine ylide intermediate which can
undergo [3+2] cycloadditions if a second
equivalent of the aldehyde is present which
leads to the oxazolidine. However the ylide
could also cyclise to generate aziridines and
6. 2
with distinct dipolarophiles make
pyrrolidine scaffolds. Nicola Kielland et al.
broaden the scope of this area by testing
different aldehydes; aromatic, hetero-
aromatic and α,β - unsaturated derivatives
as well as expanding the scope of other
reactants. It was found that the borane input
can be prepared in situ however only
aromatic isocyanides work but they can
provide an ortho substitution. They
conclude that “Although the need for
specific preparation of some boranes and
scope limitations in some reactants may
represent restrictions in the
practical/industrial applications of this
MCR, the described methodology stands as
a very efficient way to access a wide family
of heterocyclic compounds with relevant
presence in the biological and medicinal
chemistry.” (15)
Another example of trying to broaden the
scope of a multicomponent reaction is seen
in the 2011 paper by L. Banfi et al which
looks at the tandem Ugi / Mitsunobu
protocol. (16) (17) The group had previously
been doing work in this area and so knew
that they could get two high yielding steps
with stereospecific synthesis of
enantiomerically pure products in the one
pot reaction. By expanding the scope of
their research it was realised that it was not
possible to use aliphaphatic aldehydes with
unbranched α-positions and that for highest
yields in the Mitsunobu step a primary
alcohol is needed.
Scheme 5: D. Wang et al.'s scheme for one-pot synthesis
of various alkenes. (18)
D. Wang et al. worked on using
triphenylphosphine and ethyldiphenylphos-
phine to catalyse a one pot synthesis of
highly functional alkenes. These alkenes
are made from aldehydes, alkyl vinyl
ketones and amides (Scheme 5). (18) The
proposed reaction mechanism is the Morita
–Baylis – Hillman reaction of the aldehyde
with the vinyl alkyl ketone followed by a
Michael addition of the amide. The group
would like to do further work in the area
with the use of imines as a possibility in the
reactions.
A year later another similar paper by S.
Syu who was also involved in the paper by
D. Wang, uses imines in a three component
triphenyl-phosphine catalysed reactions via
aza - Morita - Baylis - Hillman method. (19)
The mild conditions used allowed for
efficient reactions with high yields for all of
the aryl-substituted imines.
Other researchers such as Clark et al.
focused more on the optimisation of just
one reaction (scheme 6). The idea for the
reaction is to find a better way to synthesise
furan. (20) Clark et al. studied the addition of
excess benzoic acid to enynedione with a
stoichiometric amount of (THT) tetra-
hydrothiophene to yield furfuryl benzoate.
The seminal reaction showed 50 %
conversion of the substrate over 24 hours to
the furan. Through optimisation Clark et al.
improved the yield to 99% by using the
protecting group PMB (p-methoxybenyl)
however reactions that used electron rich
and electron poor aryl carboxylic acids
were slow unless THT concentrations were
increased to 50 mol %. Clark et al. worked
successfully to find a wide range of
substrates and nucleophiles that give highly
decorated furans with good yields.
Scheme 6: Seminal reaction by Clark et al. (20)
7. 3
In addition to Clark et al.’s work on
decorated furan, Jakubec et al. published a
similar paper for synthesis of highly
decorated 5- nitropiperidin- 2- ones and
related heterocycles. (21) The general
strategy employed is a Michael addition
followed by a nitro-Mannich/Lactamisation
cascade for a 4 component organocatalytic
reaction. To widen the scope of their
research Jakubec et al. created a range of
Michael adducts on a gram scale using
active methylene, or methane carbon acids
with nitro olefins and DABCO (20 – 30 %,
1,4-diazabicyclo[2.2.2]octane) in THF
(tetrahydrofuran). When the stereocontrol
was low the adducts were recrystallized,
with the range of adducts multiple nitro-
Mannich/ Lactamisations were achieved
with moderate to good yields however in
some cases the reaction took a lot of time
with one taking 20 days to complete. (21)
One of the substrates a ‘6e’ was used to
experiment at synthesising polycyclic
natural products of the piperidine variety
and found the reactions required the
successful employment of preformed cyclic
imines. To conclude that Jakubec et al. have
successfully completed a versatile direct
synthesis of decorated 5- nitropiperdin- 2-
ones and related heterocycles in a four
component one- pot cascade.
Moving along with the spiro synthesises
Ahadi et al. published a paper in 2012 on
organocatalytic three component cascade
reactions for the synthesis of spiro-[indeno
[1,2-b]furan]- triones]. (22) Within the paper
the group show their results of employing
cyclic α- halo compounds in the synthesis
of dihydrofuran fused coumarin via a
pyridium ylide. They managed a domino
reaction of aldehydes, α- bromo
compounds, and 1,3- dicarbonyles via an
acetic acid and DBU (1,8- Diazabicyclo-
[5.4.0]undec-7-ene) combination. This is
believed to be the first time the synthesis of
spiroindeno [1,2-b]furan- pyranes, dihydro-
indenopyrans and spirochroman- indeno[1,
2-b]furans have been achieved in this way.
For the model reaction (synthesis of spiro-
chroman-3,2`- indeno[1,2-b]furan- trione)
the best conditions were found to be
potassium carbonate (30 %) in acetonitrile
to be refluxed for 24 h to gain a yield of 65
%. Higher levels of potassium carbonate
were found to have no affect and lower
levels lowered the yield, when completely
removed the yield dropped significantly to
40 %. When using aromatic aldehydes in
the reaction initial results showed low
yields (table 1) until the acetic acid DBU
combination was used which gave good
yields (table 2).
Table 1: Scheme and table of yields for use of aromatic
aldehydes by Ahadi et al. before using acetic acid/ DBU
combinations (22)
Table 2: Scheme and table of yields for use of aromatic
aldehydes by Ahadi et al. after using acetic acid/ DBU
combinations (22)
From the tables of yields a general
increase in yield of about 20 % is seen by
swapping out the potassium carbonate for
the acetic acid/ DBU combination, this
can’t be explained by the initial proposed
8. 4
mechanism (Scheme 7, Eqn 1) so a new
mechanism (Scheme 7, Eqn 2) was
proposed to accommodate for the change.
This new mechanism depicts that a salt is
formed in situ by reaction of acetic acid and
DBU, then the salt bridges to the aldehyde
via hydrogen bonding. The activated
aldehyde undergoes Knoevenagel
condensations with the 1,3- indandione,
followed by a Michael addition of the ylide
to get an enolate, and then annulation to get
the product. The second mechanism is a
prime example of how the hydrogen
bonding is used in organocatalytic
reactions.
Scheme 7: The initial and second proposed mechanisms
by Ahadi et al. (22)
In 2013 Ahadi et al. published another
paper using the acetic acid/ DBU system,
this time the system was used for the
Diastereoselective synthesis of pyrano
fused coumarins in a 3- component organo-
catalytic reaction. (23) The results were
successful giving multiple advantages from
the method employed that include; good
novelty options, operation simplicity, good
yields and easy work up procedures.
Moving back to spiro compounds a great
paper that demonstrates utilizing hydrogen
bonding to synthesise spirooxindoles is
‘Construction of bispirooxindoles contain-
ing three quaternary stereocentres in a
cascade using a single multifunctional
organocatalyst’ by Barbas et al. in 2011. (24)
The group use hydrogen bonding of
thiourea type catalysts in a Michael/ Henry
tandem reaction with great success getting
stereocontrol of up to >99:1 d.r.
(diastereomeric ratio) and 98:2 e.r.
(enantiomeric ratio) and with catalyst
reconfiguration giving access to the
opposite enantiomer (Scheme 8). The
reactions gave yields from 56 – 94 % but
over 80 % was seen for the majority of the
reactions.
Scheme 8: Generic thiourea type catalysed reaction by
Barbas et al. (24)
Enantioselective multicomponent
domino reactions using enamine and
other intermediates:
Of course not all recent research into
enantioselective multicomponent tandem
reactions uses hydrogen bonding and so this
section looks at the advances that have
come recently by other methods.
Back in 2011 a paper by Wu et al. studies
three component syntheses of Indoloquin-
olizidine derivatives using an organo-
catalytic Michael addition with subsequent
Pictet- Spengler cyclization. (25) The group
used tryptamines, α,β-unsaturated alde-
hydes and alkyl propiolates to obtain yields
of 30 - 88 % with enantioselectivy yields in
general being above 90 % (ee). The group
also realised during testing that aromatic
α,β- unsaturated aldehydes wouldn’t work
in the cascade reaction resulting in a ‘messy
mixture’. . . . . . .
9. 5
The following year a similar reaction
mechanism was also employed by Cόrdova
et al. (26) The group used a three component
asymmetric Michael/ Pictet- Spengler/
Lactamisation cascade as well as a tandem
Swern oxidation/ Wittig and a domino
hydrogenation sequence for the syntheses
of Dihydrocorynanthenol, proto-emetinol,
protoemetine, 3-epi-protoeme-tinol and
emetine. The synthesis of (-)-
dihydrocorynanthenol was composed of a
three component synthesis of an enal,
malonate and tryptamine. The complete
synthesis taking five steps: Malonate added
to the enal in presence of the catalyst to
generate an aldehyde. Addition of TFA
(trifluoroacetic acid) and an amine to the
aldehyde created the reaction mixture that
was then refluxed at 50 °C for 16 hours. The
crude product of the reflux was then
reduced by LiAlH4 to give an alcohol. The
alcohol underwent a Wittig reaction to give
an olefin. The olefin was used in a one pot
hydrogenation to give the final product in a
yield of 86 %. However although this
method worked for the synthesis of (-)-
dihydrocorynanthenol when attempted for
protoemetinol the reaction didn’t proceed
as planned. The Pictet- Spengler product
was not observed but the Michael adduct
was the product, Initially the group
attempted to change this by using other
acids to the TFA however this didn’t work
as no cyclisation was seen. The group
realised that the imine intermediate wasn’t
reactive enough, and so placed the
dopamine derivative they were using for an
N-Boc protected dopamine derivative to
give an iminium intermediate. The iminium
intermediate worked allowing the reaction
to proceed similar to the previous method
except that the alcohol formed was more
resistant to the Swern conditions that
permitted a one pot oxidation/Wittig
sequence that removes a step and so
granting a 4 step total synthesis. The
syntheses of (-)- protoemetine and (-)-3-
epi-protoemetinol proceeded with no
additional problems. Emitine was
synthesised stereoselectively in 2 steps
from protoemetine. These syntheses are
great examples of how organocatalytic
reactions can be used to form complex
compounds enantioselectively. . . .
Chemists are constantly referring back to
nature as chemical biology has created a lot
of compounds that have important roles.
Synthetically these compounds are usually
hard to synthesis and so these organo-
catalytic domino reactions that produce
these complex compounds with high
enantiostereoselectively and diastereo-
selectively are highly valued. One such
example is the work by Enders et al. on
tetracyclic indole structures with six
stereocenters. (27) The group developed a
three component quadruple cascade
reaction using α,β- unsaturated aromatic
aldehydes and indole-2-methyleme
malonontriles. The reaction (scheme 9)
forms 4 carbon carbon bonds, a carbon
nitrogen bond as well as the 6 stereogenic
centers. . . . . . . . . . . . . . . .
Scheme 9: Enders et al.’s one pot synthesis for creating
tetracyclic indole structures with six stereocenters (27)
The synthesis itself is quite simple with
one aza-Michael reaction, followed by two
Michael reactions, and then one aldol
reaction to give the intermediate seen in
scheme 9 but in enol form, aldehyde
olefination of the keto form completes the
synthesis. Therefore the reaction
parameters were altered so that the
10. 6
intermediate was trapped in the keto form
by a stabilised Wittig reagent to give the
product. The scope was then widened by
testing multiple aromatic α,β- unsaturated
aldehydes which were isolated with yields
from 25-70 % and enantioselectivities of
91-99 % ee. A few other parameters were
adjusted to widen the scope with similar
results. . . . . . . . . . . . . . . .
Scheme 10: Enders et al. retrosynthesis of a tetracyclic
pyridocarbazole.. . . . . . . . . . . .
Enders et al. published another paper on
tetracycles a year later in 2013, the paper on
synthesis of tetracyclic pyridocarbazole
derivatives. (28) Enders et al. applied a
retrosynthesis on a simplified tetracyclic
pyridocarbazole (scheme 10) leaving two
external groups simply as ‘R’ groups. The
molecule was split into 3- vinylindole, and
two α,β-unsaturated aldehydes, the
conceived forward reaction was a Diels-
Alder/ aza- Michael/ Aldol condensation
procedure for the domino reaction. The
initial reaction was performed with 3-
vinylindole and cainnamaldehyde in DCM
(dichloro-methane) and 20 mol% of (S)-
TMS-diphenylprolinol as the catalyst. After
24 h the product was obtained as a single
diastereoisomer in 44 % yield. Other
catalysts were tested but found to give only
trace amounts or be completely inefficient
for the reaction in DCM. Other solvents
were tested and it was found that dry
solvents in argon got better yields and so
the solvent was changed to chloroform to
give the optimum conditions yielding 84 %
with d.r. of >20:1 and 98 % ee. Different
aldehydes and vinylindoles were used to
give a range of novel compounds with
yields of 14-84 % but all with high
enantioselectivity and diastereoselectivity.
Also in 2013 another paper was
published by Enders et al. however, this
time an entirely different approach to
domino reactions is seen. (29) Enders et al.
successfully complete a branched domino
synthesis of polyfunctionised cyclohexene
by using an aldehyde to work as both
electrophile and nucleophile. This is done
by addition of an amine catalyst to the
aldehyde to generate an enamine that acts
as a Michael donor however when oxidised
gets converted to an iminium ion that works
as a Michael acceptor allowing one
aldehyde to act as both an electrophile and
a nucleophile. This style of reaction has
great potential for pharmaceutics research
and diversity oriented syntheses as only a
couple of cheap starting materials are
needed to create complex compounds.
Another interesting paper is the synthesis
of spiro-oxindole derivatives organo-
catalyzed in an aqueous medium by Singh
et al. (30) The use of water as a solvent for
the catalyst is a prime example of how eco-
friendly some organocatalytic reactions are.
The findings showed that when using isatin,
6-aminouracil and acetylactone to
synthesise a spiro-oxindole, that the best
catalyst is L-Proline and the best solvent is
water, giving a yield of 94 % compared
with other solvents giving yields of 70-
79%. The combination of L-proline and
water didn’t just give higher yields but also
shorter reaction times, eradication of bi-
products and easier work ups for
purification. . . . . . . . . . . . .
Hasaninejad et al. also used an L-proline
catalyst to synthesise spiro- compounds. (31)
In this case however water only gave a yield
of 51 % for the synthesis of spiro
[benzo[c]pyrano[3,2-a]phenazines], and
ethanol was found to be the best solvent
with a yield of 94 % and a shorter reaction
11. 7
time than the water. 18 novel spiro-
compounds were achieved when changing
the diamines, cyclic ketones and nitriles
giving yields of 80-94 % for all except one,
which had a yield of 68 %. This once again
highlights the use of an organocatalysts that
gives high yields whilst being cost effective
and reasonably simple. . . . . . . . . .
Scheme 11: Yadav et al.’s synthetic reaction for the
formation of N-formylpiperidines.. . . . . .
The simplicity of these one pot cascade
reactions is often due to the catalytic cycles
for the reaction, such as the enamine-
catalysed cycle seen in the formation of N -
formylpiperidines by Yadav et al. (Scheme
11). (32) The cycle itself is very simple yet
doing an important part in the overall
reaction. The trimethylsilyl ether catalyst,
the aldehyde and the nitroalkene are all
easily obtainable starting materials that
highlight the importance of this catalytic
cycle with its [2+2+2] - annulation.
Tandem annulations being straight
forward obviously have gained good
ground for research and so it is no surprise
to find multiple papers that employ
organocatalytic tandem annulation. A
paper by Wen et al. demonstrates tandem
annulation very well with synthesising 17
different examples of tetrahydropyridine
derivatives from β-aroylthioacetanilides
and 14 different examples of thiochromeno-
[2,3-b]pyridine derivatives from β-(2-
haloaroyl)-aroylthioacetanilides. (33) All 31
compounds were synthesised by a
DABCO- catalysed tandem reaction with
the starting material, an aryl aldehyde and
an aroyl acetonitrile. The method used is
very efficient whilst also being regio-
stereo- and chemoselective with good
yields. . . . . . . . . . . . . . . .
Never the less sometimes for the best
reactions, combination of synthetic tactics
are needed and the 2013 paper by Wang et
al. on ‘Facile construction of structurally
diverse thiazolidinedione- derived
compounds…’ is a prime example of this.
(34) The group combine divergent synthesis
and cascade organocatalysis for the reaction
set using an asymmetric Michael- Michael-
aldol cascade for the synthesis of chiral
spiro-thiazolidinediones and spiro-
rhodanines. The strategy allows diverse
products from similar starting materials
whilst keeping high efficiency. . . .
Diastereoselective multicomponent
domino reactions:
Now obviously high enantio- and
diastereoselectivity are favoured and so
most of the time they will go hand in hand.
So far the reviews have been focused more
towards enantiostereoselectivity, however
the following papers are directed more
towards their diastereoselective
approaches. . . . . . . . . . . . .
Mellor and Merriman used a bronsted
acid organocatalyzed Povarov reaction in
1995 to synthesise julodines in low yields.
(35) In 2013 the synthesis was repeated by
Fernandes et al. who then tried to optimise
it. (36) Starting out with 4-bromoaniline,
formaldehyde and styrene, catalysed by
CX4SO3H at 25 mol % in acetonitrile, to
give a yield of 54 % and de
(diastereoisomeric excess) of 50 %. When
the solvent was switched to a protic solvent
yields and de % increased, however when
using non-protic or aprotic solvents the
yield decreased dramatically. Water was
found to be the best solvent having
increased the yield to 64 % and de to 74 %.
Catalyst amount was then changed finding
that 2.0 mol % was best, with higher
12. 8
amounts no improvement was seen and
yield and de % dropped when lowered to
lower than 2.0 mol %. The reaction time
was the final component of the reaction to
be optimised, finding that a time of 2 hours
was better than one hour, increasing the
yield to 70 % but with no increase in de.
The 4-bromoaniline was replaced with
other p-aniline derivatives to find other
novel julodines. Different substituents gave
yields between 64-89 %, but with no clear
correlation, however electron withdrawing
groups all reduced diastereoselectivity.
Another paper that shows good
optimisation to improve diastereo-
selectivity is Shi et al.’s 2014 paper on
‘construction of a bispirooxindole scaffold
containing a tetrahydro-β-carboline
moiety’. (37) The group first optimised the
catalyst to increase the yield from 28 % to
78 %, and d.r. increase from 54:46 to 88:12.
Further optimisation allowed for an
increase to >95:5 d.r. but with a decreased
yield of 61 %. The group completed the first
catalytic asymmetric construction using a
CPA-catalysed three component cascade
Michael/ Pictet- Spengler reaction. The
bispirooxindoles has one quanternary and
one tetrasubstituted stereohenic centers,
with the intergration of tetrahydro-β-
carboline the formed compounds have high
bioactivities that paves the way for
organocatalytic drug synthesises. . . . . . .
Another good paper for showing how
organocatalytic domino reactions can be
used for synthesis of biological molecules
is Wiese et al.’s paper on synthesis of
Jatrophane diterpenes. (38) 18 different
Jatropha-5,12-diene diterpenes were
successfully synthesised with the key
diastereoselective step studied by DFT
(density functional theory) calculations to
explain the induced diastereoselectivity of
the substrates. The non-natural jatrophane
diterpenes showed similar inhibitory effects
to the natural counterparts and so giving a
gateway into non-natural drug synthesis.
The final paper that is being reviewed is
‘An Asymmetric Organocatalytic
Quadruple Cascade to Tetraaryl-Substitued
2-Azabicyclo[3.3.0]octadienones’ by
Enders et al. (39) The paper shows the
development of an organocatalytic
quadruple cascade for multiple α-
ketoamides with α,β-unsaturated aldehydes
getting yields of 34-71 % and great
enantiostereoselectivity. Reaction follows
an aza-Michael/ aldol condensation/
vinylogous Michael/ aldol condensation
pathway that allows for diastereo-
selectivities of >20:1.. . . . . . . . .
Conclusions and future
directions for the area:
The future looks bright in this area of
chemistry with more and more applications
being found. The general cost efficiency
compared to previous methods of doing a
lot of the reactions seen by organocatalytic
synthesises, such as reactions that would
normally require a transition metal catalyst
alone promote healthy growth in the field.
In addition to this the high yields and
stereo- control/selectivity that are usually
found in the reactions makes many of them
applicable to industry which other methods
that take many steps may not. Although
there are some organocatalytic domino
reactions being used for synthesis of
biological compounds, I would like to see
far more for the generation of natural
compounds and their derivatives. The ease
of the domino reactions allows access to
many novel compounds that might show
activity for drug screens and so should be
used more. Never the less the high
enantiostereoselectivity and diastereo-
selectivity will ensure that the field
continues to expand and progress. . . .
13. 9
Acknowledgements
Firstly I would like to thank members of
the academic staff including my supervisor
Dr R. R. Torres for their guidance.
Secondly I would like to thank my family
members, especially my dad for proof
reading my dissertation at multiple
instances throughout the writing process
even though their lack of knowledge in
chemistry made it rather trying for them.
Finally I would like to thank my
grandmother B. M Harris, for although she
passed away many years ago her influe nce
has remained strong and without her I
would never have gone to university to
study Chemistry.
References
1. Akiyama, T. 2007, Chem. Rev, Vol. 107,
pp. 5744-5758.
2. B. List, M. Mahlau. 2013, Angew.
CHem, Vol. 125, pp. 540-556.
3. R. J. Phipps, G. L. Hamilton, F. D. Toste.
2012, Nat. Chem, Vol. 4, pp. 603-614.
4. Wilhelm Ostwald's Happiness Formula.
Szabadvary, Ferenc. 1965, Journal of
Chemical Education, p. 678.
5. nobelprize.org. [Online] [Cited: 01 April
2015.]
http://www.nobelprize.org/nobel_prizes/ch
emistry/laureates/1909/.
6. F.WÖhler, J.Liebig. 1832, Ann. Pharm,
Vol. 3, pp. 249-282.
7. Liebig, J. von. 1860, Ann. Chem, Vol.
113, pp. 246-247.
8. Knoevenagel, E. 1896, Ber. Dtsch.
Chem. Ges, Vol. 29, pp. 172-174.
9. J. C. Sheehan, D. H. Hunneman. 1966, J.
Am. Chem. Soc, Vol. 88, pp. 3666-3667.
10. U.Eder, G. Sauer, R. Wiechert. 1971,
Angew. Chem. Int. Ed. Engl, Vol. 10, pp.
496-497.
11. B. List, R. A. Lerner, C. F. Barbas.
2000, J. Am. Chem. Soc, Vol. 122, pp.
2395-2396.
12. W. S. Jen, J. J. M. Wiener , and D. W.
C. MacMillan. 2000, J. Am. Chem. Soc,
Vol. 122, pp. 9874-9875.
13. D. Enders, M. R. M. Huttl, C. Grondal,
G. Raabe. 2006, Nature, Vol. 441, pp. 861-
863.
14. G. Hesse, H. Witte, W. Gulden. 1965,
Angew. Chem. Int. Ed. Engl, Vol. 4, p. 596.
15. N. Kielland, E. Vicente-Garcia, M.
Reves, N. Isambert, M. J. Arevalo and R.
Lavilla. 2013, Adv. Synth. Catal, Vol. 355,
pp. 3273-3284.
16. L. Banfi, A. Basso, L. Giardini, R. Riva,
V.Rocca, G.Guanti. 2011, Eur. J. Org.
Chem, pp. 100-109.
17. K. C. K. Swamy, N. N. B. Kumar, E.
Balaraman, K. V. P. P. Kumar. 2009,
Chem. Rev, Vol. 190, pp. 2551-2651.
18. D. Wang, S. Syn, T. Hung, P. Chen C.
Lee, K. Chen Y, Chen and W. Lin. 2011,
Org. Biomol.Chem, Vol. 9, pp. 363-366.
19. S. Syu, Y. Lee, Y. Jang and W. Lin.
2011, J. Org. Chem, Vol. 76, pp. 2888-
2891.
20. S. J. Clark, A. Boyer, A. Aimon, P. E.
Garcia, D. M. Linsay, A. D. F. Symington
and Y. Danoy. 2012, Angew. Chem. Int.
Ed, Vol. 51, pp. 12128-12131.
21. P. Jakubec, D. M. Cockfield, M.
Helliwell, J. Raftery, and D. J. Dixon. 2012,
Beilstein J. Org. Chem, Vol. 8, pp. 567-578.
22. S. Ahadi, M. Abaszdeh, and A. Bazgir.
2012, Mol Divers, Vol. 16, pp. 299-306.
14. 10
23. S. Ahadi, M. Zolghadr, H. R. Khavasi,
and A. Bazgir. 2013, Org. Biomol. Chem,
Vol. 11, pp. 279-286.
24. B. Tan, N. R. Candeias, C. F. Barbas.
2011, Nat. Chem, Vols. 473-477, p. 3.
25. X. Wu, X. Dai, H. Fang, L. Nie, J.
Chem, W. Cao, and G. Zhao. 2011, Chem.
Eur. J, Vol. 17, pp. 10510-10514.
26. S. Lin, L. Deiana, A. Tseggai, and A.
Cordova. 2012, Eur. J. Org. Chem, pp. 398-
408.
27. D. Enders, A. Greb, K. Deckers, P.
Selig, and C. Merkens. 2012, Chem. Eur. J,
Vol. 18, pp. 10226-10229.
28. D. Enders, C. Joie, and K. Deckers.
2013, Chem. Eur. J., Vol. 19, pp. 10818-
10821.
29. D. Enders, X. Zeng, Q. Ni, and G.
Raabe. 2013, Angew. Chem. Int. Ed, Vol.
52, pp. 2977-2980.
30. P. Rai, M. Srivastava, Jaya Singh, and
Jagdamba Singh. 2013, RSC Adv, Vol. 3,
pp. 18775-18782.
31. A. Hasaninejad, S. Firoozi, and F.
Mandegani. 2013, Tetrahedron Letters,
Vol. 54, pp. 2791-2794.
32. R. Chawla, A. Rai, A. K. Singh, and L.
D. S. Yadav. 2012, Tetrahedron Letters,
Vol. 53, pp. 5323-5326.
33. L, Wen, Y. Shi, G. Liu, and M. Li. 2012,
J. Org. Chem, Vol. 77, pp. 4252-4260.
34. Y. Zhang, S. Wang, S. Wu, S. Zhu, G.
Dong, Z. Maio, J. Yao, W. Zhang, C.
Sheng, and W. Wang. 2013, ACS Comb.
Sci, Vol. 15, pp. 298-308.
35. J. Mellor, and G. Merriman. 1995,
Tetrahedron, Vol. 51, p. 6115.
36. J. B. Simoes, A. de Fatima, A. A.
Sabino, F. J. T. de Aquino, D. L. da Silva,
L. C. A. Barbosa, and S. A. Fernandes.
2013, Org. Biomol. Chem, Vol. 11, pp.
5069-5073.
37. W. Dai, H. Lu, X. Li, F. Shi, and S. Tu.
2014, Chem. Eur. J., Vol. 20, pp. 11382-
11389.
38. C. Schnabel, K. Sterz, H. Muller, J.
Rehbein, M. Wiese, and M. Hiersemann.
2011, J. Org. Chem, Vol. 76, pp. 512-522.
39. C. Joie, K. Deckers, G. Raabe, and D.
Enders. 2014, Synthesis, Vol. 46, pp. 1539-
1546.
. . . . . . . . . . . .. . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . .
. . . . . .
. . . . . .
. . . . . . . . . . . .. . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . .. . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . .. . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . .. . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . .
. . . . . .
