A synthesis is a specific sequence of chemical reactions that converts starting materials into the desired compound called the target of the synthesis or the synthetic target A synthesis is often ID: 585642
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Slide1
Organic Synthesis
A
synthesis
is a specific sequence of chemical reactions that
converts
starting materials into the desired compound, called the
target
of the synthesis (or the
synthetic target
).
A synthesis is often
the culmination of
several separate reactions, which are called
synthetic steps
.
Often a synthesis is necessary to produce a natural product when the demand for the compound outweighs nature’s supply.
Syntheses are also used to produce new compounds that are not produced by nature.Slide2
1965 Nobel Prize in Chemistry
“
outstanding achievements in the art of organic synthesis
Also made VERY important observations in the development of the Woodward-Hoffman rules of ring closure1st step in the application of quantum mechanics to organic molecules1981 Nobel Prize in Chemistry (Roald Hoffmann)
1st modern synthetic organic chemistProbably greatest organic chemist
R.B. Woodward (1917-1979
)Slide3
R.B. Woodward (Early Career
)Slide4
R.B. Woodward (Later Career
)Slide5
R.B. WoodwardSlide6
Penn (1977-1989)
Scripps Research Institute and UC-San Diego (1989-present)
Modern day R.B. Woodward
K.C. NicolaouSlide7
11 stereocenters => 2
11
= 2048 stereoisomers
2 rings & 1 bicyclic ring
Isolated in 1967 from bark of Pacific yew tree
Lung, ovarian, breast, head and neck cancer
K.C.
Nicolaou
TaxolSlide8
23 stereocenters => 2
23
= 8,400,000 stereoisomers
11 trans-fused rings83 steps, 12 years91% yield for each step but 0.043% total yield
Neurotoxin that binds to voltage-gated sodium channels in nerve cells
Naturally found in
Karenia brevis
which are marine organisms typically found in fish
K.C.
Nicolaou
Brevotoxin
BSlide9
94 stereocenters => 2
94
= 1.98 x 10
28 stereoisomers31 trans-fused rings
Neurotoxin that binds to calcium channels
Naturally produced by
Gambierdiscus toxicus
which are marine organisms typically found in fish
K.C.
Nicolaou
MaitotoxinSlide10
Writing the Reactions of
an Organic SynthesisThere are essentially three main conventions routinely used in writing a synthetic scheme.
The first stems from the fact that a synthesis is an abbreviated recipe.Slide11
Example of a Synthetic Step
This
synthetic step shows how to convert 2-phenyl-2-tosylpropane into 2-bromo-2-phenylpropane.Notice that it does
not show the individual elementary steps.It doe not contain curved arrows, nor does it contain reactive intermediates.Slide12
Example of a Mechanism
This is the mechanism for the previous synthetic step.
It is composed of elementary steps.It contains curved arrows and reactive intermediates.Slide13
Example of a an Incorrect Synthetic Step
This proposed synthetic step, therefore, is technically incorrect because Br
⁻ cannot be added in pure form. Slide14
Common Simplifications to Synthetic Steps
Notice, for example, that
TsO⁻ was not included in this synthetic step.Slide15
Reagents versus Reaction ConditionsSlide16
Combining Separate ReactionsSlide17
More Information in Scheme
Using this convention for sequential steps, reaction conditions can be written
after the reagent for each numbered step.The reaction conditions are typically
separated from the reactant or reagent by either a comma or by a slash. Slide18
Cataloging Reactions
There are two major types of reactions
Functional group transformations, which only convert one functional group into another without affecting the carbon skeleton.Reactions that result in the formation and/or breaking of a C–C
s bond.Slide19
Cataloging Reactions
continued…Slide20
Retrosynthetic Analysis:
Elias
J. Corey (1928–) of Harvard University pioneered a
new method of designing a synthesis scheme, called retrosynthetic analysis.The basis of retrosynthetic analysis is the transform, which is the proposed undoing of a single reaction or set of reactions.An open arrow, called a retrosynthetic arrow, is the convention used to indicate a transform, and is drawn from the target to the precursor.Slide21
Retrosynthetic Analysis:
work backwards
desired compound target
What can I make
the target from?
new target (simpler)
repeat
available compound
repeat
The Strategy of Organic SynthesisSlide22
Example of a Retrosynthetic Analysis
How can we synthesize 1-methoxypent-2-yne from precursors containing three or fewer carbon atoms?
The C3–C4 bond 1-Methoxypent-2-yne is disconnected.
Of those two precursors, only bromoethane is acceptable for our starting material, because it contains three or fewer C atoms. Slide23
Example of a Retrosynthetic Analysis
continued…
3-Methoxyprop-1-yne contains four C atoms
, however, so it cannot be used as starting material. One must apply a transform to dissect it into smaller precursors. 3-Methyoxyprop-1-yne contains an ether functional group, so we can apply a transform that undoes an ether-forming reaction. Slide24
The Complete Synthesis
for 1-Methoxypent-2-yne
Both of these precursors now contain three or fewer carbons and can be used as starting materials.
What remains to complete the synthesis is to reverse the transforms and to include the necessary reagents and conditions that will accomplish each reaction.Slide25
Retrosynthetic Analysis ExamplesSlide26
Percent Yield
To
minimize the costs of a synthesis and to help make the synthesis as green as possible, the percent yield of the target should be maximized
.Slide27
Linear Synthesis
These rules are essentially an outcome of how percent yield is computed for a
linear synthesis (i.e., a synthesis composed of sequential steps)For a linear synthesis, the overall percent yield is equal to the product of the yields of the individual steps
.Slide28
Linear Synthesis
continued…
Consider two syntheses, one with three synthetic steps and the second with six synthetic steps.If both syntheses proceeds with an 80% yield of
product for each step, what would be the overall yield for each?The three-step synthesis will have an overall yield of (0.80) x (0.80) x (0.80) = (0.80)3 = 0.51, or 51%. The six-step synthesis will have an overall yield of 26%. The synthesis with the fewer number of steps has the greater yield.Slide29
Overall Yield and Number of StepsSlide30
Convergent Synthesis
In
a convergent synthesis, portions of a target molecule are synthesized separately and are assembled together at a later stage. The yield can generally be improved.Slide31
Linear versus Convergent SynthesisSlide32
Best Choice: Convergent
The better yield often obtained from a convergent synthesis leads to the following general rule
:Slide33
Problems