Planning Synthetic Strategies

Planning Synthetic Strategies

Synthesis
Synthesis is simply the production of a desired chemical from available starting chemicals Synthesis is important for:
Production of consumer products Production of pharmaceuticals
Even natural products with desirable biological effects (anti-cancer agents, etc.) are often produced synthetically in order to protect and conserve the natural sources
taxol, an anti-cancer agent found in the bark of the Pacific yew tree. Purification of taxol from bark requires larges amounts of bark (killing the trees) and provides small amounts of drug Solution: a starting material is available in the needles (a renewable resource) that can be synthetically converted to taxol

Retrosynthetic Analysis
Target Molecule 1st Precursor 2nd Precursor Starting Material

Retrosynthetic analysis involves starting from the desired final product (target molecule) and determining precursors that can be converted to the desired product, until available starting materials are reached A tool box of known reactions is an important key to being able to perform retrosynthetic analysis

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Retrosynthetic Considerations
1. 2. 3. 4. Construction of the carbon skeleton Functional group conversions Control of regiochemistry Control of stereochemistry

Carbon Skeleton Construction

Available carbon-carbon bond forming reactions:
Generally require a carbon electrophile and a carbon nucleophile Carbon nucleophiles (strong enough to react with the carbon electrophiles we have worked with) are less common:
Grignard reagents (R-MgX) Organolithium reagents (R-Li) Acetylide anions (R-C C ) Cyanide anion ( N C )

Planning a Grignard Synthesis

Grignard reactions are most useful for the production of alcohols (either as target molecules or as precursors leading to the target molecule) The carbon-carbon bond between the C-OH and a neighboring carbon can be formed
O 4-octanone pentyl magnesium bromide MgBr + O butyl magenesium bromide BrMg O + 5-decanone propyl magnesium bromide + 4-nonanone MgBr

5-butyl-5-decanol OH

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Further Structural Simplification

O MgBr +

OH

O + BrMg

Why is this necessary?

Neither 5-butyl-5-decanol nor 5-decanone are listed in the Aldrich catalog! If you cant buy them, you have to make them. Sometimes you might be able to buy them, but it would be cheaper to make them.

Problem
Select precursors with 5 or fewer carbons that could be used to make the following compounds:

OH

OH

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Your tool box of functional group conversions

Problem
What intermediate functional group type(s) will your synthesis involve if you want to convert:
An alkane to an alkene? An alkane to an alkyne? An alkyne to an alkene? An alkene to a ketone? An alkane to a ketone?

Control of Regiochemistry - I
Remember that elimination reactions often have several possible regiochemical outcomes:
Thermodynamically favored, most strong bases will give this as the major product elimination Not thermodynamically favored, can only be the major product if a large, bulky base is used that reacts faster with the more exposed site (Kinetic product)

Br

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Control of Regiochemistry - II
Remember that addition reactions also have several possible regiochemical outcomes:
X addition Most of the additions we looked at involved the H pi bond reacting with an electrophilic hydrogen the favored regiochemical result involved the more stable carbocation, giving this product

Several additions were studied where the hydrogen X was NOT the electrophile that initially reacted with the pi bond (HBr+peroxide, BH3 followed by oxidation), thus this regiochemical outcome was possible

Functional Group Conversions by SN2

Benefits of the SN2 Reaction

Control of stereochemistry
SN2 reaction occurs with stereochemical inversion, thus a particular stereoisomer can be produced if the correct starting stereoisomer is available

Control of carbon skeleton

SN2 reactions do not involve carbocation intermediates, therefore carbon skeleton rearrangements do not occur

Planning Synthetic Strategies

Learning Group Problem pg 528

Form small groups (2-3 people) to work on the following problem:
Write as many chemically reasonable syntheses as you can think of for ethyl 2-methylpropyl ether (ethyl isobutyl ether). Be sure that at some point in one or more of your syntheses you utilize the following reagents (not all in the same synthesis, however): PBr3, SOCl2, p-toluenesulfonyl chloride (tosyl chloride), NaH, ethanol, 2-methyl-1-propanol (isobutyl alchol), conc H2SO4, Hg(OAc)2, ethene (ethylene) Evaluate the relative merits of your syntheses on the basis of selectivity and efficiency. [Decide which ones could be argued to be the best syntheses and which might be poorer syntheses.]