Multi-step Organic Synthesis

Conversion of existing molecules into other useful molecules. Pharmaceuticals Natural sources: petroleum natural gas natural products Commercial sources Textiles Etc. Etc. Little molecules ----> big molecules Synthesis of unnatural products Modification of existing structures Synthesis of rare and useful natural products Polymers Gasoline

Example: Paclitaxel (taxol): anticancer drug and rare natural product

O O O N H H OH HO Ph O O H O O O H O H O

O H OH

Example #2: Synthesis of indynaprost from cyclopentadiene

into

HO2C

O H H

HO

HO

Cyclopentadiene

Indynaprost (Experimental platelet aggregation inhibitor)

Lecture Supplement: Multi-step Organic Synthesis

Fundamental Synthesis Operations C-C bond formation functional group interconversions (FGI): oxidation reduction substitution elimination addition others

skeletal rearrangements protection/deprotection

Keys to Doing Synthesis Problems Use reactions you know (flash cards) Keep an eye on the requirements of the problem: Can I solve the problem in one step from where I am? Think backwards: retrosynthesis (E.J. Corey, Harvard, Nobel Prize in Chemistry, 1990) Retrosynthesis (Coreys definition): a problem solving technique for transforming the structure of a synthetic target molecule to a sequence of progressively materials along a pathway which ultimately leads to a simple or commercially available starting material for chemical synthesis

Practice Sample Problem #1

Practice

Practice

Practice

from

Target molecule

Starting material

Hint: Unless otherwise specified, any other reagents can also be used.

Lecture Supplement: Multi-step Organic Synthesis

Can the target molecule be made from the starting material in one reaction?

one step ??? Ph

Ph

Analysis: No change in carbon count FGI: alkene aldehyde How to make an aldehyde? Alkene ozonolysis (alters carbon count) Oxidation of a primary alcohol (carbon count unchanged) Hint: Flash cards may suggest reactions to carry out the desired FGI.
H O OH

oxidation Ph

Ph

means: "thinking backwards" "the molecule on the left could be made from the molecule on the right by the reaction above the arrow" Can the new target molecule (the alcohol) be made in one step from the starting alkene?
OH

hydroboration Ph

Ph

Complete Retrosynthesis:
H O OH hydroboration Ph Ph

oxidation

Ph

Forward Direction: Fill in the reaction details Carefully check each step: stereochemistry, carbocation rearrangements, etc.

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Lecture Supplement: Multi-step Organic Synthesis

oxidation PCC

OH hydroboration Ph 1. BH3 2. H2O2, NaOH

Ph

Ph

Or:
1. BH3 2. H2O2, NaOH Ph Ph OH PCC H O

Ph

Sample Problem #2
CH3S

HO

from
Ph OCH2CH3

Ph

Can the target molecule be made from the starting material in one reaction? Analysis: Target has three more carbons than starting material, but no new C-C bonds. FGI: Alcohol thioether Alkene ether How to make an ether? SN2 with CH3 CH2 O SN2 with RO- and CH3 CH2 I Alkoxymercuration
CH3S Ph OCH2CH3 Williamson CH3S Ph OH

Can the target molecule be made from the new starting material in one reaction? How to make an alcohol? SN2 with HO Alkene hydration Nucleophilic addition to epoxide
CH3S Ph OH oxymercuration CH3S Ph

Lecture Supplement: Multi-step Organic Synthesis

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Can the target molecule be made from the new starting material in one reaction? How to make a thioether? SN2 with RS- (Must first convert OH into LG)
CH3S Ph CH3S- SN2 TsO Ph TsCl Ph HO

Complete Retrosynthesis
CH3S Ph CH3S- SN2 Ph CH3S Ph TsCl Ph HO oxymercuration OH CH3S Ph

Williamson OCH2CH3 TsO

Forward Direction

HO Ph CH3S Ph OH

TsCl pyridine Ph

TsO

Na SCH3 CH3S Ph CH3S Ph OCH2CH3

1. Hg(OAc)2, H2O 2. NaBH4

1. NaH 2. CH3CH2I

Shorter Forward Direction: Alkoxymercuration achieves the alkene ether conversion in just one step
1. Hg(CF3CO2)2, CH3CH2OH 2. NaBH4

HO Ph CH3S Ph

TsCl pyridine Ph

TsO

Na SCH3 CH3S Ph

OCH2CH3

Hint: Thorough reaction knowledge increases flexibility and simplifies synthesis problems. Some problems might not be doable without good mastery of reactions!

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Lecture Supplement: Multi-step Organic Synthesis

Sample Problem #3
C N

into
O

Can the target be made in one step from the given starting material? Analysis: New C-C bond between ring and nitriles FGI: Alkene ether + nitrile + another alkene, with trans stereochemistry How to make a nitrile? SN2 with -CN and alkyl halide, alkyl sulfonate, or epoxide How to make an ether? SN2 with RO oxymercuration with ROH Williamson ether synthesis Several routes to consider. Pick one and explore it! The trans relationship of the ether and nitrile groups suggests an epoxide opening.
C N C N
-

Williamson

CN (SN2)

OH

Can the new target molecule (the epoxide) be made from the original starting material (alkene) in one step?
RCO3H O

Complete Retrosynthesis
C N Williamson C N -CN (S 2) N O RCO3H

OH

Forward Direction
CH3CO3H C O KCN CH3OH OH N 1. NaH 2. Br C N

Lecture Supplement: Multi-step Organic Synthesis

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