Organic Synthesis

Vince Lambert H. Padilla, RPh

Instructor 1

PhCh 126 - Organic Synthesis, SS '16-'17 | VLHP

 O bje c tive s
At the end of this session, you should be able to:
 Assign the appropriate reagent to be used to protect reactive
functional groups
 Determine the reactants and intermediates given the product
 Identify the necessary reagents and reaction conditions needed in the
functionalization of compounds
 Propose a multi-step synthetic pathway from a starting material to a
desired product
 Recognize the importance of organic synthesis in drug discovery and
development

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 O utline
I. Protecting Groups
II. Retrosynthetic Analysis
III. Examples of Syntheses
IV. Reactions that Form C-C Bonds
V. Preparation of Functional Groups

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 I. P rote c ting Groups
 Protecting groups for Alcohols
 Protecting groups for Aldehydes and Ketones
 Protecting groups for Caboxylic acids
 Protecting groups for Amines

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I. P rote c ting Groups
 Purpose?

 Deprotection

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I. P rote c ting Groups for RO H
 Reactivity of Alcohols → acidic Hydrogen
 Replaced by an alkyl group
 Has to be easily removed
 Examples:
 Tetrahydropyranyl ether
 Methoxymethyl ether
 Benzyl ether
 Silyl ether

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I. P rote c ting Groups for RO H
 Tetrahydropyranyl ether
 Reagent: Dihydropyran and acid

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I. P rote c ting Groups for RO H
 Tetrahydropyranyl ether
 Acid-catalyzed alkene hydration mechanism
 Inert toward bases and nucleophiles
 Readily cleaved under acidic conditions

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I. P rote c ting Groups for RO H
 Tetrahydropyranyl ether

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I. P rote c ting Groups for RO H
 Methoxymethyl ether
 Reagent: (1) NaH, (2) Chloromethyl methyl ether

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I. P rote c ting Groups for RO H
 Benzyl ether
 Reagent: (1) NaH, (2) Benzyl bromide

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I. P rote c ting Groups for RO H
 Benzyl ether
 Stable to base and dilute acid
 Hydrogenolysis

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I. P rote c ting Groups for RO H
 Silyl ether
 Reagent: Trimethylsilyl chloride, Triethylamine

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I. P rote c ting Groups for RO H
 Exercise:
 A Grignard reagent cannot be prepared from 4-bromo-1-butanol due
to the presence of the acidic hydrogen of the hydroxy group. Show how
the use of a protecting group enables this compound to be used to
prepare 1,5-hexanediol by a Grignard reaction.

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I. P rote c ting Groups for RC H O and RC O R
 Acetals
 Reagents: Ethylene glycol or 1,3-propanediol
 Stable to basic and nucleophilic reagents

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I. P rote c ting Groups for RC H O and RC O R
 Exercise

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I. P rote c ting Groups for RC O O H
 Reactivity of Carboxylic acids → acidic Hydrogen
 Replaced by alkyl groups
 Examples:
 Simple methyl esters
 Benzyl esters
 t-Butyl esters

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I. P rote c ting Groups for RC O O H
 Simple methyl esters
 Acyl chloride or Fischer esterification
 Deprotection: Acid- or base-catalyzed hydrolysis

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I. P rote c ting Groups for RC O O H
 Benzyl esters
 Fischer esterification
 Hydrogenolysis

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I. P rote c ting Groups for RC O O H
 t-Butyl esters
 Reagent: Acid, Isobutylene

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I. P rote c ting Groups for RC O O H
 t-Butyl esters
 Cleaved by reaction with dilute acid under milder acid conditions that
simple methyl esters – SN1

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I. P rote c ting Groups for RC O O H
 Exercise
 Show the mechanism of this reaction.

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I. P rote c ting Groups for RNH 2 /R2 NH
 Reactivity of Amines → lone pair
 Addition of an acid derivative

 Examples:
 Carbamates – t-butoxycarbonyl
 Carbamates – benzyloxycarbonyl

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I. P rote c ting Groups for RNH 2 /R2 NH
 Carbamates – t-butoxycarbonyl
 Reagent: Di-t-Butyl dicarbonate, Triethylamine, DMF

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I. P rote c ting Groups for RNH 2 /R2 NH
 Carbamates – t-butoxycarbonyl
 t-butyl group of BOC can be removed by treatment with dilute acid

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I. P rote c ting Groups for RNH 2 /R2 NH
 Carbamates – benzyloxycarbonyl
 Reagent: Carbobenzoxy chloride, Base

 Hydrogenolysis

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I. P rote c ting Groups for RNH 2 /R2 NH
 Exercise
 An example of the use of a protecting group for an amine is provided
by the following reaction scheme. Show the structures of the missing
compounds, A and B, in this sequence of reactions and explain why the
final amide cannot be prepared directly, that is, by reaction of the
original amino acid with SOCl2 followed by (CH3)2NH.

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 II. Re trosynthe tic Analysis
Key terms:
 Bond disconnections
 Synthons

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II. Re trosynthe tic Analysis
 Working backward from the target compound
 The simpler compound then becomes the next target compound

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II. Re trosynthe tic Analysis
 3-methyl-1-phenyl-1-butanol OH CH3
 Bond disconnections
 Synthons
CH3

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II. Re trosynthe tic Analysis
 2-methyl-6-methylideneoct-7-en-4-ol OH CH2
 Insect pheromone

CH2
H3C CH3

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II. Re trosynthe tic Analysis

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II. Re trosynthe tic Analysis
 WHAT MAKES A GOOD SYNTHESIS?
 Time required to complete the synthesis
 Overall cost
 Environmental concerns
 % Yield

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II. Re trosynthe tic Analysis
 Exercise
 Use disconnections of carbon–carbon bonds to generate electrophile
and nucleophile synthon fragments that could be used to prepare 3-
methyl-4-heptanone. Then show an actual reaction suggested by these
synthons.

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 III. Example s of S ynthe s e s
 Synthesis of Dispalure
 Synthesis of Brevicomin
 Synthesis of Oxanamide

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III. S ynthe sis of Dispalure

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III. S ynthe sis of Dispalure

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III. S ynthe sis of Bre vic omin

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III. S ynthe sis of Bre vic omin

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III. S ynthe sis of O xanamide

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III. S ynthe sis of O xanamide

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 IV. Re ac tions that Form C -C Bonds
V. P re paration of Func tional Groups
 Reading Assignment:
 Study Tables 23.1, 23.2, and 23.3 of Organic Chemisty
(2nd Edition, 2006) by Joseph M. Hornback

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IV-V. C -C Bond Formation and Func tionalization

“Note that the purpose of Tables 23.2 and 23.3 is NOT to provide
a list of reactions for you to MEMORIZE.
Rather, use these tables as references when you are designing
syntheses.”
(Hornback, 2006, 1022-1023)

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Re fe re nc e s
 Bruice, P. (2005). Organic Chemistry (4th ed.). Prentice-Hall.
 Hornback, J. M. (2006). Organic Chemistry (2nd ed.).
Belmont, CA: Thomson Learning, Inc.
 McMurry, J. (2011). Organic Chemistry with Biological
Applications (2nd ed.). Belmont, CA: Brooks/Cole, Cengage
Learning
 Vollhardt, K., & Schore, N. (2011). Organic Chemistry: Structure
and Function (6th ed.). USA: W. H. Freeman and Company.

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TH ANK YO U FO R YO UR
PARTIC IPATIO N!


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