Retrosynthetic Analysis of Organic Synthesis Introduction Synthetic Methods Total Synthesis by Retrosynthetic Analysis

Introduction

Synthetic Methods

Total Synthesis by Retrosynthetic Analysis

Retrosynthetic (or antisynthetic) analysis is a problem-solving technique for transforming the structure of a synthetic target (TG) molecule to a sequence of progressively simpler structures along a pathway which ultimately leads to simple or commercially available starting materials for a chemical synthesis. The transformation of a molecule to a synthetic processor is accomplished by the application of a transform, the extract reverse of a synthetic reactions. E. J. Corey, 1989

Retrosynthetic (or antisynthetic) analysis is a problem-solving technique for transforming the structure of a synthetic target (TG) molecule to a sequence of progressively simpler structures along a pathway which ultimately leads to simple or commercially available starting materials for a chemical synthesis. The transformation of a molecule to a synthetic processor is accomplished by the application of a transform, the extract reverse of a synthetic reactions.

E. J. Corey, 1989

Retrosynthetic analysis Disconnection of T.M. Intermediate Starting material Synthesis tree

3.2 Common terms in retrosynthetic analysis FGI ( functional group interconversion) disconnection ： ~~~~ position ；  process synthons: fragments from disconnection synthetic equivalents: reagents as synthons

FGI ( functional group interconversion)

disconnection ： ~~~~ position ；  process

synthons: fragments from disconnection

synthetic equivalents: reagents as synthons

Factors in Design of Synthesis Cheapest starting material Least number of steps High Yield In commercial syntheses, costs of starting materials and economy of operations play a dominant role, whereas in many syntheses carried out for research purposes, the dispatch with which a compound can be obtained is more important.

Cheapest starting material

Least number of steps

High Yield

In commercial syntheses, costs of starting materials and economy of operations play a dominant role, whereas in many syntheses carried out for research purposes, the dispatch with which a compound can be obtained is more important.

Reactions involved in Synthesis Skeleton construction- construction from smaller units called synthons Functional alteration- interconversion of the functional groups on the skeleton .

Skeleton construction- construction from smaller units called synthons

Functional alteration- interconversion of the functional groups on the skeleton .

Major Ionic Reactions for Carbon

Pericyclic Reactions Diels-Alder Reaction [2+2] Cycloaddition Reaction Cope and Claisen Rearrangements

Diels-Alder Reaction

[2+2] Cycloaddition Reaction

Cope and Claisen Rearrangements

Rearrangements Useful in Synthesis

Criteria for Evaluating Synthetic Methods Convergent Synthesis- two or more fragments of the molecule are assembled separately and are then brought together at a late stage in the synthesis Linear Synthesis – the molecule is constructed in a stepwise fashion.

Convergent Synthesis- two or more fragments of the molecule are assembled separately and are then brought together at a late stage in the synthesis

Linear Synthesis – the molecule is constructed in a stepwise fashion.

Key Points in Designing Synthesis The relationship between functional groups in a target molecule may reveal disconnections in the retrosynthetic analysis. Other disconnections may be revealed by functional group interconversions. The identification of particular rings may suggest specific strategies A convergent synthesis has significant advantages over a linear synthesis.

The relationship between functional groups in a target molecule may reveal disconnections in the retrosynthetic analysis.

Other disconnections may be revealed by functional group interconversions.

The identification of particular rings may suggest specific strategies

A convergent synthesis has significant advantages over a linear synthesis.

Grignard and related organometallic reagents Grignard reagents (RMgX) Organozinc reagents Alkyl- and aryl-lithium compounds Organocopper reagents Organopalladium reagents

Grignard reagents (RMgX)

Organozinc reagents

Alkyl- and aryl-lithium compounds

Organocopper reagents

Organopalladium reagents

Organometallic and Ylide Methods of Carbon-Carbon Bond Formation

Stereochemistry of Grignard Addition

Orthometallation Cross Coupling (Suzuki Rxn 1,4-Addition

Acetylides and Nitriles

Wittig Reaction

Carbonyl Activation and Enolate Chemistry in Carbon-Carbon Bond Formation

Regiospecificity in Enol Ether Formation

Carbanion Generators

Alkylation of Carbanion CH 3 -OSO 2 F methyl fluorosulfonate oxirane (epoxide) CH 3 -OSO 2 O-CH 3 dimethyl sulfate (R-OTs) toluene-p-sulfonates (or tosylates) R-OSO 2 CH 3 (R-OMs) methanesulfnates (or mesylates) R-X alkyl halide Structure Alkylating agent

Enolate Anions in Carbonyl Addition Reactions Aldol Condensation-the electron-deficient carbon is an aldehyde or ketone and the product is a  -hydroxy ketone or an  ,  -unsaturated ketone Claisen Condensation- the electron-deficient carbon is an ester carbon and the product is a 1,3-diketone or  -keto ester. Michael Condensation (addition)- the electron-deficient carbon is the b-carbon of an  ,  -unsaturated ketone and the product is a 1,5-diketone.

Aldol Condensation-the electron-deficient carbon is an aldehyde or ketone and the product is a  -hydroxy ketone or an  ,  -unsaturated ketone

Claisen Condensation- the electron-deficient carbon is an ester carbon and the product is a 1,3-diketone or  -keto ester.

Michael Condensation (addition)- the electron-deficient carbon is the b-carbon of an  ,  -unsaturated ketone and the product is a 1,5-diketone.

Aldol Condensation

Claisen Condensation

Michael Addition

4. Robinson annulation - a special class of Michael additions which lead to one six-membered ring fused to another

Functional Group Interconversion Dehydrogenation Rxn- Sulfur, Selenium, DDQ, Chloranil Oxidation of Alcohols- Chromium (VI), Swern Oxidation, Dess-Martin periodinane oxidation Oxidation of alkenes-Epoxidation, O3, OsO4 Bayer-Villiger Oxidation

Dehydrogenation Rxn- Sulfur, Selenium, DDQ, Chloranil

Oxidation of Alcohols- Chromium (VI), Swern Oxidation, Dess-Martin periodinane oxidation

Oxidation of alkenes-Epoxidation, O3, OsO4

Bayer-Villiger Oxidation

General Pattern of Reduction

Reductions with Hydride Reagents

Carbocations in Synthesis Friedel-Craft Alkylation, Acylation Prins Reaction- alkene (aromatic) + H 2 CO, conc. HCl, ZnCl 2 Mannich Reaction- H 2 CO, N(CH 3 ) 2 , Ketone ( generate  ,  -unsaturated ketone )

Friedel-Craft Alkylation, Acylation

Prins Reaction- alkene (aromatic) + H 2 CO, conc. HCl, ZnCl 2

Mannich Reaction- H 2 CO, N(CH 3 ) 2 , Ketone ( generate  ,  -unsaturated ketone )

Free Radical and Pericyclic Reactions Benzoyl peroxide, AIBN (azobisisobutyronitrile) – Polymerization AIBN/Bu 3 SnH – cyclization reaction Carbene Formation- CH 2 I 2 , Zn/Cu (Simon-Smith Rxn)

Benzoyl peroxide, AIBN (azobisisobutyronitrile) – Polymerization

AIBN/Bu 3 SnH – cyclization reaction

Carbene Formation- CH 2 I 2 , Zn/Cu (Simon-Smith Rxn)

Alkene Metathesis Grubb’s Catalyst- using this catalyst, the reaction between two alkenes, a=b and c=d, the bonding partners are interchanged to give a=c and b=d.

Grubb’s Catalyst- using this catalyst, the reaction between two alkenes, a=b and c=d, the bonding partners are interchanged to give a=c and b=d.

Protection Groups 1. Protection of alcohol a. Methylethers (allyl ether, benzyl ether, triphenylmethyl ether, methoxymethyl ether b. Silyl ethers (trimethyl silyl, triethylsilyl, TBDMS c. Protection of Carboxylic Acids 2. Protection of Carboxylic Acids 2,2,2-trichloroethyl ester  -(trimethylsilyl)ethoxymethyl ester 3. Protection of Carbonyl Groups Formation of 1,3-dioxolanes from ethane-1,2-diol (provide selectivity for compounds containing two carbonyl groups Formation of thioacetals from ethane-1,2-dithioacetal (needs Hg or Cd salts) Amino Groups N-terminal – Cbz or Z (benzyloxycarbonyl), Boc (t-butoxycarbonyl) – stable to basic condition 9-fluorenylmethoxycarbonyl (Fmoc)- acid stable but base labile C-terminal- activation with DCC (Dicyclohexylcarbodiimide

1. Protection of alcohol

a. Methylethers (allyl ether, benzyl ether, triphenylmethyl ether, methoxymethyl ether

b. Silyl ethers (trimethyl silyl, triethylsilyl, TBDMS

c. Protection of Carboxylic Acids

2. Protection of Carboxylic Acids

2,2,2-trichloroethyl ester

 -(trimethylsilyl)ethoxymethyl ester

3. Protection of Carbonyl Groups

Formation of 1,3-dioxolanes from ethane-1,2-diol (provide selectivity for compounds containing two carbonyl groups

Formation of thioacetals from ethane-1,2-dithioacetal (needs Hg or Cd salts)

Amino Groups

N-terminal – Cbz or Z (benzyloxycarbonyl), Boc (t-butoxycarbonyl) – stable to basic condition

9-fluorenylmethoxycarbonyl (Fmoc)- acid stable but base labile

C-terminal- activation with DCC (Dicyclohexylcarbodiimide

Retrosynthesis

Synthesis