Biotech 4

Strategy in Chemical Synthesis:

Retrosynthetic Analysis and Synthesis Design

Roman LOPEZ 2022

 Retrosynthetic Analysis and Synthesis Design

Synthetic Organic Chemistry:

Importance of Organic Synthesis

Total synthesis of Industrially relevant molecules
Total synthesis of Natural compounds

Compounds of theoretical interest

Proof of structure

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 Retrosynthetic Analysis and Synthesis Design
Synthetic Organic Chemistry - the demand on Natural products:
Natural products is one of the most important sources of bioactives molecules, only available
in very low quantities.

Example of Natural sources of anticancer compounds

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 Retrosynthetic Analysis and Synthesis Design
Synthetic Organic Chemistry - the demand on Natural products:
Larger quantities required for screening / biological experiments and safety requirements

(+) Azaspiracid 1

AzaspiracidProtoperidinium crassipes

Causative agent of human

poisoning Synthetic compound needed
for GC monitoring in fisheries

Bryostatin 1
Bugula neritina

Bryostatin 1
1 ton of bryozoans organisms lead to 1 g of bryostatin 1

Bugula neritina

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 Retrosynthetic Analysis and Synthesis Design
Synthetic Organic Chemistry - the demand on Natural products:
Larger quantities required for screening / biological experiments and safety requirements
Discodermolide Discodermia dissoluta

Novartis
extreme
scarcity of natural sources (0.002% w/w from frozen
marine sponge),
(+) Discodermolide

60-g total synthesis with an overall yield of 0.65%

Salinosporamide A

Salinispora tropica Salinispora arenicola

Salinispora tropica In 2013, Marizomib received approval as Orphan Drug for glioblastoma and (+) Salinosporamide A
multiple myeloma treatments.

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 Retrosynthetic Analysis and Synthesis Design

The birth of total Synthesis

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 Retrosynthetic Analysis and Synthesis Design
Total synthesis: the modern Era
Erythromycin so hopelessly
difficult that its conquest cannot be
conceived within a foreseeable future

Erythromycin A

RB Woodward died in July 1979

Kishi

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 Retrosynthetic Analysis and Synthesis Design
Total synthesis: the modern Era

Calicheamicin

Monensin

Maytansine

(±) Longifolene

Epothilone B

(+) Calyculin A Spongistatins

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 Retrosynthetic Analysis and Synthesis Design
Total synthesis: the modern Era
Palytoxin

0.15 µg/kg for death

1971
1981 revised

Total Synthesis (Kishi, Harvard) 1989

J. Am. Chem. Soc 1989

the largest single molecule

Roman LOPEZ Biotech 4

 Retrosynthetic Analysis and Synthesis Design

Roman LOPEZ Biotech 4

 Retrosynthetic Analysis and Synthesis Design
Trends in organic Synthesis: key Nobel Prizes

The Nobel Prize in Chemistry

was awarded jointly to
, and
"for the
development of the metathesis
method in organic synthesis."»

(Max Planck Institute)

and Princeton University’s
were awarded with the
for « the development of
asymmetric organocatalysis »

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 Retrosynthetic Analysis and Synthesis Design

Retrosynthetic Analysis:

retrosynthesis
E. J. Corey
based on known reactions

there was no formalized approach

trial and error

retrosynthesis helps
in discovering

efficient
industrial

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 Retrosynthetic Analysis: definitions

Organic Synthesis or Chemical synthesis:

Target molecule TM TGT

Total synthesis:

Formal total synthesis:

Retrosynthetic Analysis or Retrosynthesis

disconnecting
to assess

A B
A could/can be obtained from” B

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 Retrosynthetic Analysis: definitions

Functional group interconversion (FGI)

Disconnection

Disconnection is represented by a wavy or dot ( or ) line.

Synthon

“synthon”
Synthetic equivalent (retron) real
Reagent

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 Retrosynthetic Analysis: definitions
Starting materials

Databases www.emolecules.com

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 Retrosynthetic Analysis and Synthesis Design
Retrosynthetic Analysis

Not exactly

artistic activity
beauty or elegance

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 Retrosynthetic Analysis and Synthesis Design
The logic, the tactics, the art

Roman LOPEZ Biotech 4

 Retrosynthetic Analysis and Synthesis Design
Synthesis Retrosynthesis
FGI

Backward / Transform
vs
Forward / Reaction

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 Requirements of a good synthetic route

Short
- Convergent synthesis involving the assembly of fragments

high yielding
readily available
Flexible

Optional: General

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 Linear vs Convergent Synthesis 1/2

Linear Synthesis:

Convergent Synthesis:

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