CHEM F311 Organic Chemistry – III

Lecture 1 – 23rd Aug. 2021

1. Course Description:
This course emphasizes on applications of important reagents and reactions in organic
synthesis and disconnection or synthon approach. In disconnection or synthon approach
the target molecule is broken down by a series of disconnections into possible starting
materials followed by synthesis.

2. Scope and Objective of the Course:

The aim of this course is to familiarize students with various common organic reagents,
expose them to some of the important transition metal catalyzed organic reactions and
retrosynthetic analysis and enable the student to design the synthesis of various
organic compounds using appropriate reagents.

3. Text Book:
TB1: Michael B. Smith & Jerry March, Advanced Organic Chemistry, John Wiley & Sons,
6th ed., 2012.
TB2: Stuart Warren: Organic Synthesis: The Disconnection Approach: John Wiley &
Sons, 2004.

Reference Books:
R1: Carruthers and Coldham, Modern Methods of Organic Synthesis, Cambridge, 4 th
edition, 2004.
R2: Fuhrhop and Li, Organic Synthesis: Concepts and Methods; Wiley, 3rd edition, 2014.
4. Course Plan:
Lec. No. Learning Objectives Topic(s) to be Covered Chap(s). No(s).

1 Introduction Organic synthesis and its applications Class notes

2-5 Common organic NaBH4 (SS), LAH (SS), DIBAL, BH3, Birch TB1: 15-13;
reagents reduction, Swern oxidation, OsO4, O3 Class notes, SS:
(SS), DMP, m-CPBA (SS), Ti(iOPr)4, self-study
Lindlar catalyst, NBS (SS), NaIO4 (SS)

6-9 Organometallic Grignard reagent (SS), organolithium Class notes,

reagents reagents (SS), organocuprates (SS), SS: self-study
organozinc reagents, organoboranes,
organosilicon reagents, organotin
compounds
10-12 Transition metal C-C bond forming reactions (Suzuki, TB1: 13-12, 13-
catalyzed organic Heck, Negishi, Sonogashira, Stille 10, class notes
reactions reaction), C-N bond forming reactions
(Buchwald-Hartwig reaction)

13 Introduction of Basic principles of disconnection TB2: 1

disconnection approach in organic synthesis
approach
Lec. No. Learning Objectives
14-16 Synthesis of aromatic
Compounds
17-24 One group C-X and
C-C disconnections
25-31 Two group C-X and
C-C disconnections
Topic(s) to be Covered Chap(s). No(s).
Basic Principles: Synthesis of Aromatic TB2: 2, 3
Compounds, The Order of Events
One Group C-X Disconnections, TB2: 4, 5, 10-16
Chemoselectivity, Synthesis of Alcohols,
General Strategy of Choosing
Disconnection, Stereoselectivity, Synthesis
of Carbonyl Compounds, Regioselectivity,
Alkene Synthesis, Use of acetylenes for
synthesis.
Two Group C-X Disconnections, Reversal TB2: 6-9, 17-28
of Polarity, Cyclisation Reactions,
Summary of Strategy, Amine Synthesis,
Diels-Alder Reactions, 1,3-Difuntionalised
Compounds and ,-Unsaturated Carbonyl
Compounds, Control in Carbonyl
Condensations, 1,5-Difuntionalised
Compounds, Michael addition and
Robinson annelation, Use of Aliphatic
Nitro Compounds in Synthesis, 1,2-
Difuntionalised compounds, FGA and its
Reverse, Reconnections, 1,4- and 1,6-
Difuntionalised Compounds, Strategy of
Carbonyl Disconnections.
Lec. No. Learning Objectives Topic(s) to be Covered Chap(s). No(s).

32-38 Ring synthesis Introduction to Ring synthesis, TB2: 29, 30, 34,
(saturated Synthesis of three, four, five and six 36, 37
heterocycles) membered Rings and general strategy of
Ring Synthesis
39-40 Synthesis of Aromatic Heterocycles TB2: 39
heterocyclic
compounds
 5. Evaluation Scheme
Component Duration Weightage (%) Date and Time Remarks
Midsem. Test 90 min 30 22/10/2021 3.30 - 5.00PM Closed Book

Class tests* 25 min 20 Continuous Closed Book

Assignment# 10 Open Book

20 % Closed book
Comprehensive Partially
120 min + 24/12 FN
Examination Open Book
20 % Open book

*Six class tests will be conducted at regular intervals. Best four will be considered.
Make Up is not permissible for class tests.

One home assignment would be given and each student is expected to submit (last
#

week of Oct) a handwritten scanned report (5 %) (approx 7-8 pages) on the

assigned topic. Online VIVA (5 %) will also be conducted based on the assignment.

Note: Active and regular participation in class discussions is expected from each student.
6. Chamber Consultation Hour: Thursday, 11.00-12.00 noon
 What is Organic Chemistry?
Largest area of specialization among the various fields of chemistry
Synthetic Organic Chemistry

· Pharmaceutical Chemistry
· Polymer Chemistry
· Dye and Textile Chemistry
· Pulp and Paper Chemistry
· Agricultural Chemistry
· Formulation Chemistry (paint, food, petroleum products, adhesives, etc.)

Physical Organic Chemistry

Correlates the physical and chemical properties of compounds
with their structural features.
 What is Organic Synthesis?
 Intentional construction of molecules by means of chemical
reactions.
 A synthesis is a specific sequence of chemical reactions that
converts starting materials into the desired compound, called the
target of the synthesis (or the synthetic target).
Target

Synthesis is championship of
human being against nature.

The order in which you do

things to reach target is known
as method.

Method
 R.B. Woodward (1917-1979)

• 1st modern synthetic organic chemist

• Probably greatest organic chemist

•1965 Nobel Prize in Chemistry.

•Outstanding achievements in the art of organic synthesis
•Also made VERY important observations in the development of the
Woodward-Hoffman rules of ring closure
•1st step in application of quantum mechanics to organic molecules
•1981 Nobel Prize in Chemistry (Roald Hoffmann)
 R.B. Woodward (1917-1979)
Robert Burns Woodward, who received the 1965 Nobel Prize
in Chemistry for several total syntheses (e.g., his 1954
synthesis of strychnine), is regarded as the father of modern
organic synthesis.
During the late 1940s, Woodward synthesized many complex
natural products: quinine, cholesterol, cortisone, strychnine,
lysergic acid, reserpine, cephalosporin and colchicine.

quinine
cholesterol cortisone
R.B. Woodward (Early Career 1940’s…)
R.B. Woodward (Later Career…)

Vitamin B12
1972
 K.C. Nicolaou

 Penn (1977-1989)
 Scripps Research Institute and
UC-San Diego (1989-2012)
 Currently at Rice University since
2013
 Modern day R.B. Woodward

 He is the author or co-author of more than 790 scientific articles, reviews, and book
chapters, 79 patents, and five books.

 He holds 10 honorary degrees from universities around the world.

 Several hundreds of PhD students and postdoctoral fellows.

 K.C. Nicolaou
Taxol (1994)
• Isolated in 1967 from bark of Pacific yew tree
• Anti-Lung, ovarian, breast, head and neck cancer activity

11 stereocenters => 211 = 2048 stereoisomers

2 rings & 1 bicyclic ring
 K.C. Nicolaou
Brevotoxin B (1995)
• Neurotoxin that binds to voltage-gated
sodium channels in nerve cells
• Naturally found in Karenia brevis which are
marine organisms typically found in fish
23 stereocenters => 223 = 84,00,000
stereoisomers
11 trans-fused rings
90 steps, 12 years
93% yield for each step but 0.14% overall yield
 Epibatidine

~200 times more potent analgesic compared to morphine.

Several total syntheses have been devised due to the relative

scarcity of epibatidine in nature

less than 15 mg isolated from 750 frogs

withdrawn from Phase II trials

Palytoxin was isolated in 1971 in Hawaii by Moore and Scheuer from deadly
seaweed of Hana. It is one of the most toxic compounds known requiring only
about 0.15 microgram per kilogram for death by injection.

40 hydroxy groups
64 chiral centers
1021 stereoisomers
 Why do people synthesize organic molecules?
 Prove structure of a natural product
 Prove it can be synthesized in laboratory
 Gain insights to reactivity based on structure 1930-1975
 Test synthetic methodology
 Physical organic chemical studies

Synthesis these days is done for all of the above reasons & to

 Construct nanostructure
 Apply or test a biological utility or theory
 Gain enough synthetic knowledge of the molecular architecture of
natural product to be able to make analogues for drug testing.
 For organic synthesis
The targets can be natural products……….

Swinholide A
Antibiotic of last resort against Cytotoxic potent activity against
drug resistant bacteria MDR resistant carcinoma cell lines
J. Am. Chem. Soc.1999, 121, 10004-10011
J. Am. Chem. Soc. 2016, 138, 14246−14249
The targets can be compounds with interesting activities……….

Parathion
insecticide
Fluoxetine, Prozac
Aspirin anti-depressant

Indinavir, Crivixan
anti-HIV

Allura red
red pigment

Bedaquiline, Sirturo
anti-TB
Doxorubicin, Adriamycin
anti-cancer
The targets can be compounds with interesting activities……….
Remdesivir
Anti-viral
DOI: 10.1056/NEJMoa2007764
NEJM - 22 May 2020

Developed as a treatment for Ebola, remdesivir

interrupts replication of viral RNA and is one of the
more promising agents being tested against coronavirus

Favipiravir is approved for treating influenza and is

proposed to act by inhibiting a viral RNA polymerase
enzyme, hence stopping the virus replicating its RNA

Ivermectin is a lipophilic macrolide usually used

as a broad-spectrum anti-parasitic drug. In
Tocilizumab is a recombinant humanized
parasites, it acts by binding glutamate-gated
monoclonal antibody IL-6 receptor
chloride ion channels, which leads to
inhibitor used to treat inflammatory and
depolarization of the cells and paralysis the
autoimmune conditions
parasite. When directed against COVID-19, is
thought to work by binding and destabilizing cell-
transport proteins used to enter the nucleus.
 4 years 5.5 years 11 years 12.5 years

For every 25,000 compounds that start in the laboratory, 25 are tested in
humans, 5 make it to market and just one recoups what was invested.
Phase I trials, usually in healthy volunteers, determine safety and dosing.

Phase II trials are used to get an initial reading of efficacy and further
explore safety in small numbers of sick patients.

Phase III trials are large, pivotal trials to determine safety and efficacy in
sufficiently large numbers of patients.
Costs for one drug molecule vary from around $500 million to $2
billion depending on the therapy or the developing firm.
The targets can be compounds with artistic & anthromorphic
attributes………….

Journal of Organic Chemistry, 2003, 68, 8750

 Ξ

Any complex cyclophane having multiple

Superphane Pagodane (C20H20)
aromatic rings and a cagelike structure.

Betweenanenes Bicyclic alkenes having a double bond between the bridgehead

atoms and a trans attachment of each branch to the double bond.
They are planar-chiral and have an extremely sterically hindered
double bond.
Knowing how to make molecules is not enough just like knowing how
to speak and write is not enough — you have to have something
worthwhile about which to speak or write

To do this you need to know something about chemistry & science

that can often be far away from synthesis……

Synthesis is the central area of organic chemistry where the chemist’s

art and imagination are involved.

Involves two vital parts:

1) Proper planning which involves disconnection or retrosynthetic
analysis of target molecule

2) Knowledge of various chemical transformations and the reagents.