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Chemistry 634: Advanced Organic Chemistry – Synthesis and Reactivity
Fall 2013, University of Delaware
Lecture: Tuesday and Thursday, 2-3:15p, Brown Lab (BRL) 116
Office hour: By appointment.
Please see printed syllabus for more details.
Website: http://www.udel.edu/chem/dawatson/classes/Chem634_F13/Chem634_F13-home.html
Required Text:
Strategic Applications of Names Reactions in Organic Synthesis. Kurti, L.; Czako, B.
Advanced Organic Chemistry, Part B: Reactions and Synthesis.
Carey, F. A.; Sundberg, R. J.
Classics in Stereoselective Synthesis. Erick M. Carreira, Lisbet Kvaerno
Recommend Texts (Optional):
Advanced Organic Chemistry · Part A: Structure and Mechanisms Carey, F. A.; Sundberg, R. J.
March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6th Edition Smith,
M. B.; March, J.
I have requested that all three of these texts reserve in the Chemistry Library this semester.

Required :
Strategic Applications of Names Reactions in Organic Synthesis. Kurti, L.; Czako, B.
Advanced Organic Chemistry, Part B: Reactions and Synthesis.
Carey, F. A.;
Sundberg, R. J.
Classics in Stereoselective Synthesis. Erick M. Carreira, Lisbet Kvaerno
Recommend (Optional):
Advanced Organic Chemistry · Part A: Structure and Mechanisms Carey, F. A.;
Sundberg, R. J.
March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6th
Edition Smith, M. B.; March, J.
I have requested that all three of these texts reserve in the Chemistry Library this semester.

Comprehensive Organic Transformations: A Guide to Functional Group
Preparations, 3rd Edition Larock, R. C.
Stereochemistry of Organic Compounds Eliel, E.; Wilel, S. H.
Protective Groups in Organic Synthesis, 4th Ed, Greene and Wuts
Transition Metals in the Synthesis if Complex Organic Molecules, 3 rd Ed,
Hegedus, L. S.
The Logic of Chemical Synthesis, Corey, E. J.; Cheng, X.
I have requested that all these texts reserve in the Chemistry Library this semester.

REQUIRED!
I do not care what model kit you have.
HGS Models – Nice but expensive
Darling – okay at best, but cheap

Breakdown:
Midterm Exam 340 points, 34%
Final Exam 340 points, 34%
Final Project (Written) 100 points: 10%
Final Project (Presentation) 100 points: 10%
Problem Sets 120 points, 12%
Total: 1000 points
All requests for regrades must be submitted in writing within 24 hours of the material being returned. Please note, the entire exam will be regraded – if grading errors are found the final grades may be higher or lower than original score. Also note, photocopies may be made prior to returning exams. If answers are altered, it will be obvious and provable (see below).

Six Problems Sets
Graded
12% of grade
Will likely only pick one or two problems to grade – see syllabus for details.
DO NOT USE DATABASES TO ANSWER
QUESTIONS UNLESS ASKED TO DO SO
Two Exams
Midterm in class – Oct 15 - will be shorter than previous years.
Final – 3 hours, time TBD.
34 % of grade each
Closed book.

There will be a short term paper and presentation to class.
10% of grade, each
Details in syllabus
Outline (25% of written grade, due Oct 22 )
Presentation will be on SATURDAY Nov. 23 rd from 9a-2pm
If you can not attend this, I need to know by the end of this week
Topic sign-up list is on my office door, first come, first serve
Paper Due Dec 3 rd .

On Sept 10 th , we will meet in 221 BRL to learn to use computer databases in computer lab.

My assumption is that you understand and can efficiently push arrows.
The 12-step guide to arrow pushing (adapted from Prof. Keith Woerpel, NYU):
1)   Electrons flow from sites of high electron density to sites of low electron density (show arrows accordingly).
2)   Balance the equation. It helps.
3)   Don’t violate basic rules of physics.
a.
Converse mass and energy (see rule 2) b.
Conserve charge
4)   Three Arrow Rule: Don’t push more than 3 arrows at one time
5)   Draw out all intermediates.
a.
It may seem tedious at time, but it will avoid mistakes and often reveal new insights.
b.
3-D depictions may help. Use models if needed.
6)   Use your lone pairs (often the site of FMO’s).

7)   All steps are, in principle, reversible.
8)   Contemplate your options and carry each to its conclusion before discarding (this is seriously useful advice).
9)   The correct mechanism gives the observed product (should not be taken to mean that all mechanisms that lead to the product are necessarily correct).
10)   Use connectivity to tell you how the puzzle fits together.
a.
Number atoms logically b.
“Principle of least action” usually holds.
11)   Always identify the nucleophiles and electrophiles at each step. a.
At times it may be useful to substitute oxidants and reductants above.
12)   Work backwards from the product to the likely precursors.

•   Pharmaceuticals and Medicines
•   Biology and Biological Probes
•   Electronics
•   Bioconjugation - for proteomics
•   Mechanism Questions
•   Inorganic Chem – ligands
•   Polymers & Materials
•   Agrochemicals
•   Energy Problems
All require complex organic molecules.

Unnatural
Natural
N N
N N
Me
(Xanax-Upjohn)
Alprazolam
(anxiety)
O
Me OH
H H
H H testosterone
Me Me O
O
H
2
N
NH
2
(Tamiflu- Gilead)
Oseltamin
OEt
O
HO
H
HO
O
O
O
Me OH O
O
O
H ginkgolide B
(EJ Corey, 1967, 31 steps)

EJ Corey, Harvard University
1990 Nobel Prize In Chemistry
•   size
•   topology
•   functional groups
•   atom content
•   stereochemistry
•   functional
•   group density
•   stability/reactivity

Molecules are made from other molecules
(occasionally with the use of elemental reagents)
O
O
H
2
N NH
2
OEt OEt
O
Me Me heat
O
O
HN NH
O
Me Me
C
8
H
12
N
2
O
3
Barbital (early drug)
Bayer, 1904
(Emil Fisher)
This means we need to know how molecules react so we can predict who they will go together.

1)   Yield:
Consider a three step sequence:
A B C
If average yield is 90%, what is the over all yield?
0.9 X 0.9 X 0.9 = 0.73
73% overall yield => 1/4 of the material is lost
If 70% (more realistic), you will get 34% overall yield, 2/3 lost.

2) Length
15 steps at 70% = 0.47% overall (999/1000 SM lost)
Means that you need to start with 1000 times the material you need!
Also, in lab: Each step is 2-4 weeks (minimum) sometimes years
Longer if new

3) Convergence
Consider:
A B C D
5 steps @ 70% = 17%
E
A
D then
B
E
C + G
F
C
G
F
Now Consider: longest sequence now 3 steps
70% average per step is 34% yield
2X material

4) Selectivity (many types)
Chemoselectivity (which group)
+
O
Me has 2 pi bonds
O
Me vs.
Favored
O
Me

4) Selectivity (many types)
Me
+
O
Me
Regioselectivity (which site)
Me
Favored
O
Me vs.
Me regioisomers
O
Me

4) Selectivity (many types)
Diastereoselectivity (which diastereomer)
Me
+
O
Me
Me O
Me vs.
Me O
Me exo diasteromers endo
Favored

4) Selectivity (many types)
Enantioselectivity (which enantiomer)
Me
+
O
Me
Me O
Me vs.
Me O
Me enantiomers

5) Precedent
What is known in the literature and how close is the analogy to the reaction you want to do?
1 hour in library = 1 month in lab
Exact vs. Close
If close, consider FG, ring size, substituents, stereochemistry
ALL can effect outcome

5) Other Factors waste stream, cost, toxicity, contaminates, safety, scale, starting material availability, intellectual property issues, etc.

Molecules can be complex, requires rational approach to prepare them.
Retrosynthetic analysis is used to plan routes to target molecules.
Focus of Chem 635, but we need rudimentary understanding here

N
Me tropinone
O
"disconnection arrow"
2 CO
2 H
2
2
O
O
H
H
+ MeNH
2
+
CO
2
H
O
O
CO
2
H
Sir Robert Robinson
"imaginary hydrolysis”
Now called disconnection: means to work backwards
Robinson JACS , 1917 , 111 , 762

Robinson JACS , 1917 , 111 , 762
Author, Journal, Year , volume , page
JACS = J. Am. Chem. Soc. = Journal of the American Chemical Society

E.J. Corey
Harvard University
Nobel Prize 1990
"Retrosynthetic analysis" - 1960’s codified strategy to “disconnecting” a target back to starting materials work backwards approach very successful way to think about how to prepare molecules

1) maximize convergence
2) minimize steps
a) look at multiple routes
b) avoid functional group interconversion (FGI) & protecting groups
when possible
3) add FGs if they can help
4) C–X & C–CX bonds are usually good disconnections
5) disconnect stereocenters when possible (clear them)

6) minimize medium & large rings (or have a really good plan)
Me
O
Michael
O
H
Wieland-Miescher Ketone
Me
O
O poor: 10 membered ring
H
2 or H -
Functional Group Addition
(FGA)
Me
O aldol
Me
O
O base
O
O
Me
Robinson Annulation
Michael base O Me
Me
+
O
O

6) minimize medium & large rings (or have a really good plan)
O
O
O
Me
Me
( ± periplanone B)
PO
O
Me
Me
PO
OH
Me
Me
WC Still JACS , 1979 , 101 , 2493

7) disconnect unstable groups early
O OH
N
H
Indolizomycin unstable at pH 7, rt
Me
Me
O O
Me
3
Si
O
N
O
H
FGI O
TEOC
N
H
Note: the molecule requires medium ring disconnection! Needed a good plan.
MeO
Me
3
Si
O
Cl
N
O
H
Danishefsky (Columbia)
JACS , 1990 , 112 , 2003

O
O
O
O
8) Recognize embedded symmetry
Me
Me
O
( ± ) carpanone
H
O
O
O
Me
[4+2]
Me
O Me
=
O
O
O
O
O O
Me
O
O
O
2 steps
O
O
OH
O.L Chapman
JACS , 1971 , 93 , 6696

9) identify embedded "complex" molecules
H
Me Me
Me
=
O
Me
Me
O
Me
N
H
Me
O
Me
(S)-carvone
(S)-carvone comes from caraway seeds.
Obtaining chiral centers from readily available natural product starting materials is often called "chiral pool” strategy.
Baran (Scripps), Nature , 2007 , 446 , 404

10) use topology (shape) of molecule to guide disconnections
HO
O
HO
(–) morphine
NMe
OMe
OH
=
MeN
MeN Pd
H
Heck tandem reaction
MeN
H
Pdπ -allyl
OH
O
OH
H
FGI/FGA
MeN
H
I
OMe
OH
=
H
O
OMe
MeO
OH
I
NP
Build Models!!!!! Overman (Irvine)
Pure & Applied Chem 1994 , 66 , 1423