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Paul Bracher Chem 30 – Synthesis Review
Guide to Solving Sophomore Organic Synthesis Problems
Disclaimer
Omission of a topic on this handout does not preclude that material from appearing on the final exam. Any material that we have covered in lecture, in a problem set, or in the book is fair game. The exam is cumulative and may include information from previous exams and Chem 20. I have not seen the exam and the concepts discussed here are my personal choices for what I believe to be especially pertinent to synthesis on the exam. Have a nice day.
Undergraduate Organic Synthesis vs. “Real” Organic Synthesis
The synthesis problems you encounter in undergraduate organic chemistry are usually different from those tackled by academic research groups. First of all, Chem 30 problems are designed to test your knowledge of the course material. As you wind through the semester, you pick up new reactions which may be placed in your “synthetic toolbox.” While a modern chemist is free to choose from all sorts of reactions, you are limited to those presented in the course. Furthermore, while a practicing organic chemist is only limited by what is commercially available, in undergraduate synthesis problems, you are often restricted to using specific starting materials or reagents. The take-home message is not to associate exam problems too closely with what chemists actually do. Nevertheless, it is important to learn basic organic reactions and the skills you learn are still very applicable to “real” organic synthesis.
Managing your Synthetic Toolbox
Your “synthetic toolbox” encompasses all of the material you’ve learned that is useful in constructing organic compounds. These can be single reactions that transform one functional group into another, a sequence of reactions used to construct a more complex functionality, or general techniques and methods that are universally applicable. As you come across a new reaction or technique, you should keep track of it in your notes. One of the best ways to do this is by making index cards. While there are a couple of sets of pre-made organic chemistry cards available in bookstores, they are a poor substitute for making your own. Look for reactions in:
- Problem set and exam synthesis questions
- Lecture packets, especially the reactions that are discussed in detail or given their own section
- Loudon and other undergraduate textbooks
General Advice on How to Study
- Do practice problems. Start with problems from the book (they are easier) then move on to problems associated with the course (do the practice exam, redo the problem sets, do the section practice problems, do the problems in the lecture notes, do the problems on the database).
- Focus on the interconnectivity of functional groups—know how to get from one group to another in both directions. Make “cheat sheets” that detail the reactions and transforms (how to make particular structural motifs). Please refrain from actually using the cheat sheet to cheat on an exam.
General Approaches to Synthesis Problems
Basic Synthetic Strategies
See if the synthons you are given suggest an obvious forward step
Try “mapping” the synthons on to portions of the target. If you can figure out where a synthon “fits into the puzzle,” you can then worry about properly arranging reactions to establish the connectivity.
If these methods don’t work, take your target molecule and break it apart by going backwards one reaction at a time. With each step back, see if it is now more obvious how to work forward from the starting materials. Try to put the most complicated steps towards the end of your synthesis.
1) Trained Response / Reflex In some cases, it is not hard to look at a target and immediately see the key functional transformations. You’ll find that this “easy” approach will occur more frequently as you do practice problems and study your synthetic transforms.
Target
Ph
S Ph O
Transforms
Ph
S Ph
terminal olefin transform: Wittig Olefination
former carbonyl
β-functionalized carbonyl transform: Conjuga te Addition
former α,β-unsaturated ketone
α,β-unsaturated ketone transform: Aldol Condensation
1
4
5
2 3
5
4
Conversion
O
O
H Ph
NaOH
O
Ph
PhCH 2 SH pyridine
Ph
O Ph 3 P CH 2 S Ph
Ph
S Ph
Conversion
EtO OEt
O O
NaH
O
H
- nBuLi
- H 3 O+
OH
nBu
DMP O
nBu
O
EtOOC
COOEt EtOH^
O O
COOEt
NaOEt
O O
- NaOH
- H 3 O+
- ∆
excess
3) Retrosynthetic Analysis – The “Backward” Approach
Target
OH
H
O
NMe 2
O NMe 2
O
O
O
and any other necessary reagents
Approach
The product and starting material are giveaways for a Diels-Alder reaction somewhere in the synthesis. However, we must work backwards to get to this point. When you are initially working through the problem, don’t waste time writing every specific detail in case the path becomes a dead end. Jump backwards as many moves as you can keep straight in your head.
O
O
O
O
O
O
TBSO
O
O
NMe 2
O^ NMe 2 OH
H
O
NMe 2
O NMe 2
alcohol transform: carbonyl reduction
1
amides originate from anhydride opening and DCC-activated amide formation
2
Ketone from enol tautomerization gives obvious Diels- Alder retrosynthon:
3
obvious Diels-Alder adduct
4
O
1 5 (^34)
2 6
Conversion
O
O
O
TBSO
O
O
TBSO
O
Me 2 NH
O
NMe 2
TBSO O NMe 2
KF
O
NMe 2
O O NMe 2
NaBH 4
OH
H
O
NMe 2
H 2 O H 2 O O NMe 2
2 eq.
DCC
In reality, the method that you end up using will be a combination of the three. Since usually you are given starting materials that you must use, it is impossible to work entirely backwards—chances are won’t arrive at the given starting material. Instead, it makes sense to work backwards, then forwards, then repeat this process until your chemical intuition sparks so that you can join the backwards and forward routes by reflex.
5) Protect Reactive Functionality
HO
Br 2
CH 3 OH TBSCl NEt 3
TBSO
Br 2
CH 3 OH
TBSO Br OCH 3
O
Br not HO Br OCH 3
TBAF
pH 7 H 2 O
6) Be Careful in Deciding Upon the Conditions for Generating Your Enolate
O (^) Ph H
O
NaOMe MeOH
O
Ph
O
Ph H
O
O
Ph
LDA, 0oC
3) H 3 O+
OH
O
Ph H
O
O
Ph
LDA, 0 oC
O
Ph H
O
LDA, -78 oC
3) H 3 O+
O
Ph H
O
LDA, -78 oC
O
O
Ph
OH
Ph
NaOR base is usually fine here, although I prefer the LDA method, especially for crossed aldols.
O
O
- LDA, 0 oC
- CH 3 I
O (^) 1) LDA, -78 oC
- CH 3 I
O
Do not use NaOR/ROH to make thermodynamic enolates for alkylation. The enolate generation is an equilibrium and you will end up hydrolyzing the alkyl halide.
O
OEt
- NaH or NaOEt
EtO 2) CH 3 I
O O
EtO OEt
O
Malonates are quite acidic, so you needn't worry about equilibria with weak bases and there is no need to use expensive basic reagents.
7) It is difficult/impossible to alkylate enolates with 2° and 3° alkyl halides. Find a better way.
O
Ph
Et
Br CH 3
O
Ph
1) LDA
1) LDA
2) CH 3 CHO
3) H 3 O+
O
Ph CH 3
Bad!
- Et 2 CuLi
- H 3 O+
Good
8) Avoid Overalkylating
Unless you want an extensively alkylated product (e.g. 4 o amine), don’t alkylate amines or benzene with alkyl halides. It is very hard to prevent the monoalkylated product from reacting further.
9) Play By the Rules (Read the Question)
Don’t just dive in by looking at the figure—be sure to read the question prompt as well. If a synthesis problem says to use a certain starting material or to use only “compounds with n or fewer carbons,” then abide by these rules (or face the wrath of our red pens).
Pay attention to detail—don’t get nickeled and dimed for points!
Common Reduction-Oxidation (Redox) Reagents
Oxidants
DMP 2° alcohols → ketones, 1° alcohols → aldehydes (Swern oxidation does the same)
CrO 3 1° alcohols → aldehydes; toluenes → benzaldehydes (basic conditions) olefins → α,β-unsaturated ketones (Allylic oxidation)
KMnO 4 1° alcohols → carboxylic acids, 2° alcohols → ketones (fairly harsh) 1° and 2° alkyl benzenes → benzoic acids
O 3 olefins → aldehydes (w/ DMS or Zn/AcOH workup) olefins → carboxylic acids (w/ H 2 O 2 , NaOH workup)
OsO 4 olefins → vicinal diols (glycols)
Br 2 olefins → vicinal dibromides, olefins → bromohydrins (w/ ROH) 3° hydrocarbons → alkyl halides (photohalogenation, w/hν)
NBS alkyl benzenes → benzyl bromides (w/hν or peroxide initiator) olefins → allylic bromides
RCO 3 H olefins → epoxides ketones → esters (Baeyer-Villiger)
H 2 O 2 alkylboranes → alcohols (w/NaOH, hydroboration workup)
I 2 + RCOO–^ olefins → esters with neighboring alkyl iodide ( e.g. , iodolactonization)
Reductants
H 2 olefins → alkanes (w/ Pd on carbon) ketones → alcohols (w/ PtO 2 ) alkynes → olefins (w/ Pd-BaSO 4 , quinoline)
R 2 BH olefins → anti-Markovnikov alkylboranes
NaBH 4 ketones, aldehydes → alcohols (Felkin product)
Zn(B H 4 ) 2 ketones, aldehydes → alcohols (chelation control product)
NaBH 3 CN protonated imines (at pH 5) → amines (used in reductive aminations)
DIBAL-H esters, nitriles → aldehydes (relatively mild conditions)
LiAlH 4 carboxylic acids, ketones, aldehydes → 1° alcohols (relatively harsh conditions) amides, imines, nitriles → amines
RLi aldehydes → 2° alcohols; esters, ketones → 3° alcohols
RMgBr aldehydes → 2° alcohols; esters, ketones → 3° alcohols (Grignard reagent)
RZnCl acid chlorides → ketones (reagent won’t add to ketones)
Synthetic Routes to Common Nucleophiles and Electrophiles
O^ O
O
O
R H
O
R
O
R OR'
R Cl
O
Common Nucleophiles
Common Electrophiles
Reversible bases (alkoxides, hydroxides); LDA at high temperatures (0 oC)
kinetic enolates
thermodynamic enolates
From alcohols with SOCl 2 or PBr 3 ; alkenes with HBr (with or w/o peroxides); alkanes by photohalogenation
alkyl halides
esters
ketones
aldehydes
Fischer esterification of acids and alcohols; solvolysis of acid chlorides and anhydrides with alcohols; Baeyer-Villiger oxidation
Oxidation of alcohols; Friedel-Crafts reaction; Oxidation of Grignard products
α,β-unsaturated carbonyls Aldol reactions; α-keto halogenation (Hell-Volhard-Zelinsky) then elimination of HBr
nitriles R C N
Cyanide substitution of alkyl halides; dehydration of amides by P 2 O 5 ;
Swern or DMP oxidation of alcohols; DIBAL-H reduction of nitriles and esters; CrO 3 oxidation of toluenes
Synthetic Preparations
O
Irreversible bases at low temperature (LDA, -78 oC); bulky bases
O
RO
malonic ester enolates R'
OR
O O
RO
R'
OR
O
H
Bases with pKa > 8 (NaH, RO-)
O
R
OTMS
R
TMSCl and an amine base in anhydrous solvent silyl enol ethers
N
R R' O^ +
HN
R'
R
enamines pH = 5 catalyzed condensation
NR
imines (^) Reaction of primary amines with ketones and aldehydes in acid
HO
R^1 R^2
Substituted Alcohols
O
R^1 O
R
R^2 1) R (^2) MgBr (2 eq.)
- H 3 O+
HO
R^1 R^2
O
R^1 H
R^3 1) R
(^2) MgBr
H 3 O+
DMP
R^3 MgBr
H 3 O+
Horner-Wadsworth- Emmons
Robinson Annulation
R R
O
R R
O
O
P
O
EtO
EtO
O O
R
O
R
see reductions list earlier in packet
R
O
R' R
O O
H R'
+ + 1) LDA
Aldol Reaction 2) H 3 O+
R
O
β-Keto Alcohols Aldol Reaction R
O OH
R'
1) LDA
2) R'CHO
α,β-Unsaturated Ketones
O
EtO R
O
R
α-Functionalized Ketones (^) R' +
R
O
R' R
O O
EtO R'
- NaOEt CondensationClaisen 2) H^3 O+
1,3-Diketones (^) O
X O O
Review which nucleophiles add 1,4 vs. 1,
β-Functionalized Ketones Conjugate Additions +^ CN, RSH, RNH^2 , Et^2 CuLi, etc.
O (^) 1) NaH
- R'X
- NaOH
4) H+
- heat
OH
R
X
α-Functionalized Alcohols (^) +
R
O X
Epoxide Opening
O
XR
O
RX n
n
1) O 3
- H 2 O 2 , NaOH
- DCC, R XH
Symmetric Carboxylic Acid Derivatives
O
R^1 O
R^2
O
R^1 R^2
RCO 3 H
O
N
H
R^1 R^3
R^2 O
R^1
R^3
R^2
- NH 2 OH, pH 5
- TsCl, pyridine
- heat
O
1) KCN
- H 3 O+, heat
Carboxylic Acids See Oxidations Earlier in Packet
R
OH R Br
R^1 N
R^2
Substituted Amides
- BuLi
- R^2 I
- BuLi
- R^3 I
O
R^1 NH 2
O
R^3
Amide Alkylation
Beckmann Rearrangement
R^1 N
R^2
O
R^3
O
R^1 XR
NH
R^2
R^3
Acid Deriva tive Substitution
Esters
Baeyer-Villiger
Acid Deriva tive Substitution
O
R^1 XR
R^2 OH
O
R^1 O
R^2
larger group migrates
use DCC with acids
- KMnO 4
- H 3 O+
COOH
Oxidations of Aryl Hydrocarbons
H
R^2
O
OH
R^3
O
R''O
H
O
OR''
H
BuLi
R^2 I
BuLi
R^3 I
NaOH
H+
heat
Malonic Ester Alkylation
Nitrile Hydrolysis
Important Stereoselective Reactions
2) H 3 O+
O
OR
OH
OR
Zn(BH 4 ) 2
Equatorial Attack
Chiral Alcohols
t-Bu
OH
t-Bu
O
- LiAlH 4
- H 3 O+
Axial Attack t-Bu
OH
t-Bu
O
K+HB 3
O
OR
OH
OR
R^2 MgBr
R^2
R^2 H
D
H
R^2
D
H
O
D R
D
H
D
D
R
O
Diels-Alder Reactions
Cis / Trans Cyclohexanes
Chelate Controlled Reductions
H
R^2
D
H
O
D R
OHC D
CHO
R^2 H
D
R D
D H
- heat or L.A.
- ozonolysis
Chiral Cyclohexanes and 1,6-Dicarbonyl Derivatives
O
HO
O OH
R'
Evans' Aldol Reaction
R
O N
O O
R
Bn
HO
O OH
R'
R
O N
O O
R
Bn
via ( Z )-enolate
Ph
O OH
R'
R
Ph
O
R
O
H R'
Ph
O OH
R'
R
Ph
O OH
R'
R
Ph
O O
H R'
Ph
O OH
R'
R
R
Syn Aldol Products
Anti Aldol Products
( Z )-enolates
( E )-enolates
Chiral α-Alkyl-β-Keto Alcohols
Cannot generate ( E )-enolates of oxazolidinones
Bu 2 BOTf, NEt 3
R'CHO
LiOOH
H+
Bu 2 BOTf, NEt 3
R'CHO
LiOOH
H+
Chiral 1-Alkyl-2-ol Acids
HO
O
R
R'
O N
O O
R
Bn
1) LDA
- R' Cl
- LiOOH
- H+
Alkylation with Chiral Auxiliaries
Chiral α-Alkyl Acids
Use LAH or LiBH 4 to get terminal alcohols
( Z )-enolates: use Bu 2 BOTf, NEt 3 ( E )-enolates: use Cy 2 BCl, NEt 3
soft enolizations
via ( Z )-enolate
Amines
protected form
deprotected form
stable to mild base
O
N
H
O
R
tBoc anhydride R NH 2 R NH 2
F 3 CCOOH
(TFA)
O NH
O
R
N
H
DMF/H 2 O
Fmoc chloride R NH 2 R NH 2
stable to mild acid
Cbz chloride R NH 2 R NH 2
O
N
H
O
R
Ph
H 2
Pd/C
stable to mild acids and mild bases
Carboxylic Acids R
O
OH
CH 2 N 2 LiOH
R
O
OCH 3 MeOH/H 2 O^ R
O
OH
R
O
OH
H+
DBU R
O
OtBu R
O
OH
Br
(hindered base)
stable to mild acids and bases
stable to base
Take note of orthogonal protecting groups that are removed with different conditions so you can selectively deprotect one group at a time
