Advanced Organic Chemistry 2022 For SCST in Tigp

Advanced Organic Chemistry (2022)
Sustainable Chemical Science and Technology (SCST)

The Logic of Chemical Synthesis
(retrosynthetic analysis and strategy in total synthesis)
Jiun-Jie Shie
Location: Room B105, Institute of Chemistry, Academia Sinica Institute of Chemistry,
13:30~16:30 Academia Sinica
" There is excitement, adventure, and challenge, and there can be great art
in organic synthesis."
-These alone should be enough, and organic chemistry will be sadder when
none of its practitioners are responsive to these stimuli.-
Robert Burns Woodward

(1917-1979), who received " The structure known but not yet accessible by synthesis, is to the
the 1965 Nobel Prize in
chemist what the unclimbed mountain, the uncharted sea, the untilled
Chemistry for several total
syntheses, is regarded as field, the unreached planet, are to other man."
the father of modern organic
synthesis.
" The organic chemist is more than a logician and strategist; he is an

explorer strongly influenced to speculate, to imagine, and even to create."
Elias James Corey (1928-), who received the 1990 Nobel

Prize in Chemistry for the development of retrosynthetic
analysis theory in organic synthesis.
Course: Advanced Organic Chemistry (2022) The Logic of Chemical Synthesis Thursday, 2022
Sustainable Chemical Science and Technology (SCST) in TIGP (retrosynthetic analysis and strategy in total synthesis) Page 1
"When we have been faced with a problem of affecting a chemical synthesis,
We have sought know methods.
We have not paused to think why we do not invent a new method every time. If we
adopt this philosophy we are going to be extremely busy till the end of the century
trying to equal the enzymes, and thinking of new ways of synthesis."
Derek. H. R. Barton (1918-1998),

"in defining strategies and reactions to construct complex molecules we
who received the 1969 Nobel Prize
in Chemistry for his contributions to require synthetic methods that can
the development of the concept of  perform a wanted structural change and none other - chemoselective
conformation and its application in  orient the reacting partners in a correct fashion - regioselective
chemistry.  create the correct orientations of the various parts of the molecules
with respect to each other - diastereoselective
 enable the formulation of a molecule of one handedness or a mirror
isomer - enantioselective.
Such extraordinary demands are exciting challenges."
Barry M. Trost (1941-), The Tsuji-Trost reaction and the Trost ligand are named after him. He is
prominent for advancing the concept of atom economy.
Organic Chemistry and Organic Synthesis
ORGANIC SYNTHESIS
TOTAL SYNTHESIS Method Oriented

(target oriented)
Natural Designed
Reagent Catalyst Strategy Tactics
Products Molecules
Theoretically Medicinally Biologically Materially

Interesting Interesting Interesting Interesting
Molecules Molecules Molecules Molecules
Synthetic Chemistry in the 21st Century
 My science knowledge: Education: 30%; Research: 20%; Review paper: 20%; Other: 30%
(continued learning)
Safe Simple
One step 100% yield

Ideal Synthesis
Resource Available
efficient material
Environmentally
acceptable
Searching the Chemical Resources All the information you need can be
found from these sources.
in Organic Synthesis Of course, to actually pass the course,
you need to understand the material...
general Specific Chemical Databases

Chemical Databases
 Reaxys https://www.reaxys.com/reaxys/secured/search.do
 SciFinder https://scifinder.cas.org/scifinder/login
 Scopus http://www.scopus.com/
 Organic Chemistry Portal https://www.organic-chemistry.org/
 Organic Syntheses http://www.orgsyn.org/
 Web of Science http://apps.webofknowledge.com/
Steps in Planning a Synthesis
 In planning an organic synthesis, the following key interrelated factors may be involved:
A. Construction of the carbon skeleton C. Control of relative stereochemistry

B. Functional group interconversion D. Control of enantioselectivity
Retrosynthesis: The Synthetic Route to a Target Molecule
H H H
N S
PhO
O N
TM : Target molecule
O
CO2H FGI : Functional group interconversions
HO SE : Synthetic equivalents
HO
HO OH
IP : Inverting the polarity (Umpolung in German)
H2 N O
O
O
O
O O Cl Transform
Cl
HO OH
O
H
O
H
O
TM Synthons Synthetic equivalent
O N
H
N
N
H
N
N
H
NHMe
or reagents
O O
NH
NH2
HO2C O
OH
HO OH
 Synthetic design involves two distinct steps:
(1) retrosynthetic analysis

(2) subsequent translation of the analysis into a "forward direction" synthesis.
In the analysis, the chemist recognizes the functional groups in a molecule and disconnects them
proximally by methods corresponding to known and reliable reconnection reactions.
Construction of the Carbon Skeleton
Transform

or reagents
Reactions that result in formation of new carbon-carbon bonds are of paramoun importance in organic
chemistry because they allow the construction of complex structures from smaller starting materials.
• Reactions of organolithium and Grignard reagents, such as RLi, RC=CLi, RMgX, and RC=CMgX,
with aldehydes, ketones, esters, epoxides, acid halides, and nitriles.
• Reactions of 1o alkyl halides with -C=N to extend the carbon chain by one carbon.
• Alkylations of enolate ions to introduce alkyl groups to carbons adjacent to a carbonyl group. (e.g.,
acetoaretic ester synthesis, malonic ester synthesis)
• Condensations such as aldol (intermolecular, intramolecular), Claisen, and Dieckmann.
• Michael additions, organocuprate additions. (1,4-additions)
• Friedel-Crafts alkylation and acylation reactions of aromatic substrates.
• Wittig reactions, and Horner-Wadsworth-Emmons olefination.
• Diels-Alder reactions giving access to cyclohexenes and 1,4-cyclohexadienes.
• Ring-closing olefin metathesis.
Summary of Important Disconnection
Transform

or reagents
1,2-addition
O
OH + OH MgX +
H H
1,3-addition
OH
+ MgX +
OH O
CN + Br
CN + NaCN
SN2 reaction
Transform

or reagents
aldol Reaction
OH O O O
OH O
+ +
H H H
H
Claisen aldol Reaction

O O O O
O
O +
+ OR
OR OR OR
Michael addition
O O
O O
O O
+ +
CO2R CO2R
CO2R
Transform

or reagents
Wittig Reaction
O
H O H O
OR + +
O OR O OR
PPh3 PPh3 Br
Diels-Alder Reaction
CO2Me
CO2Me
+
CO2Me CO2Me
Important Guidelines for Disconnection
 Disconnections of bonds should be carried out only if the resultant fragments can be reconnected
by known and reliable reactions.
A O B O
+ +
O
bad disconnection straightforward disconnection
 Aim for the fewest number of disconnections. Adding large fragments in a single reaction is more
productive than adding several smaller fragments sequentially (convergent vs. linear synthesis).
 Choose disconnections in which functional groups are close to the C-C bonds to be formed since the
presence of functional groups often facilitates bond making by a substitution reaction.
O O
O O O O
+ + Br
Ph OEt
OEt OEt
 A preferred disconnection of cyclic esters (lactones) or amides (lactams) produces hydroxy-carboxylic
acids or amino-carboxylic acids as targets. Many macrocyclic natural products contain these functional
groups, and their syntheses often include a macrocyclization reaction.
O
COOH
X XH
n n
 Functional groups in the TM may be obtained by functional group interconversion (FGI).
H FGI
+ OH
H CH2OH CH2OH
TM
H
+ O
Li H
 Symmetry in the TM simplifies the overall synthesis by decreasing the number of steps required for
obtaining the TM.
O O O
FGI OH BrMg
C C
EtO H
TM MgBr
 Introduction of an activating (auxiliary) functional group may facilitate carbon-carbon bond formation.
This strategy works well for the synthesis of compounds exhibiting a dissonant charge pattern. After
accomplishing its role, the activating group is removed.
O O CO2Et
FGI O CO2Et O CO2Et
Ph Ph Br
Ph Ph
O O
TM O O
 There is no simple way to disconnect the TM shown below (dissonant charge pattern). However, the
presence of a 1,6-dioxygenated compound suggests opening of a six-member ring. A variety of
cyclohexene precursors are readily available via condensation and Diels-Alder reactions or via Birch
reductions of aromatic compounds.
CH3 CH3 CH3
O
FGI FGI FGI
H
H 3C
CH3 O
H 3C OH
CH3 O
TM
 Disconnection of an internal (E)- or (Z)-double bond or a side chain of an alkene suggests a Wittig-
type reaction or an alkylation of a vinylcuprate, respectively.
R1 O R2
R1 R2 Ph3P
R1 R2
H X
alkylation of a vinylcuprate TM
Wittig reaction
R1 Br R2
CuR2
 The presence of a six-member ring, especially a cyclohexene derivative, suggests a Diels-Alder
reaction.
CO2Me FGI CO2Me CO2Me
CH3 CH3 H 3C
 The structural feature of an α,β-unsaturated ketone or a α-hydroxy ketone in a six-member ring

suggests a double disconnection coupled with functional group interconversions [Michael addition
followed by intramolecular aldol condensation (Robinson annulation)].
O
O O O
O O O
O O
Functional Group Interconversions
Control of Relative Stereochemistry
 It is important to use stereoselective and stereospecific reactions (where applicable), such as
 SN2 substitutions (anti-attack, conversion of configuration); E2 eliminations (syn-elimination)

 Asymmetric aldol reactions [using chiral ligand, auxiliary or catalyst; steric control (open TS) vs. chelate
control (cyclic TS)]
 The Sharpless asymmetric epoxidations (using titanium chiral-DET complexes)

 Oxidation of alkenes with osmium tetroxide (syn-addition, cis-diol)
 Catalytic hydrogenation of alkynes (syn-addition, cis-product)
 Birch reduction and Metal (Li, Na, K…) reduction of alkynes in liquid ammonia (trans-product)
 Electrophilic Aromatic Substitution (ortho-/para- directing groups vs. meta- directing groups)
 Electrocyclizations, cycloadditions and sigmatropic rearrangements (Woodward-Hoffmann rule)
 Addition of halogens, interhalogens (e.g., BrI) or halogen-like species (e.g. HBr, PhSCl) to double bonds
[acid-catalytic reaction (Markovnikov addition) vs. free-radical reaction (anti-Markovnikov addition)]
 Cyclopropanation of alkenes (carbene-type syn-addition)

Choice of Synthetic Method
The choice of a method for synthesizing a compound derived from a retrosynthetic analysis should be
based on the following criteria:
 Chemoselectivity, selective reaction of one functional group in the presence of other functional
groups, exemplified by the preferential reaction of an aldehyde in the presence of a keto group.
 Regioselectvity, the preferential addition of the reagent in only one of two possible regions or
directions, exemplified by the preferential alkylation of 2-methylcyclohexanone by the derived enolate
at C-2 and not at C-6.
 Stereosclectivity, the exclusive or predominant formation of one of several possible stereoisomeric

products, exemplified by the preferential formation of cis-3-methylcyclohexanol on reduction of
3-methylcyclohexanone with lithium aluminum hydride in THF or Et2O.
 Efficiency, fewest number of steps.
 High yields in each step.
Linear Synthesis vs. Convergent Synthesis
 Linear Synthesis: The overall yield in a multistep step synthesis is the product of the yields for each
separate step. In a linear synthetic scheme, the hypothetical TM is assembled in a step-wise manner.
For the seven-step synthesis of the hypothetical TM below, if the yield of the intermediate at each step
is 80%, the overall yield will be 21% (0.87 x 100); for a 70% yield at each step, the overall yield would
be only 8%. B C D E
A B C D E F G H
A A B A B C A B C D A B C D E
TM
F G H
A B C D E F A B C D E F G TM
 Convergent Synthesis: Since the overall yield of the TM decreases as the number of individual steps
increases, a convergent synthesis should be considered in which two or more fragments of the TM are
prepared separately and then joined at the latest-possible stage of the synthesis. The overall yield in a
convergent synthesis is the product of yields of the longest linear sequence. For the synthesis of the
above TM, only three stages are involved in the convergent strategy shown below, with an overall yield
of 51% (0.83 x 100). A+B A B C+D C D E+F E F G+H G H
A B + C D A B C D E F + G H E F G H
A B C D + E F G H TM
Synthetic Strategy: Protecting Groups and Their Deprotection
1st disconnection
 2nd disconnection
 Here, the electrophilic carbon can react with two

 Molecule has two nucleophiles so electrophile nucleophiles (O as desired or N in intramolecular
can attack either of them (the oxygen as attack of the amine, leading to aziridine formation
desired or the nitrogen). by cyclization).
 This is the 1st problem of chemoselectivity.  2nd problem of chemoselectivity.
Protecting Groups and Their Deprotection
 1st solution – use better disconnection – 3rd disconnection
 But here the disconnection do not split the molecule to half.
 2nd solution – prevent the N to act as nucleophile in synthons of 1st and 2nd disconnection.
 This can be achieved by introducing a protecting group in NH2 moiety.

 Let’s consider the reaction using RNH-Boc. ( Boc = tert-butyloxycarbonyl group)
 Protection of amino group using Boc2O
 The amine attacks a carbonyl C on di-tert-butyl dicarbonate (Boc2O) with tert-butyl carbonate leaving
as a leaving group.
• tert-butyl carbonate picks up the proton from the protonated amine.
• tert-butyl bicarbonate breaks down into CO2 (gas) and tert-butanol.
 2nd solution – prevent the N to act as nucleophile in synthons of 1st and 2nd disconnection.
 But, we must remove the

Boc group from amine.
 Deprotection of Boc group using TFA
 The tert-butyl carbamate becomes protonated.

• Loss of the tert-butyl cation results in a carbamic
acid.
• Decarboxylation of the carbamic acid results in the
free amine.
 Here Boc group protected amine from undergoing reaction.
 So this group is termed protecting group.
 So Protecting groups are usually used to temporarily mask a functional group which may interfere with a
certain reaction.
 The addition of protecting groups to functional groups is termed “protection” and removal of protecting
group is “deprotection”.
 Protecting group (PG) is a small molecule, which has the capability to protecting temporarily the a
specific functional group of a molecule from undergoing reaction, allowing the rest of the functional
groups present in the molecule to react without affecting the original reactivity and leave from the
host molecule without affecting the rest of the functional groups.
A Good Protecting Group
 should react with the desired functional group quickly,
 should form the protected compound in good yield,
 the protected compound should have good stability when stored for a long time.
 should have a minimum functional group to avoid side reaction during the course of the main reaction
 should not create a new chiral center at the molecule.
 at the time of deprotection, should cleave under mild reaction condition, should give good yield and the
purification must be simple.
 Protected compound must be highly hydrophobic, thus enabling extractive work-ups easier, and if the
product is crystalline, so as to provide suitable purification.
General Facts on Protection

 Generally there are 5 types of functional groups , having –OH, -SH, -COOH, -C=O, NH.
 Alcoholic and phenolic hydroxyl groups and its sulphur analogues (thiols and thiophenols) are protected
as ethers or esters.
 Carboxylic acids are protected as esters or amides.
 Adehydes and ketones are protected as acetals or ketals.
 The amino group was protected as carbamates, amides or imines.
Common Hydroxy-Protecting Groups and Their Deprotection
 Ethers
 Esters
Common Hydroxy-Protecting Groups and Their Deprotection
 Acetals
 Silyl ethers
 the stability of silyl ethers towards acidic media increases as indicated:

TMS (1) < TES (64) < TBS (20,000) < TIPS (700,000) < TBDPS (5,000,000)
Common Amine-Protecting Groups and Their Deprotection
 Carbamates
 N-Substituents
 Amides
Common Carbonyl-Protecting Groups and Their Deprotection
 Dimethyl acetals  1,3-Dioxanes
 1,3-Dithiolanes and 1,3-dithianes

 1,3-Dioxolanes
Common Carboxylic Acid-Protecting Groups and Their Deprotection
 Methyl esters  Silyl esters
 Benzyl esters  Oxazolines
 tert-Butyl esters
Retrosynthetic Analysis: Guidelines of Planning
 Below are a set of guidelines to help you logically approach retrosynthesis or the planning stage. They
are not rules, the only rule is that you want to simplify the problem whilst using chemically allowable
transformations!
O
O amine H 2N ketone
CH3 O
C-N C-C H 2N
NH2
ortho/para meta
Meta-directing, directing directing ortho/para-directing,
NO synthetic equivalent (+NH2) (C-N bond) (C=O bond) NOT meta-directing
FGI
O
 Identify function groups O 2N  Identify problems
 Identify patterns  Consider FGI
 Examine disconnections  Repeat 1-5
Simple Retrosynthesis: Ocfentanil (Painkiller)
OCH3
O
N
F
Ocfentanil
(Painkiller)
Retrosynthesis: Ocfentanil (Painkiller)
amide
OCH3 ether
amine O
C-N
N amide
N
F
C-N
amine
Identify FG & patterns connecting them (guidelines 1 and 2)
C–N bonds are easy to identify.
These disconnections are our starting point.
Retrosynthesis: Ocfentanil (Painkiller)
OCH3 FGI
C-N OCH3 (imine
O
amide O H reduction)
N N N
Cl
N N N
F F F
Et3N/CH2Cl2 NaBH3CN
C-N
H+ amine
K2CO3/DMF condensation
C-N O
H 2N
alkylation
Br O N
F
HN
Which C–heteroatom bond would you disconnect first?

Remember we want to simplify the problem & use reliable reactions.
Simple Retrosynthesis: Tazadolene (Anti-depressant)
Ph
Tazadolene
(anti-depressant)
Retrosynthesis: Tazadolene (Anti-depressant)
Ph Ph O Ketone
FGI
1,3-diketone
N O Ketone
acylation O
of enolate O Ph
Cl
Identify FG & patterns connecting them (guidelines 1 and 2)

New disconnection is our 1,3-diketone
-retrosynthesis-
Retrosynthesis: Tazadolene (Anti-depressant)
O
O O
O Ph O Ph OH
N Cl Ph
H N O O
(enamine (acylation
formation) of enamine)
(reductive BnNH2;
amination) H2, Pd/C
Ph Ph Ph OH
BrCH2CH2CH2Br H+
N NH2 NH2
(N-alkylation) (dehydration)
Simple Retrosynthesis: ICI-D7114 (Anti-Obesity Drug)
O
O OCH3
OH N
H H
O N
O
ICI-D7114
Retrosynthesis: ICI-D7114 (Anti-Obesity Drug)
 How would you make this intermediate from the synthesis of ICI-D7114? Consider our guidelines...
SN2 alkylation
SN2 alkylation O
O OCH3
OH N
H H
O N
O
ICI-D7114
Amide bond formation
epoxide-ring opening
OH O
O Br OCH3
O H 2N N
Br H
HO
FGI protection
OH
OH O
SN2 alkylation
O BocHN Br OCH3
Br HO OH H2N
Br
OH
Examples of ‘Extreme Targets’ in Total Synthesis O
H2NOC HO O
NH2 HO H
OH
Vitamin B12 Me HO H
Me HO Vancomycin, OH
O H2 N Azadiractin,
H O O Antibiotic, insect antifeedant and H O
O O Evans, 1999. growth disruptor
H2NOC O
Me N CNN O
Ley, 2007.
O
Me Co O O Cl O
NH2
H Cl MeO O O
N N Me HO OH
Me O O O O
H2NOC H H
H CONH N N NHMe
Me 2 O N N N OH
O Me Me H H H O HO OH
N O O O
NH O OH HO OH
NH Me NH2
HO N Me
O O OH
Me O HO2C OH H2 N OH OH
P O HO OH
O O
O H HO OH
OH toxic marine
Palytoxin - HO OH
natural product.
Synthesised by Woodward Synthesised by Kishi in 1994
OH
and Eschenmoser 1973. OH OH
HO O
HO OH O
O OH OH
O OH
H
O OH OH
H O HN N O H
Brevetoxin B: H
A marine neurotoxin H H HO HO
OH
H Me HO HO
H O O H
H H O OH
O OH O
O Me O
H Synthesised by Nicolaou O Me HO
O in 1995. OH
Me
O OH H
H H H O
O O O OH
H H H
HO OH HO
HO OH
Early Classics of Total Synthesis in Organic Chemistry
Morphine, Strychnine
Colchicine, Toxic alkaloid.
various biological OMe Analgesic, HO
Gates 1952. Woodward 1954. N
properties MeO OMe
MeO O H
NMe
N
H H H H H
O
HO O O
Eschenmoser,1959 NH H
O
Penicillin V Thienamycin Cephalosporin C

Antibiotic. Antibiotic. Antibiotic.
Sheehan 1957. OH H H H
H H H H H HO2C N S
N S
PhO S
N NH2 O N OAc
O N NH2 O
O O
CO2H HO2C
CO2H
Total Synthesis of Colchicine by Eschenmoser in 1959
SO4
i) Me2Pd/C MeO i) CO2Me MeO
HO
ii) H2 Et3N
ii) MeI MeO
HO MeO O
iii) LiAlH4 OMe
OH OH O
OH O iv) H3PO4
(step i) proceeds via initial OH alkylation) O
Purpurogallin (available Cl
starting material)
175oC
O O (Diels-Alder Reaction
MeO O and decarboxylation)
MeO
then
tBuOK Cl H2SO4
i) CH
. MeO
MeO tBuOH MeO 2 N2
CO2Me
OMe CO2Me
OMe Cl
MeO O
CO2Me H CO2Me OMe
O
(radical-reaction) H
O
MeO
MeO MeO O
MeO CO2Me i) NBS, (PhCO2)2
ii) NH3, EtOH. NH
OMe
MeO MeO
OMe iii) KOH, EtOH. OMe
CO2Me iv) CH2N2
OH O
v) Ac2O racemic
O OMe
Total Synthesis of Colchicine by Schmalz in 2002 Graening, Timm; Schmalz, Hans-Guenther ,
Angew. Chem. Int. Ed. 2002, 41, 1524-1526.
O O Enantioselective OTBS
MeO reduction using
OH MeO MeO
chemical catalyst.
TMS TMS
MeO I 2 steps. MeO I MeO I
OMe OMe OMe
ii) iBuOCOCl then
i) iPrMgCl, O O .
O CH2N2
MeO i) (H-
L-selectride
source) OTBS
MeO
OTBS
OTBS MeO
MeO
MeO
OMe ii) TMSOTf then [Rh2(OAc)4]
K OMe MeO O
2CO3, MeOH. O reflux
OH
OMe
OH N2
DMSO, O
(CF3CO)2O O
(Swern oxidation)
then Et3N.
(last steps are from Banwell synthesis)
MeO
i) MeI, K2SO4, ii) TBAF. * MeO O
OTBS iii) Zn(N3)2.py DIAD, PPh3 NH
MeO
MeO
OMe iv) PPh3, H2O.
OMe
O v) Ac2O, pyridine.
O
OH (* Mitsunobu reaction) enantiomerically pure.
OMe
Total Synthesis of Morphine by Trost in 2002 Trost, B.M.; Tang, W. J. Am. Chem. Soc. 2002, 124,
14542-14543.
Ph Ph O
HO O O O
NH HN
CO2Me Pd
PPh2 Ph2P Br
Morphine, Cl3C O MeO
Analgesic, O + CO2Me
NMe MeO Br O
Gates 1952. O Palladium catalysed
H H H OH
asymmetric allylation H
HO (racemic)
MeO
MeO Pd-catalysed MeO
Combination of Pd- Br intramolecular
Codeine catalyzed asymmetric
O Heck reaction.
NMe reactions and coupling
O CN O CN
H H H reactions. Pd(OAc)2
HO H diphosphine H H
AcO
MeO HO
Heroin Cyclize NMe
onto alkene
O
NMe O O
NHMe then remove NMe
H H H
H H OMe->OH H H H
AcO
HO HO
Course: Advanced Organic Chemistry (2022) The Logic

47 of Chemical Synthesis Thursday, 2022
Total Synthesis of Strychnine by Overman in 1993 S. D. Knight, L. E. Overman and G.
Pairaudeau, J. Am. Chem. Soc. 1993, 115,
H 9293–9294 .
N N HN
H OtBu
H H
N OH
Strychnine H H HO H
Toxic alkaloid. O NR2 OtBu
O A
first synthesized H NR2
by Woodward in 1954.
N N
= NMe
NR2 N O H H
HO HO Key step here is the
NMe
NR2 OtBu NR2 OtBu
transformation of A to B.
N N
N HO2C CO2H
H H
N N
O H H H H Ac2O, NaOAc, AcOH H H
NR2 OtBu HO
O O O
B H H
Wieland-Gumlich aldehyde.
Sustainable Chemical Science and Technology (SCST) in TIGP (retrosynthetic analysis and strategy in total synthesis)
48 Page 47
Total Synthesis of Strychnine by Shibasaki in 2002 T. Ohshima, Y. Xu, R. Takita, S. Shimizu,
D. Zhong and M. Shibasaki, J. Am.
Asymmetric CO2Me Chem. Soc. 2002, 124, 14546-14547.
CO2Me catalyst +
O O CO2Me
H CO2Me
EtS H
I HO N
OTIPS EtS Zn, MeOH
i) Tf2O
O O NH4Cl
H H ii) EtS O
NO2
NH2 NO2 H
OPMB EtS
OH OSEM OPMB
A OSEM OPMB Key steps are from A to
EtS EtS C (via B).
N N N
EtS EtS EtS
DMTSF
H
O N N
H H H H
NH2
B OSEM OPMB C OSEM OPMB D OSEM OPMB
N N N
EtS
NiCl2, NaBH4 (oxidation of alcohol)
H Strychnine
N N (remove TIPS) N
Ac H H Ac H H Ac H H
HO E HO OTIPS HO O
OTIPS H
Total Synthesis of Strychnine by Andrade in 2010 G. Sirasani, T. Paul, W. Dougherty Jr., S.
Kassel and R. B Andrade, J. Org. Chem.
2010, 75, 3529-3532.
O O
O NBn O Br Br
NBn NBn
Br
BnNH2 Cl AgOTf
N MgSO4 N N + N
H H H H
CO2Me
MeO OTMS A
O O OTBS
NBn NBn i) Reduction of the C=O bond. N
I Pd(PPh3)4
DBU ii) debenzylation PPh3, Et3N
N (base) N Br N
H H H H
iii) OTBS CO2Me
B
CO2Me C CO2Me D Key steps are from A
I K2CO3
to C and from D to E.
N N N
NaBH3CN DIBAL-H,
AcOH toluene
H H
Strychnine
N NaOMe, N N
H H H H H H H H
MeOH
MeO2C MeO2C HO O
E OTBS (epimerises) OH H
Total Synthesis of Strychnine by Vanderwal in 2011 D. B. C. Martin and C. D. Vanderwal,
Chem. Sci. 2011, 2, 649-651.
O2 N
N
H N NO2
Key step
N 81% based on pyridinium
H salt, 100% recovery of excess S.M.
(intramolecular Diel-Alder reaction)
N N Br OH
NH
KOtBu Pd(PPh3)4 TMS
69%
THF, 0.02 M iPrNEt2
N N O O
H 80 oC H H N
O H H
O O
O O
N OH N N
TMS NaHMDS, NMP HO2C CO2H
then CuBr-SMe2
H H
N 5-10% yield. N N
H H H H H Ac2O, NaOAc, AcOH H H
O HO O O
H O
H

Advanced Organic Chemistry 2022 For SCST in Tigp

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Advanced Organic Chemistry (2022)

Sustainable Chemical Science and Technology (SCST)

Robert Burns Woodward

" The organic chemist is more than a logician and strategist; he is an

Elias James Corey (1928-), who received the 1990 Nobel

Derek. H. R. Barton (1918-1998),

TOTAL SYNTHESIS Method Oriented

Theoretically Medicinally Biologically Materially

One step 100% yield

general Specific Chemical Databases

 Organic Chemistry Portal https://www.organic-chemistry.org/

 Organic Syntheses http://www.orgsyn.org/

 Web of Science http://apps.webofknowledge.com/

A. Construction of the carbon skeleton C. Control of relative stereochemistry

 Synthetic design involves two distinct steps:

(1) retrosynthetic analysis

TM Synthons Synthetic equivalent

TM Synthons Synthetic equivalent

TM Synthons Synthetic equivalent

Claisen aldol Reaction

TM Synthons Synthetic equivalent

bad disconnection straightforward disconnection

 Functional groups in the TM may be obtained by functional group interconversion (FGI).

CO2Me FGI CO2Me CO2Me

 The structural feature of an α,β-unsaturated ketone or a α-hydroxy ketone in a six-member ring

 SN2 substitutions (anti-attack, conversion of configuration); E2 eliminations (syn-elimination)

 The Sharpless asymmetric epoxidations (using titanium chiral-DET complexes)

 Electrocyclizations, cycloadditions and sigmatropic rearrangements (Woodward-Hoffmann rule)

 Cyclopropanation of alkenes (carbene-type syn-addition)

 Stereosclectivity, the exclusive or predominant formation of one of several possible stereoisomeric

 Efficiency, fewest number of steps.

 High yields in each step.

 Here, the electrophilic carbon can react with two

 But here the disconnection do not split the molecule to half.

 This can be achieved by introducing a protecting group in NH2 moiety.

 But, we must remove the

 Deprotection of Boc group using TFA

 The tert-butyl carbamate becomes protonated.

General Facts on Protection

 the stability of silyl ethers towards acidic media increases as indicated:

 1,3-Dithiolanes and 1,3-dithianes

 Benzyl esters  Oxazolines

Which C–heteroatom bond would you disconnect first?

Identify FG & patterns connecting them (guidelines 1 and 2)

Penicillin V Thienamycin Cephalosporin C

Course: Advanced Organic Chemistry (2022) The Logic

B OSEM OPMB C OSEM OPMB D OSEM OPMB

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