JLA Synthetic Planning

Strategies in Synthetic Planning
Modern Stylistic Points in Retrosynthetic Analysis
Jen Alleva
MacMillan Group Meeting
January 8th 2014
Thursday, January 9, 14

Development and Conceptualization of Retrosynthetic Analysis
"By the end of this course I will be able to look at all of your retrosyntheses and know which one of you
produced it. You will all develop your own unique and recognizable style over the next few months."
Paul Reider, Graduate Synthesis
Common trend: Modern organic chemists have unique retrosynthetic strategies rendering their syntheses
easily recognizable to the well-read practitioner of organic chemistry

"Retrosynthetic analysis is a problem-solving technique for transforming the structure of a synthetic

target (TGT) molecule to a sequence of progressively simpler structures along a pathway which
ultimately leads to simple or commercially available starting materials for chemical synthesis."
E. J. Corey, Harvard University

MIT 19451950, John Sheehan
Appointed as Instructor at UIUC at age 22
Earned professorship at UIUC at age 27
Moved to Harvard in 1959
Nobel Prize in Chemistry 1990
Detailed retrosynthetic analysis and techniques
Corey, E. J.; Cheng, X.-M. The Logic of Chemical Synthesis, John Wiley & Sons, New York, 1995, pp 6.

Target
Molecule
retron
keying elements
Int2
Int1
transform: Diels-Alder
SM1
Int4
Int3
SM2
Int5
Int6
SM3
SM4
Hoffmann, R. W. Elements of Synthetic Planning, Springer-Verlag, Berling Heidelberg, 2009, pp 35.


OH
Me
Me
OH
Me
Me
retron
alkene keying element
Me
Me
O
Me
O
Br
Me
Cu
OR
Me
Me
Hoffmann, R. W. Elements of Synthetic Planning, Springer-Verlag, Berling Heidelberg, 2009, pp 35.


decreasing complexity
The main goal of retrosynthetic analysis is to reduce the complexity of the target: How?

1. The application of powerful transforms:
forming key bonds in the molecular skeleton (i.e. CC bonds)
aldol, Diels-Alder, intramolecular alkylations, CH activation, cross couplings
forging stereocenters through substrate control (modernly reagent control)
cascade reactions

cascade reactions
Me
Me
Me
H
Me
Me
O
O
H
Me
Me
Me
Me
cyanthiwigin F
Enquist Jr., J. A.; Stoltz, B. M. Nature, 2008, 453, 1228.

cascade reactions
2. Lateral movement through a non-simplifying transform
skeletal rearrangements, transpositions, isomerization reactions, epimerizations

cascade reactions
O
O
Me
H
Me
N
H
Me
H
H O
Me
Me
H
N
H
Me
H
H O
Me
H
N
H
Me
H
H O
()-tuberostemonine
Wipf, P.; Rector, S. R.; Takahashi, H. J. Am. Chem. Soc., 2002, 124, 14848.

cascade reactions
3. Disconnections that actually increase molecular complexity
protecting groups, masking groups, activating/deactivating groups, adding functional groups or bonds

cascade reactions
3. Disconnections that actually increase molecular complexity
protecting groups, masking groups, activating/deactivating groups, adding functional groups or bonds
PMP
OH
AcO
SePh
PMP
O
O
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
guanacastepene E
Shipe, W. D.; Sorensen, E. J. J. Am. Chem. Soc., 2006, 128, 7025.

Classes of Retrosynthetic Disconnections
Transform-Based
Structure-Goal
Topological Strategies
look-ahead to powerfully simplifying
directed at the structure of a potential
strategic analysis of correlated
transform or tactic
intermediate or SM
bond disconnections
i.e. the "Key Step"
i.e. the branch point
i.e. rearrangements
and network analysis
Stereochemical Strategies
Functional Group-Based Strategies
retrosynthetic strategy which clears stereocenters
reduction in molecular complexity based on the
with either mechanism or substrate control
interchange, installation and removal of functional groups
most common in modern synthesis
"redox relay", directing groups, heterocycle formation

Acyclic Systems
What to disconnect and what to preserve

Acyclic Systems
Disconnect
Preserve
to make symmetrical fragments
building block groups (alkyl, aryl)
CX bonds (Cheteroatom, esters, amides, etc)
remote stereocenters (more than 3C is remote)
either E or Z double bonds
skeletal bonds proximal to remote stereocenters
13 bonds away from functional groups

bonds that attach rings to chains (produce the largest fragment)

Acyclic Systems
Disconnect
Preserve
building block groups (alkyl, aryl)
remote stereocenters (more than 3C is remote)
either E or Z double bonds
13 bonds away from functional groups

bonds that attach rings to chains (produce the largest fragment)
Wittig
HO
O
(CH2)3CO2H
TBSO
CHO
C5H11
C5H11
OH
OH
PGA2
SN2 cuprate addition

Corey, E. J.; Mann, J. J. Am. Chem. Soc. 1973, 95, 6832.

Ring-Bonds in Isolated Rings
Disconnect
easily formed rings (lactone, lactam, hemiacetal)

Ring-Bonds in Isolated Rings
Disconnect
easily formed rings (lactone, lactam, hemiacetal)
HO
O
H
HO
O
H
acylation/desulfurization
Me
iodolactonization
CH2I
Me
O
Me
PhO2S
Me
HS
Me
H
Me
(+)-dihydromevinolin
Falck, J. R.; Yang, Y.-L. Tetrahedron Lett. 1984, 25, 3563.

Disconnection of Fused Rings
Disconnect
Preserve
[2+1] and [2+2] retrons
building block rings (aryl)
cocyclic bonds (cycloaddition retrons)
bonds that make >7 membered rings
heteratom containing rings (lactones, lactam, ketal)
fused rings with exendo bonds (cation--cyclizations)
bonds that make stereocenters

Disconnection of Fused Rings
Disconnect
Preserve
[2+1] and [2+2] retrons
building block rings (aryl)
cocyclic bonds (cycloaddition retrons)
bonds that make >7 membered rings
heteratom containing rings (lactones, lactam, ketal)
fused rings with exendo bonds (cation--cyclizations)
bonds that make stereocenters
Me
Me
Me
H
Me
Me
O
O
oxidative
dimerization
O
O
O
O
O
O
OH
oxidative
dimerization
carpanone
Chapman, O. L.; Engel, M. R.; Springer, J. P.; Clardy, J. C. J. Am. Chem. Soc. 1971, 93, 6696.

Disconnection of Bridged Rings
Disconnect
Preserve
exendo bonds in 47 membered rings
bridges that if disconnected yield >7 membered rings
Cheteratom bonds preferentially over CC bonds
bonds that would yield medium size rings
bonds that contain the most bridgehead atoms (network analysis)
bonds that yield pendant chains

Disconnection of Bridged Rings
Disconnect
Preserve
exendo bonds in 47 membered rings
bridges that if disconnected yield >7 membered rings
Cheteratom bonds preferentially over CC bonds
bonds that would yield medium size rings
bonds that contain the most bridgehead atoms (network analysis)
bonds that yield pendant chains
Me
HO
Me
O
Me
Me
en route to longifolene
McMurry, J. E.; Isser, S. J. J. Am. Chem. Soc., 1972, 94, 7132.

Applied Strategies in Retrosynthetic Analysis

Topological
Functional Group-Based
O
O
CO2Me
O
HO
OBn
HO
MeO2C
H
HO
Phragmalin-type Limonoids
Sarpong Group, Berkeley
Transform-Based
OH
Me
HO
OH
OH
Ouabagenin
Baran Group, Scripps
Structure-Goal
O
O
Me
HO
N
O
Me
()-Curvularin
()-Lycojapodine A
Stoltz Group, Caltech
Lei Group, Tianjin University

Topological
O
O
CO2Me
O
HO
OBn
HO
MeO2C
H
HO
Transform-Based
OH
Me
HO
OH
OH
Ouabagenin
Structure-Goal
O
O
Me
HO
N
O
Me
()-Curvularin
()-Lycojapodine A
Synthesis of the Framework of Phragmalin-Type Limonoids

Utilizing Network Analysis: a topological strategy
potent anti-cancer, antibiotic, anti-inflammatory properties
H
AcO
O
O
CO2Me AcO
Me
AcO
Me
highly oxygenated triterpenoid

key challenge is synthesis of the carbocyclic core
Me
O
O
OH
Me
Xyloccensin O
octahydro-1H-2,4-methanoindene core
phragmalin-type limonoid
CO2Me
OTBS
6 steps
O
CO2Me
OBn
MeO2C
O
OBn
Lebold, T. M.; Gallego, G. M.; Marth, C. J.; Sarpong, R. Org. Lett., 2012, 8, 2110.

Guiding Principles of Network Analysis
in general: it is easier to synthesis fused rings that bridged systems

identify the bonds that are made to the most bridged system
retrosynthetic removal of these bonds will lead to the most simple keying element
longifolene
Corey, E. J.; Ohno, M., Mitra, R. B.; Vatakancherry, P. A. J. Am. Chem. Soc. 1964, 86, 487.

Guiding Principles of Network Analysis
in general: it is easier to synthesis fused rings that bridged systems

identify the bonds that are made to the most bridged system
retrosynthetic removal of these bonds will lead to the most simple keying element
most bridged
ring system
homodaphniphyllate framework
Heathcock, C. Angew. Chem. Int. Ed., 1992, 31, 665.

Retrosynthetic Analysis
intermolecular alkylation
O
O
CO2Me AcO
AcO
OBs
O
Me
AcO
Me
OBn
Me
MeO2C
O
OH
OBn
MeO2C
Me
Xyloccensin O
Diels-Alder
OTBS
OBs
OBs
O
OBn
H
OBn
MeO2C
CO2Me
O
CO2Me
O
OBn
more reactive
conformer

Diels-Alder Approach
OTBS
OTBS
H
PhMe, 100 C
OTBS
H
Pd/C, H2
CO2Me
(>10:1 endo:exo)
O
OBn
89%
EtOAc
O
OBn
CO2Me
OH
H
1M HCl
OBs
H
BsCl, pyr.
precursor to
intramolecular
cat. DMAP
MeOH
O
OBn
CO2Me
OBn
CO2Me
CH2Cl2
OBn
CO2Me
alkylation
82% over 3 steps

Intramolecular Alkylation
OBs
BnO2C
conditions
O
OBn
(below)
O
OBn
CO2Me
MeO2C
14
H
MeO2C
21

OBs
BnO2C
conditions
O
OBn
(below)
O
H
H
MeO2C
OBn
CO2Me
MeO2C
14
21
BnO2C
BnO
OBn
MeO2C
OBn
OBn
OBn
MeO2C
CO2Bn
MeO2C
H
MeO2C

CO2Me
OH
H
OBn
CO2Me
1. DMP, NaHCO3
CO2Me
CH2Cl2
KOtBu, THF
2. Ph3P=CHCO2Me
78 C - 0 C
CH2Cl2
49% over 2 steps
OBn
CO2Me
O
OBn
MeO2C
79%

Topological
O
O
CO2Me
O
HO
OBn
HO
MeO2C
H
HO
Transform-Based
OH
Me
HO
OH
OH
Ouabagenin
Structure-Goal
O
O
Me
HO
N
O
Me
()-Curvularin
()-Lycojapodine A
Total Synthesis of Ouabagenin

a functional group-based approach
Key Features of a Functional Group-based Approach
functional group in the target directly keys a disconnection

functional group in the target is poised to assist in the installation of a key stereocenter
often times installed and later removed in order to enable a key transform (overbred intermediate)
may extend to modern photoredox radical chemistry, traceless directing groups, CH activation
nepatalactone
enamine-,-enal cycloaddition
Clark, K. J.; Fray, G. I.; Jaeger, R. H.; Robinson, R. Tetrahedron, 1959, 6, 217.


functional group installed to assist key step
accessing
(+)-Gliocladin C
functional group
removed by photochemical
reduction
Furst, L.; Narayanam, J. M. R.; Stephenson, C. R. J. Angew. Chem. Int. Ed. 2011, 50, 9655.


reserpine
LeBold, T. P.; Wood, J. L.; Deitch, J.; Lodewyk, M. W.; Tantillo, D. J.; Sarpong, R. Nat. Chem., 2012, 5, 126.

retrosynthetic analysis
Pd-catalyzed
coupling
reduction
epoxidation/
reductive opening
deprotection
HO
HO
Me
Me
HO
H
H
OH
OH
HO
HO
Me
H
O
OH
OH
oxidation
Et
chemo/regioselective
CC fragmentation
HO
Norrish type 2
Me
Me O
O
O
O
Me
HO
O
O
Me O
HO
H
H
HO
Me
Me
H
H
O
O
andrenosterone
LeBold, T. P.; Wood, J. L.; Deitch, J.; Lodewyk, M. W.; Tantillo, D. J.; Sarpong, R. Nat. Chem., 2012, 5, 126.

Me O
O
Me
H
OH
HO
H
H
Me
HO
1. H+
2. h
O
O
H
H
Norrish Type 2
adrenosterone
55% over two steps
Renata, H.; Zhou, Q.; Baran, P. S. Science 2013, 339, 59.

Me O
O
Me
H
OH
HO
2. h
Me
HO
1. H+
O
O
H
H
Norrish Type 2
55% over two steps
adrenosterone
Me O
O
Me
HO
H
H
Me O
H
H2C
H

O
Me
H
OH
HO
O
O
H
H
2. h
Me
HO
1. H+
Me O
NIS, Li2CO3
Norrish Type 2
55% over two steps
adrenosterone
Me
H
H
HO
TiCl4
AgOAc
Me
85%
H
H
HO
1. H2O2
Me
H
O
2. SeO2
71%

HO
Me
H
H
H2O2
O
O
H
H
H
O
HO
Me
50% over 3 steps

HO
Me
H
H
H2O2
O
O
H
H
H
O
HO
Me
50% over 3 steps
Al-Hg
HO
HO
Me
H
O
H2O
OH
56%

HO
Me
H
H
H2O2
HO
Me
H
H
H
O
Al-Hg
HO
Me
O
Me
OH
Me
1. Li, NH3
Et
63% over 2 steps
Me O
HO
H
H
2. LiBEt3H
O
Me
O
1. PPTS, Me2CO
56%
O
O
H
H
50% over 3 steps
Me
H2O
HO
Me
1. PPTS, Me2CO
Et
69% over 2 steps


Me
Me
O
HO
MeCN, then FeCl3
Me
H
H
Me
1. TMSOTf, NEt3, Pd(OAc)2
Me O
HO
H
H
2. SiO2, DIPEA
F
F3C
Me O
Et
Et
F
55% over 2 steps
O
O
Me
Co(acac)2 (20 mol%)
Me
O
Me O
HO
H
O
1. N2H4: I2, NEt3
OH
2. CuTC (3 equiv)
Pd(PPh3)4 (15 mol%)
DMF
Et
86%
Me
CH2Cl2/EtOH
O2, PhSiH3
dioxane
Me
Bu3Sn
Me
HO
H
H
O
O
OH
Et
42% over 2 steps

O
Me
Me
O
Me
HO
H
H
OH
Me
1. CoCl26H2O, NaBH4
EtOH, 0 C to rt.
B
Et
2. PhH, 100 C
Me2N
Me
NtBu
Me2N
Me
HO
H
O
B
Et
OH
70% over two steps

O
Me
Me
O
Me
HO
H
H
Me
1. CoCl26H2O, NaBH4
EtOH, 0 C to rt.
Me
O
2. PhH, 100 C
OH
Me2N
O
NtBu
Me2N
Et
Me
HO
B
Et
OH
70% over two steps
O
O
HCl (conc.)
MeOH, rt.
HO
HO
Me
HO
ouabagenin
H
90%
H
HO
20 steps from andrenosterone

OH
OH

Topological
O
O
CO2Me
O
HO
OBn
HO
MeO2C
H
HO
Transform-Based
OH
Me
HO
OH
OH
Ouabagenin
Structure-Goal
O
O
Me
HO
N
O
Me
()-Curvularin
()-Lycojapodine A
Total Synthesis of ()-Curvularin

A Transform-Based Approach
Key Features of a Transform-Based Approach
in general: the late-stage key-step

look-ahead to apply a highly simplifying synthetic strategy
often cascades, rearrangements, transformations which assemble multiple CC bonds
Estrone
Corey, E. J.; Ohno, M., Mitra, R. B.; Vatakancherry, P. A. J. Am. Chem. Soc. 1964, 86, 487.

A Transform-Based Approach
Key Features of a Transform-Based Approach
in general: the late-stage key-step

look-ahead to apply a highly simplifying synthetic strategy
often cascades, rearrangements, transformations which assemble multiple CC bonds
Squalene
Werthermann, L.; Johnson, W. S.; Proc. Nat. Acad. Sci., 1970, 67, 1465.

Retrosynthetic Analysis
benzyne acylalkylation
OH
OBn
Me
O
O
BnO
HO
O
Me
OR
RCM
Me
O
Me
O
Me
known acetate
Aldol
2 steps from commercial
Tadross, P. M.; Virgil, S. C.; Stoltz, B. M. Org. Lett., 2010, 7, 1612.

preparation of the -ketolactone
1. Mg, THF, I2 (trace)

2. CuI
Me
Me
Me
Me
1.) LDA then acrolein
Br
3. Ac-Cl, pyr.
85%, >99% ee
Me
HMDS, THF 70 C;
THF, 78 C
HO
76%
(1:1)
Grubbs 3 (10 mol%)

PhH, reflux;
1 N HCl, THF
HO
Me
1. Pd/C, H2, EtOH
2. DMP, CH2Cl2
92% over 2 steps
57%
Lin, W.; Zercher, C. K.; J. Org. Chem., 2007, 72, 4390.


Key Step
OBn
OBn
Me
TMS
CsF
OTf
MeCN, 40 C
O
O
BnO
30%
BnO
O
Me

Key Step
OBn
OBn
Me
TMS
CsF
OTf
MeCN, 40 C
O
O
BnO
BnO
O
30%
OH
Me
Pd/C, H2
MeOH, THF
HO
60%
O
Me
()-Curvularin

Topological
O
O
CO2Me
O
HO
OBn
HO
MeO2C
H
HO
Transform-Based
OH
Me
HO
OH
OH
Ouabagenin
Structure-Goal
O
O
Me
HO
N
O
Me
()-Curvularin
()-Lycojapodine A
Total Synthesis of ()-Lycojapodine A

A Structure-Goal Approach
Key Features of a Structure-Goal Approach
Implemented when a large number of target structures are desired (collective synthesis)
bulk of synthetic strategy relies on the synthesis of a highly simplifying intermediate
allows the implementation of multiple retrosynthetic techniques
common intermediate
tetracycle
Jones, S. B.; Simmons, B.; Mastracchio, A.; MacMillan, D. W. C. Nature, 2011, 475, 183.

Cortisol
deoxycholic acid
targeted starting material
Fieser, L. F.; Fieser, M. Steroids Reinhold Publishing, New York, 1959. pp 645659.

Buspirone
targeted starting materials
Fieser, L. F.; Fieser, M. Steroids Reinhold Publishing, New York, 1959. pp 645659.

more than 250 Lycopodium alkaloids have been characterized
contains a unique 6/6/6/7 tetracyclic skeleton
Me
N
unprecedented carbinolamine lactone motif

biosynthesis suggests that many natural products can be
accessable through a common intermediate
()-Lycojapodine A
fawcettimine-type alkaloid
OH
H
Me
N
(+)-fawcettimine
O
H
Me
N
(+)-fawcettidine
O
H
Me
O
(+)-lycoflexine
Me
N
OH
OH
(+)-alopecuridine
Li, H.; Wang, X.; Hong, B.; Lei, X. J. Org. Chem., 2013, 78, 800.

simplified biogenesis
Me
carbon
O
skeleton
HO
N
H
lycolidine
biosynthetic common
intermediate
rearrangement
OH
H
Me
N
(+)-fawcettimine

Me
carbon
O
skeleton
HO
N
H
lycolidine
biosynthetic common
intermediate
rearrangement
OH
H
Me
N
(+)-fawcettimine
HCHO
condensation
Me
O

Me
carbon
O
skeleton
HO
N
H
lycolidine
rearrangement
OH
H
Me
N
HCHO
Me
O
condensation
(+)-fawcettimine
biosynthetic common
intermediate
O
H
Me
O
(+)-lycoflexine

Me
carbon
O
skeleton
HO
lycolidine
Me
N
H
OH
rearrangement
HCHO
Me
O
condensation
(+)-fawcettimine
biosynthetic common
H2O
intermediate
O
O
H
Me
N
(+)-fawcettidine
Me
O
(+)-lycoflexine

OH
H
Me
OH
(+)-alopecuridine
[O]
Me
carbon
O
skeleton
HO
lycolidine
Me
N
H
OH
rearrangement
HCHO
Me
O
condensation
(+)-fawcettimine
biosynthetic common
H2O
intermediate
O
O
H
Me
N
(+)-fawcettidine
Me
O
(+)-lycoflexine

O
O
OH
H
Me
OH
[O]
Me
H2O
(+)-alopecuridine
()-lycojapodine A
[O]
Me
carbon
O
skeleton
HO
lycolidine
Me
N
H
OH
rearrangement
HCHO
Me
O
condensation
(+)-fawcettimine
biosynthetic common
H2O
intermediate
O
O
H
Me
N
(+)-fawcettidine
Me
O
(+)-lycoflexine

OH
H
Me
(+)-fawcettimine
H
Me
O
Boc
Me
N
proposed common
intermediate
()-Lycojapodine A
O
H
Me
O
(+)-lycoflexine

OH
H
Me
tandem conjugate addition/

Aldol
intramolecular
alkylation
(+)-fawcettimine
H
Me
O
Boc
O
O
Boc
N
OTBDPS
N
Me
Me
N
OH
proposed common
intermediate
()-Lycojapodine A
O
O
H
Me
O
N
O
Me
MgBr
(+)-lycoflexine
Boc
OTBDPS

preparing the common intermediate
MgBr
O
CuBr, Me2S, LiCl, THF 78 C

then:
Me
OTBDPS
Boc
N
94%
NEt3HF
OTBDPS
MeCN, rt
75%
OH
1. collidine, MsCl
CH2Cl2, 4 C
2. DMP, CH2Cl2
Me
Boc
OH
Boc
OH
Me
Boc
N
Me
80% over 2 steps
OMs

preparing the common intermediate
Boc
NaI
Boc
OMs
acetone, rt.
Me
Me
84%
Boc
N
DBU
MeCN, rt.
Me
O
Me
Boc
Me
O
H
O
RBocN
65%

synthesis of (+)-alopecuridine
CHO
1. NaBH4, MeOH, rt.

H
O
Me
Boc
OsO4, NaIO4
TMSO
2. TMSOTf, 2,6-lutidine
Me
CH2Cl2, 78 C
Boc
TMSO
Me
DABCO
Boc
dioxane/H2O
87%
SmI2 (5 equiv)
OH
TMSO
H
Me
HMPA (20 equiv)

THF, 78 C to rt.
Boc
1. TBAF, THF, rt
Me
OH
2. TPAP, NMOH2O
96%
Boc
4 MS, CH2Cl2, rt
80%
50%
OH

synthesis of (+)-alopecuridine and ()-lycojapodine A
HO
O
O
H
Me
Boc
OH
TFA, CHCl3
then NaHCO3
94%
Me
TFA
OH
(+)-alopecuridineTFA
12 steps

synthesis of (+)-alopecuridine and ()-lycojapodine A
HO
O
O
H
Me
Boc
OH
TFA, CHCl3
TFA
then NaHCO3
94%
Me
OH
(+)-alopecuridineTFA
12 steps
O
O
HO
H
Me
TFA
DMP, TFA
OH
4 MS, 30 C, 4 h
80%
Me
N
()-Lycojapodine A
13 steps

Topological
O
O
CO2Me
O
HO
OBn
HO
MeO2C
H
HO
Transform-Based
OH
Me
HO
OH
OH
Ouabagenin
Structure-Goal
O
O
Me
HO
N
O
Me
()-Curvularin
()-Lycojapodine A

JLA Synthetic Planning

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JLA Synthetic Planning

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Strategies in Synthetic Planning

Modern Stylistic Points in Retrosynthetic Analysis

Strategies in Synthetic Planning

Strategies in Synthetic Planning

"Retrosynthetic analysis is a problem-solving technique for transforming the structure of a synthetic

E. J. Corey, Harvard University

Strategies in Synthetic Planning

Hoffmann, R. W. Elements of Synthetic Planning, Springer-Verlag, Berling Heidelberg, 2009, pp 35.

Strategies in Synthetic Planning

alkene keying element

Hoffmann, R. W. Elements of Synthetic Planning, Springer-Verlag, Berling Heidelberg, 2009, pp 35.

Strategies in Synthetic Planning

Strategies in Synthetic Planning

Strategies in Synthetic Planning

Strategies in Synthetic Planning

Strategies in Synthetic Planning

Strategies in Synthetic Planning

Strategies in Synthetic Planning

Strategies in Synthetic Planning

look-ahead to powerfully simplifying

directed at the structure of a potential

strategic analysis of correlated

i.e. the "Key Step"

i.e. the branch point

Functional Group-Based Strategies

retrosynthetic strategy which clears stereocenters

reduction in molecular complexity based on the

with either mechanism or substrate control

interchange, installation and removal of functional groups

most common in modern synthesis

"redox relay", directing groups, heterocycle formation

Strategies in Synthetic Planning

What to disconnect and what to preserve

Strategies in Synthetic Planning

What to disconnect and what to preserve

to make symmetrical fragments

building block groups (alkyl, aryl)

CX bonds (Cheteroatom, esters, amides, etc)

remote stereocenters (more than 3C is remote)

either E or Z double bonds

skeletal bonds proximal to remote stereocenters

13 bonds away from functional groups

Strategies in Synthetic Planning

What to disconnect and what to preserve

to make symmetrical fragments

building block groups (alkyl, aryl)

CX bonds (Cheteroatom, esters, amides, etc)

remote stereocenters (more than 3C is remote)

either E or Z double bonds

skeletal bonds proximal to remote stereocenters

13 bonds away from functional groups

SN2 cuprate addition

Strategies in Synthetic Planning

What to disconnect and what to preserve

Strategies in Synthetic Planning

What to disconnect and what to preserve

Strategies in Synthetic Planning

What to disconnect and what to preserve

[2+1] and [2+2] retrons

building block rings (aryl)

cocyclic bonds (cycloaddition retrons)

bonds that make >7 membered rings

heteratom containing rings (lactones, lactam, ketal)

skeletal bonds proximal to remote stereocenters