JLA Synthetic Planning PDF

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 1945–1950, 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

Int1 Int2
transform: Diels-Alder
SM1
Int3 Int4
SM2
Int5 Int6
SM3 SM4
Hoffmann, R. W. Elements of Synthetic Planning, Springer-Verlag, Berling Heidelberg, 2009, pp 3–5.

OH
Me Me
Me Me
OH O
O
retron alkene keying element
Me Me
Me O O O
Cu
Br Me OR Me Me
Hoffmann, R. W. Elements of Synthetic Planning, Springer-Verlag, Berling Heidelberg, 2009, pp 3–5.

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. C–C bonds)
aldol, Diels-Alder, intramolecular alkylations, C–H activation, cross couplings
forging stereocenters through substrate control (modernly reagent control)
cascade reactions

cascade reactions
Me
O O O
Me Me Me
Me
H Me O
O
H
Me Me
O O O
Me
O
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 Me O Me O Me
H H H
O H Me O H Me O H Me
Me
N H O Me N H O N H O
O O O
H H H
(–)-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 O PMP
O O
O
H OH O O O
SePh O
AcO
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)
C–X bonds (C–heteroatom, esters, amides, etc) remote stereocenters (more than 3C is remote)
either E or Z double bonds skeletal bonds proximal to remote stereocenters
1–3 bonds away from functional groups
bonds that attach rings to chains (produce the largest fragment)
Acyclic Systems
Disconnect Preserve
to make symmetrical fragments building block groups (alkyl, aryl)
C–X bonds (C–heteroatom, esters, amides, etc) remote stereocenters (more than 3C is remote)
either E or Z double bonds skeletal bonds proximal to remote stereocenters
1–3 bonds away from functional groups
bonds that attach rings to chains (produce the largest fragment)
Wittig
O HO TBSO
(CH2)3CO2H
CHO
O
C5H11 C5H11
O
OH OH
PGA2 SN2 cuprate addition
Corey, E. J.; Mann, J. J. Am. Chem. Soc. 1973, 95, 6832.

Ring-Bonds in Isolated Rings
Disconnect
to make symmetrical fragments
C–X bonds (C–heteroatom, esters, amides, etc)
easily formed rings (lactone, lactam, hemiacetal)
Ring-Bonds in Isolated Rings
Disconnect
to make symmetrical fragments
C–X bonds (C–heteroatom, esters, amides, etc)
easily formed rings (lactone, lactam, hemiacetal)

HO O
H
O iodolactonization
HO O
CH2I
H
acylation/desulfurization O
O
PhO2S
O Me
H
Me Me Me HS S
Me Me
H H
(+)-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) skeletal bonds proximal to remote stereocenters
fused rings with exendo bonds (cation-π-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) skeletal bonds proximal to remote stereocenters
fused rings with exendo bonds (cation-π-cyclizations) bonds that make stereocenters
oxidative
Me
Me dimerization
Me
Me Me
H H
O O
O O
O
O O
O O O O
O O OH
O
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 4–7 membered rings bridges that if disconnected yield >7 membered rings
C–heteratom bonds preferentially over C–C 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 4–7 membered rings bridges that if disconnected yield >7 membered rings
C–heteratom bonds preferentially over C–C bonds bonds that would yield medium size rings
bonds that contain the most bridgehead atoms (network analysis) bonds that yield pendant chains
HO Me
O
Me
O
Me
O
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 Me
HO
HO
HO H
OBn
MeO2C H OH
HO
OH
Phragmalin-type Limonoids Ouabagenin

Sarpong Group, Berkeley Baran Group, Scripps
Transform-Based Structure-Goal
OH O O
O O
Me
HO
N
O O Me
(–)-Curvularin (–)-Lycojapodine A
Stoltz Group, Caltech Lei Group, Tianjin University

O
O
CO2Me
O Me
HO
HO
HO H
OBn
MeO2C H OH
HO
OH

OH O O
O O
Me
HO
N
O O Me
Synthesis of the Framework of Phragmalin-Type Limonoids
Utilizing Network Analysis: a topological strategy
■ potent anti-cancer, antibiotic, anti-inflammatory properties

H O
CO2Me AcO O ■ highly oxygenated triterpenoid
AcO
AcO Me
Me ■ key challenge is synthesis of the carbocyclic core
Me
O
O
OH O Me
Xyloccensin O
phragmalin-type limonoid octahydro-1H-2,4-methanoindene core
CO2Me OTBS
6 steps
O
CO2Me
OBn
O
MeO2C
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
O
intermolecular alkylation
H O
O H OBs
CO2Me AcO
AcO O O
AcO Me
Me
OBn OBn
Me
MeO2C MeO2C
O
O
OH O Me
Xyloccensin O
Diels-Alder
OTBS
OBs OBs
O
OBn
H
CO2Me
OBn
O
MeO2C CO2Me O
OBn
more reactive
conformer
Diels-Alder Approach
OTBS OTBS OTBS

H H
PhMe, 100 °C Pd/C, H2
CO2Me
(>10:1 endo:exo) EtOAc
O
O OBn O
OBn 89% OBn
CO2Me CO2Me
OH OBs
H H
1M HCl BsCl, pyr.
precursor to
intramolecular
MeOH cat. DMAP
O O alkylation
OBn CH2Cl2 OBn
CO2Me CO2Me
82% over 3 steps
Intramolecular Alkylation
OBs
H BnO2C
conditions O
H
(below) OBn H
O OBn MeO2C
MeO2C
CO2Me
14 21
OBs
H BnO2C
conditions O
H
(below) OBn H
O OBn MeO2C
MeO2C
CO2Me
14 21
BnO2C
BnO
O
O
OBn CO2Bn H
OBn OBn OBn

H
MeO2C MeO2C MeO2C
MeO2C
CO2Me
OH
1. DMP, NaHCO3 CO2Me
H H
CH2Cl2 KOtBu, THF O
2. Ph3P=CHCO2Me –78 °C - 0 °C OBn

O OBn O
CH2Cl2 OBn MeO2C
CO2Me CO2Me
49% over 2 steps 79%

O
O
CO2Me
O Me
HO
HO
HO H
OBn
MeO2C H OH
HO
OH

OH O O
O O
Me
HO
N
O O Me
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, C–H activation
nepatalactone enamine-α,β-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
O epoxidation/
Me reductive opening
O Me O O
deprotection HO Me
Me O O
Me O H HO O
HO HO H
HO
HO H H OH
H H
H OH O O O
B OH
HO oxidation
OH Et
chemo/regioselective
Norrish type 2
C–C fragmentation
HO Me
O Me O
O O
Me O
O H Me H
HO O
H
O H H H H
H H O
O O
andrenosterone
LeBold, T. P.; Wood, J. L.; Deitch, J.; Lodewyk, M. W.; Tantillo, D. J.; Sarpong, R. Nat. Chem., 2012, 5, 126.
O
1. H+ HO Me
Me O
O OH O
HO H
Me H
O H H
H H 2. hυ
O O
Norrish Type 2
adrenosterone 55% over two steps
Renata, H.; Zhou, Q.; Baran, P. S. Science 2013, 339, 59.
O
1. H+ HO Me
Me O
O OH O
HO H
Me H
O H H
H H 2. hυ
O O
Norrish Type 2
Me O Me O
O HO
Me H H2C H
H H H H
O O
O
1. H+ HO Me
Me O
O OH O
HO H NIS, Li2CO3
Me H
O H H
H H 2. hυ
O O
Norrish Type 2
O O O
Me Me Me
O O O
I O HO O HO O
H TiCl4 1. H2O2
H H
O H H AgOAc 2. SeO2
H H H H
O O
O O
85% 71%
O O
Me Me
O O
HO O HO O
H2O2 O H
H
H H H H
O O
O O
50% over 3 steps
O O O
Me Me Me
O O O
HO O HO O Al-Hg HO O
H2O2 O H
H HO H
H H H H H2O H H
O O O
O O OH
O O O
Me Me Me
O O O
HO O HO O Al-Hg HO O
H2O2 O H
H HO H
H H H H H2O H H
O O O
O O OH
Me Me
Me
O Me O
O HO
Me Me O
O O
O H O H
1. PPTS, Me2CO 1. Li, NH3
H H H H
2. LiBEt3H 1. PPTS, Me2CO
O O O O
B B
Et Et
63% over 2 steps 69% over 2 steps
Me Me
Me O
1. TMSOTf, NEt3, Pd(OAc)2 Me O
HO HO
Me O MeCN, then FeCl3 Me O
O H O H
H H 2. SiO2, DIPEA H
F O O
O O
B B
F3C F
Et Et
F F 55% over 2 steps

F
O
Me Me
Me O 1. N2H4: I2, NEt3
Me
HO HO
Me Me O
Co(acac)2 (20 mol%) O
O H CH2Cl2/EtOH O H
O2, PhSiH3 H OH H OH
2. CuTC (3 equiv)
dioxane
Pd(PPh3)4 (15 mol%) O O O
O O
B B
DMF
Et O Et
Bu3Sn 42% over 2 steps
86%
O O
O O
Me Me
Me 1. CoCl2•6H2O, NaBH4 Me
HO HO
Me O Me O
EtOH, 0 °C to rt.
O H O H
H OH 2. PhH, 100 °C H OH
Me2N
O O NtBu O O
B B
Me2N
Et
70% over two steps
Et
O O
O O
Me Me
Me 1. CoCl2•6H2O, NaBH4 Me
HO HO
Me O Me O
EtOH, 0 °C to rt.
O H O H
H OH 2. PhH, 100 °C H OH
Me2N
O O NtBu O O
B B
Me2N
Et
70% over two steps
Et
HCl (conc.) Me
HO ouabagenin
HO
MeOH, rt. HO H
20 steps from andrenosterone
90%
H OH
HO
OH

O
O
CO2Me
O Me
HO
HO
HO H
OBn
MeO2C H OH
HO
OH

OH O O
O O
Me
HO
N
O O Me
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 C–C 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 C–C bonds
Squalene
Werthermann, L.; Johnson, W. S.; Proc. Nat. Acad. Sci., 1970, 67, 1465.
Retrosynthetic Analysis
benzyne acyl-
alkylation
OH O OBn O Me
HO BnO O
O O Me
RCM
OR O Me O Me
O Me O
known acetate
Aldol 2 steps from commercial
Tadross, P. M.; Virgil, S. C.; Stoltz, B. M. Org. Lett., 2010, 7, 1612.
preparation of the β-ketolactone
1. Mg, THF, I2 (trace)

O Me O Me
O
2. CuI Me 1.) LDA then acrolein
Me O O
Br
3. Ac-Cl, pyr. THF, –78 °C HO
85%, >99% ee 76% (1:1)
O Me O Me
HMDS, THF 70 °C; 1. Pd/C, H2, EtOH
O O
Grubbs 3 (10 mol%) 2. DMP, CH2Cl2
PhH, reflux; HO O
1 N HCl, THF 92% over 2 steps

57%
Lin, W.; Zercher, C. K.; J. Org. Chem., 2007, 72, 4390.

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

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

O
O O Me
30%
OH O
Pd/C, H2
MeOH, THF
HO
60%
O O Me
(–)-Curvularin

O
O
CO2Me
O Me
HO
HO
HO H
OBn
MeO2C H OH
HO
OH

OH O O
O O
Me
HO
N
O O Me
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 645–659.
Buspirone
targeted starting materials
Fieser, L. F.; Fieser, M. Steroids Reinhold Publishing, New York, 1959. pp 645–659.
O O ■ more than 250 Lycopodium alkaloids have been characterized

Me ■ contains a unique 6/6/6/7 tetracyclic skeleton
N
■ unprecedented carbinolamine lactone motif
(–)-Lycojapodine A ■ biosynthesis suggests that many natural products can be

accessable through a common intermediate
fawcettimine-type alkaloid
O O O O
OH OH
Me H H Me H H H Me H OH
Me
N N O N
N
(+)-fawcettimine (+)-fawcettidine (+)-lycoflexine (+)-alopecuridine
Li, H.; Wang, X.; Hong, B.; Lei, X. J. Org. Chem., 2013, 78, 800.
simplified biogenesis
Me
carbon O
O OH
skeleton H
Me H
HO
N N
H rearrangement
lycolidine (+)-fawcettimine
biosynthetic common
intermediate
Me
carbon O
O OH O
skeleton H HCHO
Me H H
HO Me
N N O
H rearrangement condensation N
biosynthetic common
intermediate
Me
carbon O
O OH O
skeleton H HCHO
Me H H
HO Me
N N O
biosynthetic common
intermediate
O
H
Me
O
N
(+)-lycoflexine
Me
carbon O
O OH O
skeleton H HCHO
Me H H
HO Me
N N O
biosynthetic common –H2O

intermediate
O O
H H H
Me Me
N O
N
(+)-fawcettidine (+)-lycoflexine
O
OH
Me H OH
N
(+)-alopecuridine
[O]
Me
carbon O
O OH O
skeleton H HCHO
Me H H
HO Me
N N O

intermediate
O O
H H H
Me Me
N O
N
O
O
OH
H [O] O O
Me OH
N Me
–H2O N
(+)-alopecuridine
(–)-lycojapodine A
[O]
Me
carbon O
O OH O
skeleton H HCHO
Me H H
HO Me
N N O

intermediate
O O
H H H
Me Me
N O
N
O
OH
Me H H
N
(+)-fawcettimine
O O H
O
Me
O O N
Boc
Me
N
proposed common
intermediate
(–)-Lycojapodine A
O
H
Me
O
N
(+)-lycoflexine
O
OH
Me H H tandem conjugate addition/
N Aldol
intramolecular
alkylation
(+)-fawcettimine
O OH Boc
O O H
O N OTBDPS
Me
O O N
Boc Me
Me
N
proposed common
intermediate
O O
H H
Me N OTBDPS
O
N O Boc
Me
MgBr
(+)-lycoflexine
preparing the common intermediate
MgBr
O O OH Boc
CuBr, Me2S, LiCl, THF –78 °C NEt3•HF
N OTBDPS
then: MeCN, rt
Me Me
H
N OTBDPS
75%
O Boc
O OH Boc 1. collidine, MsCl O O Boc

N OH CH2Cl2, 4 °C N OMs
Me 2. DMP, CH2Cl2 Me
94% 80% over 2 steps
preparing the common intermediate
O O Boc O O Boc
NaI
N OMs N I
acetone, rt.
Me Me
84%
O O Boc
DBU Me
N I O H
O
MeCN, rt. Me
H O
N
Me Boc
O
RBocN
65%
synthesis of (+)-alopecuridine
CHO
1. NaBH4, MeOH, rt. OsO4, NaIO4 TMSO H
O H TMSO H O
O O Me
Me 2. TMSOTf, 2,6-lutidine Me DABCO N
N CH2Cl2, –78 °C N dioxane/H2O Boc
Boc Boc
87% 96%
SmI2 (5 equiv) OH O O
TMSO 1. TBAF, THF, rt
H OH Me H OH
Me
HMPA (20 equiv) N 2. TPAP, NMO•H2O N
Boc Boc
THF, –78 °C to rt. 4 Å MS, CH2Cl2, rt
80% 50%
synthesis of (+)-alopecuridine and (–)-lycojapodine A
HO O
O O Me H OH
TFA, CHCl3
Me H OH N
•TFA
N then NaHCO3
Boc
94%
(+)-alopecuridine•TFA
12 steps
synthesis of (+)-alopecuridine and (–)-lycojapodine A
HO O
O O Me H OH
TFA, CHCl3
Me H OH N
•TFA
N then NaHCO3
Boc
94%
(+)-alopecuridine•TFA
12 steps
O
HO O
DMP, TFA
Me H OH O O
N 4 Å MS, 30 °C, 4 h Me
•TFA
N
80%
13 steps

O
O
CO2Me
O Me
HO
HO
HO H
OBn
MeO2C H OH
HO
OH

OH O O
O O
Me
HO
N
O O Me

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Strategies in Synthetic Planning

Modern Stylistic Points in Retrosynthetic Analysis

–Paul Reider, Graduate Synthesis

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

■ E. J. Corey, Harvard University

■ MIT 1945–1950, John Sheehan

■ Nobel Prize in Chemistry 1990

■ Detailed retrosynthetic analysis and techniques

retron keying elements

Hoffmann, R. W. Elements of Synthetic Planning, Springer-Verlag, Berling Heidelberg, 2009, pp 3–5.

retron alkene keying element

Hoffmann, R. W. Elements of Synthetic Planning, Springer-Verlag, Berling Heidelberg, 2009, pp 3–5.

1. The application of powerful transforms:

1. The application of powerful transforms:

Enquist Jr., J. A.; Stoltz, B. M. Nature, 2008, 453, 1228.

1. The application of powerful transforms:

2. Lateral movement through a non-simplifying transform

1. The application of powerful transforms:

2. Lateral movement through a non-simplifying transform

1. The application of powerful transforms:

2. Lateral movement through a non-simplifying transform

3. Disconnections that actually increase molecular complexity

1. The application of powerful transforms:

2. Lateral movement through a non-simplifying transform

3. Disconnections that actually increase molecular complexity

Transform-Based Structure-Goal Topological Strategies

Stereochemical Strategies Functional Group-Based Strategies

What to disconnect and what to preserve

What to disconnect and what to preserve

to make symmetrical fragments building block groups (alkyl, aryl)

either E or Z double bonds skeletal bonds proximal to remote stereocenters

1–3 bonds away from functional groups

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

What to disconnect and what to preserve

to make symmetrical fragments building block groups (alkyl, aryl)

either E or Z double bonds skeletal bonds proximal to remote stereocenters

1–3 bonds away from functional groups

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

PGA2 SN2 cuprate addition

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

What to disconnect and what to preserve

to make symmetrical fragments

C–X bonds (C–heteroatom, esters, amides, etc)

easily formed rings (lactone, lactam, hemiacetal)

What to disconnect and what to preserve

to make symmetrical fragments

C–X bonds (C–heteroatom, esters, amides, etc)

easily formed rings (lactone, lactam, hemiacetal)

Falck, J. R.; Yang, Y.-L. Tetrahedron Lett. 1984, 25, 3563.

What to disconnect and what to preserve

What to disconnect and what to preserve

What to disconnect and what to preserve

What to disconnect and what to preserve

McMurry, J. E.; Isser, S. J. J. Am. Chem. Soc., 1972, 94, 7132.

Topological Functional Group-Based

Phragmalin-type Limonoids Ouabagenin

Topological Functional Group-Based

Phragmalin-type Limonoids Ouabagenin

■ potent anti-cancer, antibiotic, anti-inflammatory properties

Guiding Principles of Network Analysis

■ in general: it is easier to synthesis fused rings that bridged systems

Guiding Principles of Network Analysis

■ in general: it is easier to synthesis fused rings that bridged systems