Principles for designing economical multistep organic synthesis.

1. ECONOMIES
OF
ORGANIC SYNTHESIS
Manoj Kumar Sahoo

3. INTROduCTIO
N
 CHEMICAL GENOME
CHEMIST IN MOLECULAR REVOLUTION
 INTERPRETING CHEMICAL GENOME
 LESSONS FROM NATURAL PRODUCTS
 REVERSE MOLECULAR ENGINEERING
 STRUCTURE, FUNCTION, DESIGN & SYNTHESIS

5. HISTORY OF ORGANIC SYNTHESIS

6. PENICILLIN
(1957)
OXAZOLONE β LACTAM

7. PALYTOXIN
128 carbon atoms
64 Stereocentres
7 Geometrical

8. HENdRICSON’S CONCEPT
“ The ideal synthesis creates a complex skeleton…. in a
sequence of successive construction reactions involving no
intermediate refunctionalizations and leading directly the
structure of the target not only it’s skeleton but also its
correctely placed functionality”
J. Am. Chem Soc.,1975, 97, 5784

9. STEP ECONOMY
Nature, 460, 2009, 197

10. GuIdELINES
A. SINGLE OPERATION, MULTISTEPPROCESS
(Cascade, tandem, domino, chain, regenerative)

11.  Pericyclic,
 electroPlilic,
 NucleoPhilic,
 radical,
 Metal based

12. N
U
C
L
E
O
P
H
I
L
L
I
C

14. B. DESIGN & DISCOVERY OF NEW
REACTIONS WITHHIGHTRC
TRC: TARGETRRELEVANT COMPLEXITY
TAXOL
ANTICANCERANTIRETROVIRAL
PROSTRATI
N
MLn

15. 0
10
20
30
40
50
60
1 2 3 4 5 6 7 8 9 10 11
NO OF STEPS
COMPLEXITY

16. C. PROTECTIVE GROUPFREE
Masks one functional group
Solves selectivity problems
X Y Y
X Z Z
PG
PG

17. GuideliNes
1. In situ protection & deprotection
O
O
PG
O
PG
HO
MgBr
O
HO
O
O
LiHMDS
OLi
O
MgBr
OLi
HO
O
HO
2. Biogenesis oriented synthesis
3. TM catalysed skeleton formation
4. Order of introduction of functional group

18. • Target-oriented
• Protecting groups
(PG) needed
• Reactivity is ‘caged’
• Target-oriented
• No protecting groups
• No enzymes
• Natural reactivity of
functional groups is
used constructively
• Function-oriented
• No protecting groups
• Enzymes needed to
promote/control reactivity
AMBIGUINE

19. Nature, 2007, 446, 404-408

20. D. FUNCION ORIENTEDSYNTHESIS (FOS)
Nature, 460, 2009, 197

21. PHORBOL ESTER DESIGNED
MAINTAINS ACTIVITY
PHORBOL ESTERS
(AcTivE TumOR PROmOTER)

22. >70 STEPS, 1.4 nM 29 STEPS, 0.3 nM
BRYOSTATiN
(REvERSE muLTidRug RESiSTANcE, ANTicANcER, mEmORY ENHANcER (ALzHEimER))
NATURE SUPPLY: 0.00014%

23. FOS : STABLE ANALOguE dESigN
(LAuLimidE)
ANTICANCER(TAXOL RESISTANT)
J. Org. Chem. 1988, 53, 3642–3644.
NATURE SUPPLY: 0.00016%

25. CONTRIBUTION FROMDRDE
N
OH
NH
O
NH
S
PSCl3/Et3N/H2O
Chem. Commun., 2009, 5409–5411

26. REdOX
EcONOmY
Angew. Chem. Int. Ed. 2009, 48, 2854 – 2867
Redox economy refers to the endeavours to reduce the
number of nonstrategic (those that do not set
stereochemistry or are not skeleton-building) or
corrective oxidation and reduction steps

27. redox economy in a synthesis achieved by properchoice of reactions
C
A
S
E
S
T
U
D
Y

30. LiNEAR iNcREASE/dEcREASE iN OXidATiON
LEvEL
BiOmimETic
APPROAcH

31. J. Am. Chem. Soc. 1995, 117,11106 – 11112.
1. Pd2(dba)3,
HCO2H
1. NaBH4, CeCl3
1.AD-mix β
NaIO42. NaBH4
3. TIPSCl
3.Bu3SnH
AIBN
HO
2.OSO4, , NaIO4
2.Raney Ni
1.NaBH4
1.HF
2. DMP
3.NaCl02

32. J. Am. Chem. Soc. 2005, 127, 15712 – 15713.

33. GUIDELINES
Redox economy should be applied tactically by examining slight
changes in the starting materials.
Choreography must be scrutinized in orderto optimally
introduce functionality and avoid chemo-unselective reactions
Whetherreagents exist that could make the redox step
unnecessary.
The most drastic maximization of redox economy( most difficult)
can occurthrough examining connectivity and choosing
challenging retrosynthetic disconnections

34. ATOM ECONOMY
Nature, 1991, 254, 1471-1477
 HOw MUCH Of rEACTANTS END Up IN THE prODUCT?
 MASS EffICIENCY
 BENEfITS : EffECTIvE USE Of rAw MATErIALS
DECrEASED EMISSIONS & wASTE DISpOSAL
 HIGHEST DEGrEE Of ATOM ECONOMY:
COMBINE TwO Or MOrE BUILDING BLOCkS wITH ANY
OTHEr rEACTANT/rEAGENT NEEDED CATALYTICALLY

35. CYCLOADDITION/ELECTrOCYCLIC
rEACTIONS
 100% Atom Economic
 Stereochemistry
 Only aromatic Transition State
(4n+2) electron
 Fails for Unactivated Dienes
UNCATALYSED
TM CATALYSED
 Co-Oligomerisation
 Regioselectivity (Tethering)
 Both 4n & 4n+2 systems
2+2, 4+2, 4+4, 3+4, 5+3, 5+2, 6+2,
6+4, 2+2+2, 2+2+2+2 etc……
MLn MLn
X
X C Y
N
X
Y

36. TMS
TMS
O
O
HO
O
H
H H
H
TMS
TMS
H
O
O
H
TMS
TMS
OO
Co complex
ESTRON
E

37. CONCLUSION
 minimizing nonstrategic redox operation & maximizing c-c bond forming
reaction
 Disconnections should be made to maximize convergency
 The overall oxidation level of intermediates should linearly escalate during
assembly of the molecularframework(except in cases where there is
strategic benefit such as an asymmetric reduction)
 cascade (tandem) reactions should be designed and incorporated to elicit
maximum structural change perstep
 The innate reactivity of functional groups should be exploited so as to
reduce the numberof (orperhaps even eliminate) protecting groups
 Effort should be spent on the invention of new methodology to facilitate
the aforementioned criteria and to uncovernew aspects of chemical
reactivity
 If the target molecule is of natural origin, biomimetic pathways (either
known orproposed) should be incorporated

38. prOf SHEEHAN prOf COrEY prOf NICHOLAU prOf BArAN
prOf TrOST prOf wENDEr prOf HOffMAN prOf HENDrICkSON

39. THANkS