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IASO
C X
V
Synt
heph
ilia:
For
the
love
of n
atur
alpr
oduc
tsyn
thes
is
Step
hen
Han
essi
an
Uni
vers
ity o
f Mon
trea
l, C
anad
aU
nive
rsity
of C
alifo
rnia
, Irv
ine,
USA
Wed
nesd
ay, S
epte
mbe
r26,
201
2
Relevant Chemistry in the Hanessian GroupWebsite: http://osiris.corg.umontreal.ca
Natural Product SynthesisDrug Prototypes Targeted Drug Delivery
NC
O
OH
OH
O
HOMe
Me Me MeOH
NH
AcHN
Me
HCO2H
OMe
MeO
NHBu
O
OHH2N
Carbohydrates
NMe
P
MeN O
R
asymmetric conjugate additionasymmetric cyclopropanationasymmetric olefinationasymmetric aziridinationasymmetric phosphonates
Molecular Recognition and Self-Assembly
Asymmetric Synthesis
MMMMMMMo
N
O
N
O
HN
HN
O
OHNO
HN OHN
CO2Me
O
BocHN
RNA Ligands and Antibiotics
Renin InhibitorJ. Org. Chem.2002, 67, 4261
E-Selectin AntagonistJ. Org. Chem.2002, 67, 3346
J. Org. Chem. 2000, 65, 5623Chem. Rev. 1997, 97, 3161.
SupraminolsJ. Am. Chem. Soc.
1995, 117, 7630
�-PeptidesJ. Am. Chem. Soc.
1998, 120, 8569
Hairpin StructureChem. Eur. J.2002, 8, 111
AminoglycosidesAngew. Chem., Int. Ed.
2004, 43, 6735
O
BorrelidinJ. Am. Chem. Soc.2003, 125, 13784
Neuraminidase Inhibitor
J. Am. Chem. Soc.2002, 124, 4716
OH
ONaO
OO
O
OH
O
O OHMe
OHHO
OH
HO
NMorphinomimetic
Angew. Chem., Int. Ed..2001, 40, 3810
NHO
H
H
NH
O
O
HO
Ph
Ph
NH
O
NNH2H2N
OscillarinJ. Am. Chem. Soc.
2004, 126, 6064
Tubular SuperstructureJ.Org.Chem. 2008, 73,1181
Chemical DiversityHNHO2C CO2H
CHO
Me
Ar
Tetrahedron Lett.2002, 43, 9441
CatalysisO
NO2
99% ee
Org. Lett.2006, 8, 4787,2000, 2 ,,2975
O O
N3Me
ONH
O OO
N
N
O
O
Fe
Bioorg.Med.Chem 2008,16, 2921
Super paramagnetic iron oxidenanopolymer
(1982)�
Lecture outline
• Definitions• The Why, What, and How of synthesis• The visual dialogue with molecules• The psychobiology of heuristic synthesis planning• Living through a total synthesis• Synthesis: from whence we came, to where we are going• Ciao
The�‘academic’ Synthetic�Chemist’s�Dilemma
1. Incentives, reasons, and rationales for synthesis (The Why of synthesis)2. Which molecule should I synthesize ? (The What of synthesis ) 3. How can I make sure I have an efficient and viable route ? (The How of
synthesis)4. Where and with what do I begin?
Expected beforeend of 2012
18 ChaptersOver 900 pages
The Why of Synthesis
• Nature: the provider, the healer and the enticer (new antibiotics)
• The supply problem (practical syntheses of sparse compounds)
• Synthesis as a seeker of truth (correction of misassigned structures)
• Beyond the molecule (buckeyballs and friends)
• Exploring new dimensions in methodology (efficiency and practicality)
• Creating new entities and materials (nanomolecules and beyond)
Fascinating Molecular Shapes
Twistane
O
Natone
Homopentaprismane
OO
OOO
O
HO2C
OH
CP-263,114 (Phomoidride B)Corannulene
Cubane Adamantane Dodecahedrane Bullvalene
C60 f ullerene
The What of Synthesis Selected Highlights in Total Synthesis
Selected Highlights in Total Synthesis of Complex Natural Products
OH
N
N N
N
O
NH2
O
NH2
OH2N
O
H2N
OH2N
H
O
NH
OP
OO
N
N
O
NH2
OH
OO
CoCN
Vitamin B12Woodward and Eschenmoser, 1973
NHN
H2N OO
O
HOOH
OH
TetrodotoxinKishi, 1972
OH
H
CO2HHO
O
H
Gibberellic acidCorey, 1978
O
O
OH
OHO
OHOH
Erythronolide BCorey, 1978
N
NMe
OAcCO2Me
OHMeO
VindolineBüchi, 1975
H
O
O
OHHO
O O
O
OH
O
O
OH
OMe
HONMe2
Erythromycin AWoodward, 1981
HO
HO
O
H
Taxol
O
OHO
O
OO H
O
HO
O
HO
Ginkgolide B
OH
H
OH
OH
HO
H
O
OH
Phorbol
N
O
N
H
H
HO
Strychnine
HN NO
NO
O O
H
H
NNH2
O
NH2
Ptylomycalin A
H
Magnus, 1992*Stork, 1992*Overman, 1993Kuehne, 1993*, 1998Rawal, 1994*Martin, 1996*†
Bonjoch, 1999Vollhardt, 2000*Shibasaki, 2002Bodwell, 2002*†
Mori, 2002Fukuyama, 2004Padwa, 2006*Andrade 2010*Reissig 2010*†
Vanderwal 2011MacMillan 2011
Corey, 1988Crimmins,1999
Nicolaou, 1994Holton, 1994Danishefsky, 1995Wender, 1997Mukaiyama, 1998Kuwajima, 1998
Overman, 1995
Wender, 1997Cha, 2001
O OH
OOBzHO
HOAc
AcO
O
O
OH
BzHN
Ph
Selected Highlights in Total Synthesis of Complex Natural Products
Selected Highlights in Total Synthesis of Complex Natural Products Selected Highlights in Total Synthesis of Highly
Oxygenated Complex Natural Products
OH
O O
NH
HN
NH
OH
O
ONH2
ONHMe
OHN
NH O
OHO Cl
ClO
OHHO
NHO
HO2C
OO
O OH
OHHOH2NHO
Vancomycin
HO2C OO O
O
O
OO
O
NH
H
H H
OHH
H
H
H
OH
Azaspiracid-1Nicolaou, 1998Evans (aglycon), 1998Boger (aglycon), 1999
Nicolaou, 2005Evans, 20007
O
OH OH
OMe
OO
O OH
O
OH O OH OH
MeO
O
OMe
OH
HO
O
OMe
Swinholide A
O
OO
O
O
O
O
O
O
O
O OO
OO
HO HH
H
H
H
H H
H H
H
H
OH
OH
OH
Halichondrin B
OH
O
O
CO2MeOH
OHAcOMeO2C
O
O
H
O OO
Azadirachtin
Paterson, 1994Nicolaou, 1996
Ley, 2007Kishi, 1992
O
O
OH
O
HOO
O
O
OH
OH
OOH
OMe
OH
OH
OH
CytovaricinEvans, 1990
Selected Highlights in Total Synthesis of Highly Oxygenated Complex Natural Products
Selected Highlights in Total Synthesis of Highly Oxygenated Complex Natural Products
HO NH
NH
OOH
O O
OH
OH
OH
HOHO
OH
H
OH
OH
HOOH
OHO
O
OOH
HOHO
OHOH
OH
OH OH
OH
HOOH
OHHO
OH
OOH
OHOH
OH
OHOH
OH
HOHO
OHO
OHHOOH
OH
OH
OO
OH2N OH
PalytoxinKishi, 1989 & 1994
Highlights in Total Synthesis of Highly Oxygenated Complex Natural Products
Selected examples of recently marketed drugs produced by total synthesis
• Asymmetric Synthesis:
• Resident-chirality control (substrate control)• Reagent or catalyst control (external control).• a. Metal and ligand-based; • b. Metal-free based (organocatalysis)
• The ‘Chiron Approach’ : (Structural and stereochemical elements dictate strategy)• Maximizing chirality and structural convergence using nature’s chiral non-racemic molecules
(amino acids, carbohydrates, hydroxy acids, terpenes)
• The ‘Synthon Approach’ (Reaction feasibility dictates strategy)
• Biomimetic Synthesis
The How of Synthesis Metal-catalyzed Chemistry
B.M. Trost
Bryostatin 16
N
NHBoc
NH
MeNO
Ph
t-Bu
1. (20 mol%), TsOH
2. NaBH4, MeOH
78% 2 steps
N
MENO
Ph
t-Bu
N
BocHN
NNHBoc
NR*
NNBoc
HBr Br
5 steps
NNMe
HBr
Flustramine B
TsO
HO
H
O+
Br
Br
Organocatalysis in Natural Product Synthesis
D.W.C. MacMillan
Biomimetic Cascade Reactions in Total Synthesis
Biomimetic Cascade Reactions in Total Synthesis
PhCO2R
CO2H
H
HH
Ph
PhH
HH CO2HHH
H
Diels-Alderdisrotatory
Ph
CO2R
conrotatory
Endiandric acid B
8 electrocyclization
6 electrocyclization
Nicolaou, K. C.; Petasis, N. A.; Zipkin, R. E.; Uenishi, J. J. Am. Chem. Soc. 1982, 104, 5555
Living Through a Total SynthesisA. Choice of target moleculeB. Perceptive powers and seeing
through the mind’s eyeC. Emergence of a strategyD. Generation of a synthesis plan
E. ExecutionF. EnduranceG. Contribution to scienceH. RecognitionI. Lasting value
� Relevance� Heuristics, open-eyed serendipity,
and personal bias� Individual prowess, creativity� Attention to detail, possible fixation
(beware!)� Efficiency, practicality� What price synthesis?� New concepts, reactions, reagents,
etc.� Fame, fortune, legacy� Coworker training
OO
Me
Me
Me
O
Me
O
OH
HOH
Me
OMe
OOMe
OMeOO
OMe
Me
HO
Avermectin B1a(1986)
Reserpine(1997)
Bafilomycin A1(2001)
Ionomycin Ca salt(1990)
Borreledin(2003)
OO
O
O OH
MeMe
Me
Me
MeMe
OMe
O
O
OMe
Me
H Me Ca
NCO
O
OH
OH
OHMeMeMe
MeHO
O
OH
OH
HO
Me Me Me Me
MeOMe
O
OMe
OH
MeO
NNH
MeO
H
MeO2C OROMe
H
H
Total Synthesis Scenarios (synthephilia)• The Nike approach: ‘Just do it’• The Kekulé approach: ‘I dreamed of it’• The Archimedes approach: ‘Eureka, eureka’• The Sinatra approach: ‘I did it my way’
OOMe
O
OMe
OMe
MeO
O
R
R
OO
Me
Me
Me
O
Me
O
OH
HOH
Me
OMe
OOMe
OMeOO
OMe
Me
HO
OO
O
O OH
MeMe
Me
Me
MeMe
OMe
O
O
OMe
Me
H Me CaNNH
MeO
H
MeO2C OROMe
H
H
O
OH
OH
HO
Me Me Me Me
MeOMe
O
OMe
OH
MeO
NCO
O
OH
OH
OHMeMeMe
MeHO
Reserpine(1997)
Borrelidin(2003)
Bafilomycin A1(2001)
Manassantin A, B(2006)
Avermectin B1a(1986)
Ionomycin(1990)
TARGET MOLECULE
Analysis, discovery, connectivity,stereochemical and functional decoding,
strategic bond-breaking, etc.VISUAL
Subunit analysis(analogic)
Suitable building block(template fitting synthon or chiron)
VISUAL ANDRELATIONAL
Reflex action(instinctive)
Key reaction type
VISUAL ANDREFLEXIVE
Suitable blueprint(reaction, reagents, schemes) LOGISTIC, ANALYTIC, LINEAR
Laboratory(execution) MANUAL, TEMPORAL, HOLISTIC
The psychobiology of heuristic synthesis planning:Visual and mental thought processing
Whereas the left hemisphere of the brain analyses over time,the right hemisphere synthesizes over space
Essentials of the Chiron Approach
August 17 issue,2012
Oidiolactones: The synthesis in a capsule
HO
O
O
H
1
4 6
89
12
14
19
Catalytic ReformatskyBurgess dehydration
BromolactonizationElimination
Baylis-Hillman
XOxidationFunctionalization
Epoxidation
O
O
Stereoselectivemethylation
H
O
H
O
CO2Me
O
OWieland-Miescher
Ketone
OO
OH
HHO
O
OH
H
CO2R
with Boyer, N.; Reddy, G. J.; Deschenes-Simard, B. Org Lett. 2009, 11, 4640
Visual relational and visual reflexive thought processing from eye to mind’s eye
Me
O
HO O
O
O
Me
MeH
H
Dihydromevinolin
MeRO
MeH
H
R'O
O
MeRO
MeH
H
NO2
O
OR'
+
nitronate anion1,4-conjugate
addition Baeyer-V illigeroxidation
MeO
MeH
H
O
Me
MeO
OO
O
OTBDPS
OMe
NH2
COOH
COOH
L-glutamic acid
intramolecularDiels-Alder
reaction
A CB
D E F
"Me"
"O"
OO
Me
HHO
O Me
HH
H
MeH
H
OO
O
O Me
HH
H
MeH
HMeH
HH
endo-transition state exo-transition state
vs.
As an entity, the target molecule is different from the sum its parts, but the visual chasm thatseparates the two gradually disappears, as the synthesis plan takes shape, like a progressive epiphany of thoughts and images
with Roy,�P.;�Petrini,�M.;�Hodges,�P.�J.;�Di�Fabio,�R.;�Carganico,�G.� J.�Org.�Chem.�1990,�55,�5766
Synthesis and the mind’s eye
NN
H
MeO2CHO
Me
Vincamine[L-Aspartic acid]
The False MirrorR.Magritte
(1928)
W. C. Still
HN
H. Rappoport
L. A. Paquette
H. Hiemstra
NOMeO
Me
O
ent-Gelsedine[L-Malic acid]
Synthesis and the mind’s eye
Mechanism and knowledge-based visual relational thinking
Key strategic bond construction-based visual reflexive thinking
Functional group and chiral template-based visual relational thinking
Pactamycin
Isolation• Isolated in 1961 from
Streptomyces pactum byscientists at the former Upjohn Company.
• Proposed structure of pactamycin was reported in 1970 and corrected in 1972 with help of X-ray crystallographic studies.
Biology
• Exhibits activity against Gram positive and Gram negative bacteria.
• Potent in vivo and in vitro cytotoxic effects as well as antimicrobial activity.
• Potent protein synthesis inhibitory activity in prokaryotes as well as in eukaryotes.Structure:
Wiley, P. F., et al. J. Org. Chem. 1970, 35, 1420.Duchamp, D. J., et al. American Crystallographic Association Meeting. 1972, April, p. 23.
Isolation and biological activity:Bhuyan, B. K., et al. Antimicrob. Agents Chemother., 1961, 184.Argoudelis, A. D., et al. Antimicrob. Agents Chemother., 1961, 191
NH2
OHNH
MeHO
OOHN
O
MeMe
O
O
HO
Me
• Aromatic stacking in pactamycin mimics two consecutive mRNA bases.Pactamycin displaces mRNA in the E-site, preventing movement through the 30S subunit.
Ramakrishnan, V. et al. Cell 2000, 103, 1143
Unique interactions
HOCO2H
Me
NH2
ROO
HA
B3
Claisen condensation
2oxazoline
1 ester
4 extension toMe ketone
5 oxidation, then intramolecular aldolwith methyl ketone
NH2
NHOH
OMeOH
NH
HOMe
O
HO
Me
O
Me2N
ketene-mediated esterification
Grignard
O
Me
Yb(OTf)3-mediatedepoxide opening
isocyanatecoupling
Claisen condensation
1 3
8
7
5
O
N
OMe
HO OR
Ar
C
Major challenge: How to orchestrate the sequence and type of reactions ?
Cyclopentenone core
Absolute configuration Epoxidation and Reduction
OTES
ON OTBDPS
Me
Ph
OH
HHO H 2.47% NOE
2.11% NOE
no NOE observed
NaBH4, CeCl3 > 20 : 1
NaBH4 5.25 : 1
LiBH4 10 : 1
KBH4 5 : 1
Zn(BH)4 > 20 : 1
BH3.THF decomposition
OO
N
Me
PMPTESO OTBDPS
H2O2, NaOH
88%
OO
N
Me
PMPTESO OTBDPS
O
conditions
OHO
N
Me
PMPTESO OTBDPS
O
OHO
N
Me
PMPTESO OTBDPS
O
Introduction of azide First major setback: wrong epoxide !
expected
=
obtained
Epoxide inversion via solvolysis
ON
Me N3
PMPOHOH
OHMe OH
ON
Me N3
PMP OTBDPSMe OH
O
1. TBDPSCl, TEADMAP, DCM
2. Tf2O, pyridine,DMAP, DCM
96%2steps
‘Good’ epoxide !
Epoxide openingOH
Me OH
HN
NH2Me
ONH
O
O
HO
Me
OMe
O
ON
Me N3
OTBDPSMe OH
O
H2NMe
Yb(OTf)3, toluene
ON
Me N3
OTBDPSMe OH
OHNH
Me
81%(91% bsmr)
(10 eq.)
80oC
MeO MeO
Pactamycin and Pactamycate
pactamycatepactamycin
Wiley, P.F.; Jahnke, H.K.; MacKellar, F.; Kelly, R.B.; Argoudelis, A.D.J. Org.Chem. 1969, 35, 1420.
�
mp 210oC (decomp.)[�]D +26o (in DMF)
Crystalline pactamycate !
ONH
Me N3
OHMe OH
OHNH
O
O
ONH
Me N3
OMe OH
OHNH
O
OK2CO3, DMA
NH2
NHOH
OMe OH
NH
OMe
O
HO
Me
O
O
MeOH: EtOH
Lindlar, H2
HO Me
OCN
O MeCO
98% 83%
O
HO
Me
Esterification method, Porco, J. A et alOrg.Lett. 2002, 4, 3103
Synthetic pactamycate
Nearing the summit ?
ON
Me N3
OTBDPSMe OH
OHNH
1. 2 N HCl,63%, 83% bsmr
MeO
HOH2N
Me N3
OTBDPSMe OH
OHNH
2. DIBALH, DCM,90%
PMBzOH2N
Me N3
OTBDPSMe OH
OHNH2 N HCl
63%, 83% bsmr
OHMeHO
HN
NH2Me
HOHN
O
O
HO
Me
OMe
O
Me2N
Cl3COCOCl, TEA
activated charcoalTHF
N3
H2N
PMBzOMe
MeOH
NH MeOH
OTBDPS
N3
MeOH
NHO
OTBDPS
HNO
PMBzO
Me
91%
D### Carbamate ! Extreme proximity effects
A very uncooperative amine ! More surprises…..OHMe
HO
HN
NH2Me
HOHN
O
O
HO
Me
OMe
O
Me2N
ON
Me N3
PMP OTBDPSMe OH
OHNH
2 N HCl,THF, r.t. PMBzO
H2N
Me N3
OTBDPSMe OH
OHNH NaH, BnBr
TBAI, THFPMBzO
H2N
Me N3
OBnMe OBn
OTBDPSNH
63%84%
Cl3COCOCl, TEA
activated charcoalTHF
N3
N
PMBzO
MeOBn
NHOTBDPS
OBn
HNMe2 neatN3
NH
PMBzO
MeOBn
NHOTBDPS
OBnMe2N
OCO
85%
96%
ON
N3
PMP OTBDPSOH
OHNH
2. TASF, THF 0oC to r.t., 95%
PMBzOH2N
N3
OHOH
OHNH 2,2-DMP : DCM (1:5)
CSA, r.t.86%
PMBzOH2N
N3
OOH
ONH
activated charcoalTEA, THF
then HNMe2neat
PMBzO
NH
N3
OOH
ONH
N
O
1. 2N HCl ,THF, r.t. 63% (93% bsmr)
Cl3COCOCl
86%
Neutralizing the ‘enemy’
PMBzON
N3
OOH
ONH
CO
via:
Pactamycin: reaching the summit !
PMBzO
NH
Me N3
OMe OH
ONH
Me
N
O
Me Me
1. DIBALH, DCM, -78oC, 90%2. Lemieux-Johnson 80%
HONH
Me N3
OHOH
OHNH
Me
O
O
NMe
Me
3. TFA: MeCN: H2O (5:1:1), 0oC to r.t. 85%
OH
Me
OCN
, K2CO3, DMA HONH
Me NH2
OMe OH
OHNH
Me
O
O
NMe
Me
O
Me
HO
1.
2. Lindlar, H2, MeOH: EtOH (1:1)
82%, 2 steps
Me
29 linear steps, 3% overall yield 700 MHz nmr, HPLC,HRMS; optical rotation
The long and arduous climb to the summit…
NH2
OHMeNH
MeHO
OOHN
O
MeMe
O
Me
O
HO
Me
NH2
NHOH
OMeOH
NH
HOMe
O
HO
Me
O
Me2N
ketene-mediatedesterif ication
Grignard
O
Me
Yb(OTf )3-mediatedepoxide opening
isocyanatecoupling
Claisen condensation
1 3
8
7
5
with Vakiti, R.R.; Dorich, S.; Banerjee, S.; Lecomte, F.; Del Valle, J. R.; Zhang, J.; Deschesnes-Simard, B. Angew. Chem. Int. Ed. 2011, 50, 3497
OH
O
OH
NC
O
CO2HH
J. Am. Chem. Soc. 2003, 125, 13784
O
O
OH
HOH OH
O
O
O
OCa
H
J. Am. Chem. Soc. 1990, 112, 5276
H
HO
OO
OHO
J. Org. Chem. 1990, 55, 5766
NNH
O
H
H
H
MeO2C
J. Org. Chem. 1991, 56, 2947
OOHOH
H H OH OH O
O
Org. Lett. 2005, 7, 3989
O
O
OMe
OMeO
MeO
MeO
MeO OMe
OH OHOrg. Lett. 2006, 8, 5477
