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Advanced
Organic
Synthesis
به نام خدا
Dr M. Mehrdad University of Guilan, Department of Chemistry,
Rasht, Iran
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2.
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J. A. C. S. 1981, 103(25), ……
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Cala Ratjada (Mallorca) isolated from soil bacteria
Ratjadone potent cancerostaticum and fungicide
trans,trans-diene
cis,trans-diene
Perhydro pyran
Perhydro pyran with double band
disconnected by a retro-Heck coupling
Wittig reactions Bhatt, U. et al., J. Org. Chem. 2001, 66, 1885-1893
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hetero-Diels-Alder reaction of an acrolein derivative
retro-opened to a -hydroxy epoxide
antitumor activity
Boger, D. L. et al., J. Am. Chem. Soc. 2001, 123, 4161-4167
Fostriecin
Frondosin B
contains four condensed rings:
phenol
furane cycloheptene
cyclohexene
from a Diels-Alder reaction
from an intramolecular Friedel-Crafts acylation
Inoue, M. et al., J. Am. Chem. Soc. 2001, 123, 1878-1889
isolated from a sponge is anti-inflammatory
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The rest is Sharpless and phenol chemistry
Furane from a base- and palladium-catalyzed intermolecular addition of a phenolate to an alkyne.
Sonogashira Coupling
Alkyne from a
10 Cohen, F. et al., J. Am. Chem. Soc. 2001, 123, 10782-10783
An alkaloid was isolated from a Jamaican sponge useful to treat autoimmune responses, and inhibits protein-protein interactions two tricyclic
guanidine derivatives
branched octanoic acid chain
was disconnected to give a guanidine hemi-aminal and a chiral alcohol in the side-chain, which could be substituted stereoselectively
attached via a -ketoester carbanion
from a 1,3-diamine and Cbz-protected carbonimidothioate
Batzelladine F
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A triazacyclophane Tripodal Receptor Molecules (as hinge)
selectively sulfonated and trifluoroacetylated
Acetylation with alkyl chloroformate
i) triflate +methanol ii) Fmoc-N-hydroxy- succinimide
Deprotection O-NBS (thiolysis) Aloc(Pd-catalyzed alkyl transfer to anilinium p-toluenesulfinate)
Opatz, T. et al. J. Comb. Chem. 2002, 4, 275-284
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3. Tandem Reactions
Tandem reactions form several covalent bonds in one sequence without isolating the intermediates. Also called “domino” or “cascade” reactions "Multistep reaction'' or "one-pot sequence“ (descriptions of the procedure)
The ACS search program produces: 507 “tandem”, 115 “cascade”and 34 “domino”titles
published since 1996-2002
1250 “tandem”, 576 “cascade”and 297 “domino”titles
published since 2008-14
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Some sterically hindered, SnCl4-catalyzed hetero-Diels-Alder cyclizations of -unsaturated ketoesters with alkene alcohols do not occur intramolecularly.
Large substituents on the ketoester prevent the formation of medium-sized rings and the first reaction is a linear dimerization combined with the formation of one dihydropyran unit. The second reaction then gives a second dihydropyran and produces a macrocyclic oligo-ether with good yield.
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Acetylacetate reacts with zinc methylene iodide (Furukawa reagent)
zinc enolate add its methylene group to the enolate's double bond
Aldehydes then decompose the cyclopropane formed and undergo a Reformatsky addition.
Chain extension-aldol addition tandem
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Acetals were then reactive enough to decompose the enolate and form a second CC bond stereoselectively the presence of chiral phosphines
three-step reaction a cyclohexanone derivative underwent zinc enolate formation and Michael addition in one step
16
Dieckmann cyclization with a neighboring benzyl ester
The synthesis of a highly functional arene derivative
coupling of a cyanide Michael addition to propargylic acid
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4. Green Chemistry
There are U.S. and European Green Chemistry Programs, which try to establish environmentally benign synthetic procedures. Energy requirements, waste, and the number of separation steps are all minimized by increased selectivity of the reactions catalyzed. Heck-, Sharpless- and Noyori-type reactions are successful endeavors. Another approach is to replace solvents by water or by supercritical fluids, in particular CO2. CO2 can replace chlorinated solvents. Replacement of soluble Lewis acids by mesoporous solids containing bound sulfonates or aluminum chloride should also become common practice. The solids can be filtered off and usually reactivated and recycled. This helps to prevent waste.
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most typical for green chemistry, educts should preferably come from renewable sources, in particular glucose
Furthermore syntheses should be atom-efficient, and reagents as simple as possible. Catalysed reactions are preferable.
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Household and large-scale industrial chemicals, e.g. chelators, should always be biodegradable, as should the intermediates in their synthesis. Boger's iminodiacetic acids are good examples, because they only use succinic acid derivatives
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The Sonogashira Coupling
16. L. Cassar, J. Organomet. Chem. 1975, 93, 253 – 259.
17. H. A. Dieck, F. R. Heck, J. Organomet. Chem. 1975, 93, 259 – 263.
18. K. Sonogashira, Y. Tohda, N. Hagihara, Tetrahedron Lett. 1975, 16, 4467 – 4470.
19. For a brief historical overview of the development of the Sonogashira reaction, see: K. Sonogashira, J. Organomet. Chem. 2002, 653, 46 – 49.
20. R. D. Stephens, C. E. Castro, J. Org. Chem. 1963, 28, 3313 – 3315.
21. a) M. Alami, F. Ferri, G. Linstrumelle, Tetrahedron Lett. 1993, 34, 6403 – 6406; b) J.-P. Genet, E. Blart, M. Savignac, Synlett 1992, 715 – 717; c) C. Xu, E. Negishi, Tetrahedron Lett. 1999, 40, 431 – 434;
• The coupling of terminal alkynes with vinyl or aryl halides via palladium catalysis was first reported independently and simultaneously by the groups of Cassar[16] and Heck[17] in 1975.
• A few months later, Sonogashira and co-workers demonstrated that, in many cases, this cross-coupling reaction could be accelerated by the addition of cocatalytic CuI salts to the reaction mixture.[18,19]
• This protocol, which has become known as the Sonogashira reaction, can be viewed as both an alkyne version of the Heck reaction and an application of palladium catalysis to the venerable Stephens–Castro reaction (the coupling of vinyl or aryl halides with stoichiometric amounts of copper(I) acetylides).[20]
• Interestingly, the utility of the “copperfree” Sonogashira protocol (i.e. the original Cassar–Heck version of this reaction) has subsequently been “rediscovered” independently by a number of other researchers in recent years.[21]
R2 Xcat. [Pd0Ln]
base
R1 = alkyl, aryl, vinyl
R2 = alkyl, benzyl, vinyl
X = Br, Cl, I, OTf
R2R1 H R2
Mechanism of the Sonogashira Coupling
PdPh3P PPh3
Ph3P PPh3
PdPh3P
Ph3P PPh3Pd
Ph3P
Ph3P
- PPh3
- PPh3
Pd0
Pd0
Pd0
Br
PdPh3P
Br PPh3
PdII
PdPh3P
PPh3
R1
R1
Cu
CuBr
H
R1
NEt3
PdPh3P
Ph3P
R1
R1
R1
NEt3H
PdII
PdII
K. C. Nicolaou, S. E. Webber, J. Am. Chem. Soc. 1984, 106, 5734 – 5736
The Sonogashira Coupling: Eicosanoid 212
MeBr
OTBS
TMS
SonogashiraCoupling
[Pd(PPh3)4] (4 mol%)
CuI (16 mol%)nPrNH2, C6H6, 25 °C
R
Me
OTBS
AgNO3,KCN
208: R = TMS
209: R = H
210, [Pd(PPh3)4] (4 mol%)
CuI (16 mol%)nPrNH2, C6H6, 25 °C
76% Overall from 208
BrCO2Me
OTBS
Me
OTBS
CO2Me
OTBS
Me
OH
CO2H
OH
SonogashiraCoupling
206
207
210
211212
P. Wipf, T. H. Graham, J. Am. Chem. Soc. 2004, 126, 15346 –15347.
The Sonogashira Coupling: Disorazole C1
Me
PMBO
Me
OH
Me
Me
PMBO
Me
OH
Me
MeO O
N
CO2Me
SonogashiraCoupling
218[Pd(PPh3)2Cl2] (4 mol%)
CuI (30 mol%), Et3NMeCN, -20 °C, 94%
220, DCC, DMAP80%
Me
PMBO
Me
O
Me
MeO O
N
CO2Me
O
N
O
I
OMe
218[Pd(PPh3)2Cl2] (5 mol%)
CuI (20 mol%), Et3NMeCN, -20 °C, 94%
SonogashiraCoupling
Me
PMBO
Me
O
Me
MeO O
N
CO2Me
O
N
O OMe
OH
Me Me
OPMB
Me
Me
OH
Me
O
Me
MeO O
N
O
N
O OMe
O
Me Me
OH
Me
O
disorazole
N
O
RO
O
I
OMe
218: R = Me220: R = H
217 219
221
222223: Disorazole C1
The Sonogashira Coupling: Dynemicin
MeO2CN
OMe
Me
O
O
Br
MeO2CN
OMe
Me
O
OIntramolecularSonogashira
Coupling
[Pd(PPh3)4] (2 mol%)CuI (20 mol%)toluene, 25 °C
243 244
MeO2CN
OMe
Me
O
O
244
HH
H
H
MeO2CN
OMe
Me
OH
246
[Pd(PPh3)4] (2 mol %)CuI (20 mol %)toluene, 25 °C
BrCO2Me
1)
2) LiOH, THF/H2O65% overall
SonogashiraCoupling
MeO2CN
OMe
Me
OH
CO2H
Diels-Alder
2,4,6-Cl3C2H2COClDMAP, toluene, 25 °C
50%
248
247
YamaguchiMacrolactonisation/
Diels-Alder
HN
OMe
Me
H
OO
O
OMe
OMe
OMe
CO2Me
dynemicin
249: tri-O- methyl dynemicin Amethyl ester
a) J. Taunton, J. L. Wood, S. L. Schreiber, J. Am. Chem. Soc. 1993, 115, 10 378 – 10379
b) J. L. Wood, J. A. Porco, Jr., J. Taunton, A. Y. Lee, J. Clardy, S. L. Schreiber, J. Am. Chem. Soc.
1992, 114, 5898 – 5900
c) H. Chikashita, J. A. Porco, Jr., T. J. Stout, J. Clardy, S. L. Schreiber, J. Org. Chem. 1991, 56, 1692 – 1694
d) J. A. Porco, Jr., F. J. Schoenen, T. J. Stout, J. Clardy, S. L. Schreiber, J. Am. Chem. Soc. 1990, 112, 7410 – 7411.