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به نام خدا
Advanced
Organic
Synthesis
6
Dr Morteza Mehrdad
University of Guilan, Department of Chemistry,
Rasht, [email protected]
2
1. Elementary Retrosynthetic Analysis
1.1. Open-chain Compounds
1.2. Mono- and Bicyclic target Molecules
1.3. Bridged Polycyclic Molecules
1.4. Summary of Antithetical Analysis of Simple Molecules
2. Learning from Research papers
3. Tandem reactions
4. Green Chemistry
2.
3
J. A. C. S. 1981, 103(25), ……
4
Cala Ratjada (Mallorca)isolated from soil bacteria
Ratjadonepotent cancerostaticumand fungicide
trans,trans-diene
cis,trans-diene
Perhydro pyran
Perhydro pyranwith double band
disconnected by a retro-Heck coupling
Wittig reactionsBhatt, U. et al., J. Org. Chem. 2001, 66, 1885-1893 5
6
hetero-Diels-Alder reaction of an acrolein derivative
retro-opened to a -hydroxy epoxide
A
B
7
antitumor activity
D-glutamic acid(chiral pool)
*
Boger, D. L. et al., J. Am. Chem. Soc. 2001, 123, 4161-4167
Fostriecin
8
Sharpless Asymmetric Dihydroxylation
AD mix
water, t-BuOH
CH2OH
OHH
*
9
10
Standard Dihydroxylation
11
Possible [3+2] Cycloaddition
(DHQD)2PHAL (found in AD-mix )1,4-bis(9-O-dihydroquinidine)phthalizine
• Coordination of a chiral amine to the OsO4
leads to an asymmetric complex.
12
(DHQD)2AQNdihydroquinidine (anthraquinone-1,4-diyl) diether
13
Sharpless Asymmetric Dihydroxylation
14
Use a Pre-mix of reagent components
15
16
98
98
The Ligand Accelerates the Reaction Transfers the Chiral Information
M. H. Junttila, O. E. O. Hormi, J. Org. Chem., 2004, 69, 4816-4820.
17
Horner–Wadsworth–Emmons Reaction
The Horner–Wadsworth–Emmons (HWE) reaction involves theaddition of a stabilized phosphonate anion to an aldehyde or ketoneto afford an intermediate which undergoes an elimination reaction toform predominately the (E)-alkene. The HWE reaction has beenapplied inter- and intramolecularly to simple as well as highlyfunctionalized systems.
19
Masamune–Roush Modification of theHorner–Wadsworth–Emmons Reaction
The Masamune–Roush modification of the HWE is a very mildvariant that does not require the use of a strong base (i.e., NaH orn-BuLi) to generate the phosphonate anion. Instead, in thepresence of LiCl, a lithium chelate forms which enhances the acidityof the α-protons. Hence, DBU (1,8-Diazabicycloundec-7-ene) issufficiently basic to carry out the deprotonation of thephosphonate.
20
Since the original paper, milder bases have been used, includingtriethylamine and disopropylethylamine (Hunigs’ base). Again, thereis strong preference for the formation of the (E)-alkene when thecoupling partner is an aldehyde.
21
Still–Gennari Modification of theHorner–Wadsworth–Emmons Reaction
The Still–Gennari modification of the HWE reaction was amajor achievement, because this modification allowed access to(Z)-olefins with high stereoselectivity using a phosphonate. In this
version of the HWE, strong preference for Z-alkenes is achievedwith the phosphonate bearing electron withdrawing groups underionic dissociating conditions (crown-ether).
22
Ando Modification of theHorner–Wadsworth–Emmons Reaction
The Ando modification of the HWE reaction is yet another majorcontribution to the formation of (Z)-alkenes via phosphonates. In
this version of the HWE, diarylphosphonates are utilized.
Review: Ando, K. J. Org. Chem. 1998, 63, 8411−8416.23
Direct Synthesis of Z-unsaturated esters; a useful modification of the Horner-Emmons Olefination
Still, W.C., JACS, 1979, 101(9), 2493 & Adams, M.A.; Nakanishi, K.; Still, W.C.; Arnold, E.V.; Clardy, J.; Persoons, C.J.; JACS, 1979, 101(9), 249524
Still – Gennari Modification
Horner-Wadsworth-Emmons
Still – Gennari Modification
- Still–Gennari modification selective for Z-alkenes ( cis):
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26
27
DMP = Dess-Martin periodinane
Preparation of the Dess−Martin Reagent
The Dess−Martin oxidation is the method of choice for theoxidation of alcohols bearing sensitive functional groups.
CAUTION! The Dess−Martin precursor [1-hydroxy-l,2-benziodoxol-3(1H)-one (IBX)]was reported to be explosive under excessive heating (> 200 ºC) or impact.Sporadically, IBX did not decompose explosively at 233 ºC, but melted withbrowning.However, this cannot be taken as an indication of absence of explosivity as thesame batch showed inconsistent results. An analytically pure sample (≥ 99%) wassubjected to explosibility tests.
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Dess–Martin periodinane
The Dess–Martin (D−M) oxidation is the method of choice forthe oxidation of alcohols bearing sensitive functional groups tothe corresponding carbonyl compounds.The reagent that accomplishes this oxidation is 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one or simply the Dess–Martin periodinane (DMP).
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Stille couplingThe Stille reaction, or the Migita-Kosugi-Stille coupling, isa chemical reaction widely used in organic synthesis whichinvolves the coupling of an organotin compound (also knownas organostannanes) with a variety of organic electrophilesvia palladium-catalyzed coupling reaction.
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Mechanism
The mechanism of the Stille reaction is one of the most extensivelystudied pathways for coupling reactions.The basic catalytic cycle, asseen below, involves an oxidative addition of a halide orpseudohalide (2) to a palladium catalyst (1), transmetalationof 3 with an organotin reagent (4), and reductive elimination of 5 toyield the coupled product (7) and the regenerated palladiumcatalyst (1)
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Cram’s Rule
C X* diastereomericfaces
X = C, O, N
stereogeniccenter How does this center control
The direction of attack atThe trigonal carbon?
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R
MS
L
O
LRNu
OHMS
LNuR
OHMS
Nu:
Less steric effects
Major product
Nu:
Minor product
OMS
RL
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R
MS
L
O
L
M
S R
O
L
S
MR
O
This is the important
interaction that must be
minimized. Thus, in this
approach the carbonyl
substituent plays the major
role.
Favored Conformer
for Attack
The interpretation of Felkin and Anh
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Bürgi-Dunitz
trajectory
109°
Obtuse attack trajectory
minimizes unfavorable
interactions between these
orbitals
C OR
M
L
S
s
p*
Nu
Houk computational view:
35
The obtuse angle of attack supports the nonpassive role of theR-group in ketones. Not only will there be steric interactionsbetween the S or M groups and the R-group, but also interactionswith the incoming nucleophile due to the attack trajectory. In this model one would predict an increase of stereodifferentiation as thesize of R increases. This has been found experimentally
O O
R R
Preferred conformation.
Less interaction between
the small group and the
R-group. Note that this
model "feels" the influence
of increasing size of R.
In this coformer, an
increased interaction
is seen between the
medium group and R.
Also, there is more
interaction with the
nucleophile. 36
A useful orbital approach by Cieplak, suggests that the nucleophilewill attack the carbonyl anti to the best donor ligand.
A.S. Cieplak, B.D. Yait and C.R. Johnson, J. Am. Chem. Soc., (1989), 111, 8447
A.S. Cieplak, J. Am. Chem. Soc., (1981), 103, 4548.
Donor
O
s* of nucleophileCarbon donors-bond
Nu:
E
37
Cases for Modification of the Models
Compare the "normal" situation with the influence ofa sterically bulky Lewis acid
L
S
MO
H
O
H
S
M
L
Lewis acid
Nu:
As the bulk of the
Lewis acid increases
Lewis acid
:Nu
This gives the
Cram product
This gives the
"anti-Cram" product
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Dipolar Model
often described as the Cornforth model
R'
RH
Cl
R"M
R'
RH
Cl
OHR"O
Preferred direction
of attack.
favored conformer
S
X L
O
R X
L S
O
R
39
Chelation ControlSee: M.T. Reetz, Acc. Chem. Res., (1993), 26, 462.
RLS
Het O
M
Preferred
direction
of attack
Het = heteroatom
M = metal
L
S
HetO
R
M
OTi
O
Cl
ClCl
ClH
Me
R
Ph
40
OS O
SMe
Me
Me Me
Me
MePh Ph
O O
Mg
MeI
MeMgI H3O+
Predict a product from the following reaction
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A potentially useful extension of Cram's rule is the asymmetricinduction provided by a remote ester (Prelog's rule):
RO L
O
O S M
R'MgX
Why would you think this might not provide as
important directing influences?
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The Evolution of Models for Carbonyl Addition
Fischer Cram Cornforth Felkin Anh/Eisenstein Cieplak Tomoda
43
Frondosin B
contains four condensed rings:
phenol
furane cycloheptene
cyclohexene
from a Diels-Alder reaction
from an intramolecularFriedel-Crafts acylation
Inoue, M. et al., J. Am. Chem. Soc. 2001, 123, 1878-1889
isolated from a sponge is anti-inflammatory
44
45
The rest is Sharplessand phenol chemistry
Furane from a base- and palladium-catalyzedintermolecular addition of a phenolate to an alkyne.
Sonogashira Coupling
Alkyne from a
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
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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
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K. C. Nicolaou, S. E. Webber, J. Am. Chem. Soc. 1984, 106, 5734 – 5736
The Sonogashira Coupling: Eicosanoid 212
48
P. Wipf, T. H. Graham, J. Am. Chem. Soc. 2004, 126, 15346 –15347.
The Sonogashira Coupling: Disorazole C1
49
The Sonogashira Coupling: Dynemicin
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. 50
51Cohen, 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
52
A triazacyclophaneTripodal Receptor Molecules(as hinge)
selectively sulfonatedand trifluoroacetylated
Acetylation with alkylchloroformate
i) triflate +methanolii) Fmoc-N-hydroxy-
succinimide
DeprotectionO-NBS (thiolysis)Aloc(Pd-catalyzed alkyl transfer to aniliniump-toluenesulfinate)
Opatz, T. et al. J. Comb. Chem. 2002, 4, 275-284
53
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”and34 “domino”titles
published since 1996-2002
1250 “tandem”, 576 “cascade”and297 “domino”titles
published since 2008-14
54
Some sterically hindered, SnCl4-catalyzed hetero-Diels-Aldercyclizations of -unsaturated ketoesters with alkene alcohols donot occur intramolecularly.
Large substituents on the ketoester prevent the formationof medium-sized rings and the first reaction is a linear dimerization combined with the formation of one dihydropyranunit. The second reaction then gives a second dihydropyran and producesa macrocyclic oligo-ether with good yield.
55
Acetylacetate reacts with zinc methylene iodide (Furukawa reagent)
zinc enolate add its methylene group to the enolate's double bond
Aldehydes then decomposethe cyclopropane formedand undergo a Reformatskyaddition.
Chain extension-aldol addition tandem
56
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
57
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 tryto establish environmentally benign synthetic procedures.Energy requirements, waste, and the number of separation stepsare all minimized by increased selectivity of the reactions catalyzed.Heck-, Sharpless- and Noyori-type reactions are successfulendeavors.Another approach is to replace solvents by water or by supercriticalfluids, in particular CO2.CO2 can replace chlorinated solvents.Replacement of soluble Lewis acids by mesoporous solidscontaining bound sulfonates or aluminum chloride should alsobecome 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 comefrom renewable sources, in particular glucose
Furthermore syntheses should be atom-efficient, and reagents assimple 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 intheir synthesis.Boger's iminodiacetic acids are good examples, because they onlyuse succinic acid derivatives
The Heck Reaction• Broadly defined as the palladium-catalyzed coupling of
alkenyl or aryl (sp2) halides or triflates with alkenes to
yield products which formally result from the
substitution of a hydrogen atom in the alkene coupling
partner.
• First discovered by Mizoroki, though developed and
applied more thoroughly by Richard F. Heck in the early
1970s.[3]
• Generally thought of as the original palladium catalysed
cross-coupling, and probably the best evolved,
including a multitude of asymmetric varients.[4]
3. R. F. Heck, J. P. Nolley, Jr., J. Org. Chem. 1972, 37, 2320
4. Review on asymmetric Heck reactions: A. B. Dounay, L. E. Overman, Chem. Rev. 2003, 103, 2945 – 2963
H
R1
R2
R3
R4 X R4
R1
R2
R3
cat. [Pd0Ln]
base
R4 = aryl, benzyl, vinyl
X = Cl, Br, I, OTf
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Mechanism of the Heck Reactionneutral
PPh3
PdPh3P PPh3
Ph3P PPh3
PdPh3P
Ph3P PPh3Pd
Ph3P
PPh3
- PPh3
- PPh3
Pd0
Pd0
Pd0
Br
PdPh3P
Br PPh3
PdII
O
O
PdPh3P
Br PPh3
O
O
PdII -Complex
PdPh3P
Br
O O
H H
PdII -Intermediate
PdPh3P H
Br PPh3
O
O
PdII -Complex
PdPh3P H
Br PPh3
B
HBr / B
PdIIO
O
OxidativeAddition
-hydrideElimination
ReductiveElimination
62
Mechanism of the Heck Reactioncationic
PPh3
PdPh3P PPh3
Ph3P PPh3
PdPh3P
Ph3P PPh3Pd
Ph3P
PPh3
- PPh3
- PPh3
Pd0
Pd0
Pd0
BrPd
Ph3P
Br PPh3
PdII
O
O
PdPh3P
PPh3
O
O
PdII -Complex
PdPh3P
O O
H H
PdII -Intermediate
PdPh3P H
PPh3
O
O
PdII -Complex
PdPh3P H
PPh3
B
PdIIO
O
OxidativeAddition
-hydrideElimination
ReductiveElimination
BrAg
HB
Ag
Abelman, M. M.; Oh, T.; Overman, L. E. J. Org. Chem. 1987, 52, 4133–4135. 63
Regioselectivity in the Heck Reaction
a) Cabri, W.; Candiani, I. Acc. Chem. Res. 1995, 28, 2–7.
b) Cabri, W.; Candiani, I.; Bedeschi, A.; Penco, S.; Santi, R. J. Org. Chem. 1992, 57, 1481–1486.
Ph
Y N
CH3 OH
O
OH
100 90 100
10
100 60 80
40 20
Y = CO2R CN CONH2
Ph
Y N
CH3 OH
O
OH
60 5
95
100 10
100 90
Y = CO2R CN CONH2
40 100
Neutral Catalytic Cycle Cationic Catalytic Cycle
• The type of mechanism in action is incredibly important, as it can manifest itself in a variety
of ways, especially the regioselectivity.
• In the neutral catalytic cycle, the regioselectivity is governed by steric factors – generally
addition occurs to the terminal end of the alkene.
• However, in the cationic cycle, regiochemistry is affected by electronics. The cationic Pd
complex increases the polarization of the alkene favouring transfer of the vinyl or aryl group
to the site of least electron density.
• The type of mechanism in effect is generally controlled by choice of halide/pseudohalide
acting as a leaving group in the cationic cycle; triflate promotes, whereas bromide detracts.
64