ادخ مان هب advanced organic 6 synthesis -...
TRANSCRIPT
به نام خدا
Advanced
Organic
Synthesis
6
Dr M. Mehrdad University of Guilan, Department of Chemistry,
Rasht, Iran
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
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 5
6
hetero-Diels-Alder reaction of an acrolein derivative
retro-opened to a -hydroxy epoxide
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
Standard Dihydroxylation
10
Possible [3+2] Cycloaddition
11
(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)2AQN dihydroquinidine (anthraquinone-1,4-diyl) diether
13
Sharpless Asymmetric Dihydroxylation
14
Use a Pre-mix of reagent components
15
16
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
18
The Horner–Wadsworth–Emmons (HWE) reaction involves the addition of a stabilized phosphonate anion to an aldehyde or ketone to afford an intermediate which undergoes an elimination reaction to form predominately the (E)-alkene. The HWE reaction has been applied inter- and intramolecularly to simple as well as highly functionalized systems.
19
Masamune–Roush Modification of the Horner–Wadsworth–Emmons Reaction
The Masamune–Roush modification of the HWE is a very mild variant that does not require the use of a strong base (i.e., NaH or n-BuLi) to generate the phosphonate anion. Instead, in the presence of LiCl, a lithium chelate forms which enhances the acidity of the α-protons. Hence, DBU (1,8-Diazabicycloundec-7-ene) is sufficiently basic to carry out the deprotonation of the phosphonate.
20
Since the original paper, milder bases have been used, including triethylamine and disopropylethylamine (Hunigs’ base). Again, there is strong preference for the formation of the (E)-alkene when the coupling partner is an aldehyde.
21
Still–Gennari Modification of the Horner–Wadsworth–Emmons Reaction
The Still–Gennari modification of the HWE reaction was a major 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 achieved with the phosphonate bearing electron withdrawing groups under ionic dissociating conditions (crown-ether).
22
Ando Modification of the Horner–Wadsworth–Emmons Reaction
The Ando modification of the HWE reaction is yet another major contribution 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), 2495
24
Still – Gennari Modification
Horner-Wadsworth-Emmons
Still – Gennari Modification
- Still–Gennari modification selective for Z-alkenes ( cis):
25
26
27
DMP = Dess-Martin periodinane
Preparation of the Dess−Martin Reagent
The Dess−Martin oxidation is the method of choice for the oxidation 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 with browning. However, this cannot be taken as an indication of absence of explosivity as the same batch showed inconsistent results. An analytically pure sample (≥ 99%) was subjected to explosibility tests.
28
Dess–Martin periodinane
The Dess–Martin (D−M) oxidation is the method of choice for the oxidation of alcohols bearing sensitive functional groups to the 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).
29
Stille coupling The Stille reaction, or the Migita-Kosugi-Stille coupling, is a chemical reaction widely used in organic synthesis which involves the coupling of an organotin compound (also known as organostannanes) with a variety of organic electrophiles via palladium-catalyzed coupling reaction.
30
Mechanism
The mechanism of the Stille reaction is one of the most extensively studied pathways for coupling reactions.The basic catalytic cycle, as seen below, involves an oxidative addition of a halide or pseudohalide (2) to a palladium catalyst (1), transmetalation of 3 with an organotin reagent (4), and reductive elimination of 5 to yield the coupled product (7) and the regenerated palladium catalyst (1)
31
Cram’s Rule
C X * diastereomeric faces
X = C, O, N
stereogenic center How does this center control
The direction of attack at The trigonal carbon?
32
R
M S
L
O
L R N u
O H M S
L N u R
O H M S
Nu:
Less steric effects
Major product
Nu:
Minor product
O M S
R L
33
R
M S
L
O
L
M
S R
O
L
S
M R
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
34
Bürgi-Dunitz
trajectory
109°
Obtuse attack trajectory
minimizes unfavorable
interactions between these
orbitals
C O R
M
L
S
s
p *
N u
Houk computational view:
35
The obtuse angle of attack supports the nonpassive role of the R-group in ketones. Not only will there be steric interactions between the S or M groups and the R-group, but also interactions with the incoming nucleophile due to the attack trajectory. In this model one would predict an increase of stereodifferentiation as the size 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 nucleophile will 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.
D o n o r
O
s * of nucleophile Carbon donor s -bond
Nu:
E
37
Cases for Modification of the Models
Compare the "normal" situation with the influence of a sterically bulky Lewis acid
L
S
M O
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
38
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 Control See: M.T. Reetz, Acc. Chem. Res., (1993), 26, 462.
R L S
H e t O
M
Preferred
direction
of attack
Het = heteroatom
M = metal
L
S
H e t O
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
41
A potentially useful extension of Cram's rule is the asymmetric induction provided by a remote ester (Prelog's rule):
R O L
O
O S M
R'MgX
Why would you think this might not provide as
important directing influences?
42
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 intramolecular Friedel-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 Sharpless and phenol chemistry
Furane from a base- and palladium-catalyzed intermolecular 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
46
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
47
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
51 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
52
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
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”and 34 “domino”titles
published since 1996-2002
1250 “tandem”, 576 “cascade”and 297 “domino”titles
published since 2008-14
54
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.
55
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
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
58
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.
59
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.
60
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