The document summarizes the Baylis-Hillman reaction, which is a carbon-carbon bond forming reaction between an activated alkene and an aldehyde or carbon electrophile catalyzed by a nucleophilic catalyst. The reaction produces densely functionalized products. Key advantages of the reaction include its atom economy, ability to generate chiral centers for asymmetric synthesis, and potential for further functionalization of products. Examples are given of the reaction being used in the synthesis of drugs such as pregabalin and sampatrilat. Mechanisms and strategies to improve the reaction are also discussed.
The video lecture for this presentation is available at the following link on YouTube
https://youtu.be/3sxal579RNM
The presenation will be useful for Ug/PG (Chemistry) students
Rearrangement to Electron Deficient Carbon
Rearrangement to Electron Deficient Nitrogen
Rearrangement to Electron Deficient Oxygen
Rearrangement to Electron-Rich Carbon
Aromatic Rearrangements
The video lecture for this presentation is available at the following link on YouTube
https://youtu.be/3sxal579RNM
The presenation will be useful for Ug/PG (Chemistry) students
Rearrangement to Electron Deficient Carbon
Rearrangement to Electron Deficient Nitrogen
Rearrangement to Electron Deficient Oxygen
Rearrangement to Electron-Rich Carbon
Aromatic Rearrangements
THE DCC I.E. DICYCLOCARBODIIMDE IS A REAGENT AND HERE THE DETAIL ACCOUNT ON IT IS GIVEN INCLUDING MOLECULAR WEIGHT, STRUCTURE, SYNTHESIS AND PHYSICAL PARAMETERS AND APPLICATIONS FOR OTERS SYNTHESIS ARE ALSO DISCUSSED, THE DIFFERENT SYNTHESIS WITH DCC COMBINATION ARE ALSO MENTIONED
THE DCC I.E. DICYCLOCARBODIIMDE IS A REAGENT AND HERE THE DETAIL ACCOUNT ON IT IS GIVEN INCLUDING MOLECULAR WEIGHT, STRUCTURE, SYNTHESIS AND PHYSICAL PARAMETERS AND APPLICATIONS FOR OTERS SYNTHESIS ARE ALSO DISCUSSED, THE DIFFERENT SYNTHESIS WITH DCC COMBINATION ARE ALSO MENTIONED
Novel creation of 3-contiguous stereocenters via a patented an asymmetric catalytic process utilizing Titanium and Zinc, in conjunction with either oxygen or peroxides.
Introduction:
RNA interference (RNAi) or Post-Transcriptional Gene Silencing (PTGS) is an important biological process for modulating eukaryotic gene expression.
It is highly conserved process of posttranscriptional gene silencing by which double stranded RNA (dsRNA) causes sequence-specific degradation of mRNA sequences.
dsRNA-induced gene silencing (RNAi) is reported in a wide range of eukaryotes ranging from worms, insects, mammals and plants.
This process mediates resistance to both endogenous parasitic and exogenous pathogenic nucleic acids, and regulates the expression of protein-coding genes.
What are small ncRNAs?
micro RNA (miRNA)
short interfering RNA (siRNA)
Properties of small non-coding RNA:
Involved in silencing mRNA transcripts.
Called “small” because they are usually only about 21-24 nucleotides long.
Synthesized by first cutting up longer precursor sequences (like the 61nt one that Lee discovered).
Silence an mRNA by base pairing with some sequence on the mRNA.
Discovery of siRNA?
The first small RNA:
In 1993 Rosalind Lee (Victor Ambros lab) was studying a non- coding gene in C. elegans, lin-4, that was involved in silencing of another gene, lin-14, at the appropriate time in the
development of the worm C. elegans.
Two small transcripts of lin-4 (22nt and 61nt) were found to be complementary to a sequence in the 3' UTR of lin-14.
Because lin-4 encoded no protein, she deduced that it must be these transcripts that are causing the silencing by RNA-RNA interactions.
Types of RNAi ( non coding RNA)
MiRNA
Length (23-25 nt)
Trans acting
Binds with target MRNA in mismatch
Translation inhibition
Si RNA
Length 21 nt.
Cis acting
Bind with target Mrna in perfect complementary sequence
Piwi-RNA
Length ; 25 to 36 nt.
Expressed in Germ Cells
Regulates trnasposomes activity
MECHANISM OF RNAI:
First the double-stranded RNA teams up with a protein complex named Dicer, which cuts the long RNA into short pieces.
Then another protein complex called RISC (RNA-induced silencing complex) discards one of the two RNA strands.
The RISC-docked, single-stranded RNA then pairs with the homologous mRNA and destroys it.
THE RISC COMPLEX:
RISC is large(>500kD) RNA multi- protein Binding complex which triggers MRNA degradation in response to MRNA
Unwinding of double stranded Si RNA by ATP independent Helicase
Active component of RISC is Ago proteins( ENDONUCLEASE) which cleave target MRNA.
DICER: endonuclease (RNase Family III)
Argonaute: Central Component of the RNA-Induced Silencing Complex (RISC)
One strand of the dsRNA produced by Dicer is retained in the RISC complex in association with Argonaute
ARGONAUTE PROTEIN :
1.PAZ(PIWI/Argonaute/ Zwille)- Recognition of target MRNA
2.PIWI (p-element induced wimpy Testis)- breaks Phosphodiester bond of mRNA.)RNAse H activity.
MiRNA:
The Double-stranded RNAs are naturally produced in eukaryotic cells during development, and they have a key role in regulating gene expression .
A brief information about the SCOP protein database used in bioinformatics.
The Structural Classification of Proteins (SCOP) database is a comprehensive and authoritative resource for the structural and evolutionary relationships of proteins. It provides a detailed and curated classification of protein structures, grouping them into families, superfamilies, and folds based on their structural and sequence similarities.
Multi-source connectivity as the driver of solar wind variability in the heli...Sérgio Sacani
The ambient solar wind that flls the heliosphere originates from multiple
sources in the solar corona and is highly structured. It is often described
as high-speed, relatively homogeneous, plasma streams from coronal
holes and slow-speed, highly variable, streams whose source regions are
under debate. A key goal of ESA/NASA’s Solar Orbiter mission is to identify
solar wind sources and understand what drives the complexity seen in the
heliosphere. By combining magnetic feld modelling and spectroscopic
techniques with high-resolution observations and measurements, we show
that the solar wind variability detected in situ by Solar Orbiter in March
2022 is driven by spatio-temporal changes in the magnetic connectivity to
multiple sources in the solar atmosphere. The magnetic feld footpoints
connected to the spacecraft moved from the boundaries of a coronal hole
to one active region (12961) and then across to another region (12957). This
is refected in the in situ measurements, which show the transition from fast
to highly Alfvénic then to slow solar wind that is disrupted by the arrival of
a coronal mass ejection. Our results describe solar wind variability at 0.5 au
but are applicable to near-Earth observatories.
Richard's entangled aventures in wonderlandRichard Gill
Since the loophole-free Bell experiments of 2020 and the Nobel prizes in physics of 2022, critics of Bell's work have retreated to the fortress of super-determinism. Now, super-determinism is a derogatory word - it just means "determinism". Palmer, Hance and Hossenfelder argue that quantum mechanics and determinism are not incompatible, using a sophisticated mathematical construction based on a subtle thinning of allowed states and measurements in quantum mechanics, such that what is left appears to make Bell's argument fail, without altering the empirical predictions of quantum mechanics. I think however that it is a smoke screen, and the slogan "lost in math" comes to my mind. I will discuss some other recent disproofs of Bell's theorem using the language of causality based on causal graphs. Causal thinking is also central to law and justice. I will mention surprising connections to my work on serial killer nurse cases, in particular the Dutch case of Lucia de Berk and the current UK case of Lucy Letby.
Professional air quality monitoring systems provide immediate, on-site data for analysis, compliance, and decision-making.
Monitor common gases, weather parameters, particulates.
THE IMPORTANCE OF MARTIAN ATMOSPHERE SAMPLE RETURN.Sérgio Sacani
The return of a sample of near-surface atmosphere from Mars would facilitate answers to several first-order science questions surrounding the formation and evolution of the planet. One of the important aspects of terrestrial planet formation in general is the role that primary atmospheres played in influencing the chemistry and structure of the planets and their antecedents. Studies of the martian atmosphere can be used to investigate the role of a primary atmosphere in its history. Atmosphere samples would also inform our understanding of the near-surface chemistry of the planet, and ultimately the prospects for life. High-precision isotopic analyses of constituent gases are needed to address these questions, requiring that the analyses are made on returned samples rather than in situ.
2. Introduction
Two most fundamental reactions in synthetic organic chemistry
functional group transformations
Carbon-carbon bond formation
Friedel-Crafts reaction
Grignard reaction
Diels-Alder reaction
Wittig reaction
Heck reaction
Suzuki coupling
Grubb’s RCM
Some C-C bond forming reactions are-
Morita-Baylis-Hillman Aldol reaction Reformatsky reaction Claisen
rearrangements
O
Aldol
1,2-Addition
1,4-addition
Baylis Hillman
Diels-Alder
Five possible ways of constructing C-C bonds with MVK
3
3. Baylis-Hilman reaction
It is a carbon-carbon bond forming reaction between the a-position
of an
activated alkene and an aldehyde or a carbon electrophile in
presence of a nucleophilic catalyst such as tertiary amine and
phosphine gives a densely functionalized product, if aldehyde as
the electrophile is used
functionalized allyl alcohol will the product.
This reaction is also known as the Morita-Baylis-Hillman reaction or
MBH.
DABCO (1,4-Diazabicyclo[2,2,2]octane) is one of the most frequently
used
tertiary amine catalyst for this reaction. In addition nucleophilic amines
such as DMAP (4-Dimethylamino pyridine) and DBU (1,8-Diazabicyclo
[5,4,0]undec-7-ene) as well as phosphines have been found to
successfully
catalyze this reaction.
4.
5.
6.
7. Advantages
1) It is an atom economic coupling reaction of easily prepared starting
material.
2) Reaction of a pro-chiral electrophile generates a chiral centre
therefore an asymmetric synthesis is possible.
3) Reaction products usually contain multiple functionalities in
proximity so that a varity of further transformations are possible.
4) It can employ a nucleophilic organocatalytic system without the use
of heavy metal under mild conditions.
8. Limitations
Because of there is a great extent of variability in reaction
substrates, it is
often challenging to develop reaction conditions suitable for certain
combination of substrates. The MBH reaction of an aryl vinyl ketone
with
an aldehyde is not straightforward, since the reactive aryl vinyl
ketones
readily adds first to another molecule of aryl vinyl ketone via Michael
addition, then the adduct adds to the aldehyde to form a double MBH
adduct.
9.
10.
11.
12.
13.
14. 28
Hill, J. S.; Isaacs, N. S.; J. Phys. Org. Chem. 1990, 3, 285
Hill and Isaacs Mechanism
Based on pressure dependence, rate, and kinetic isotope effect
(KIE) data.
ESMS and Tandem mass spectrometry.
No α-proton cleavage occurs in the rate-determining step (RDS).
Addition of the enolate to the aldehyde was the RDS.
Ph
R3N
OMe
O O
R3N
OMe
O
OMe
O
Ph OMe
OH O
NR3
Proposed RDS
Int 1
Int 2 Ph H
O
15. Robiette, R.; Aggarwal, V. K.; Harvey, J. N.; J. Am. Chem. Soc., 2007, 129, 15513
Mechanism of MBH reaction –
based on computational
method
O
OMe
Alcohol catalyzed TS 1
NMe3
O
OMe
O
Ph
O
H
OMe
Me3N
Int 2
O
3
Me N
Ph
O OMe
H
O
Ph
Hemi 1
O
OMe
Ph
Me3N
O H
O
Ph
RDS
TS3-hemi
O
Me N
Ph
O OMe
OH
Ph
3
Hemi 2
O O
Ph O
Ph
O
Ph
O OMe
OH
Ph
Hemi 3
Non-alcohol catalyzed
O
Ph
O
H
OMe
MeOH
Me3N
Int 2 -MeOH
TS 2-MeOH
Ph
O
Me3N
HOMe
Me N
COOMe
O
Ph
H
O
Me
H
3
TS3-MeOH
RDS
Ph O
OH OMe
HOMe
Me3N
Int-MeOH
OH OMe
O
Ph
29
PhCHO
PhCHO
Int.1
16. Hindered bases with high pKa
Higher the pKa of the conjugate acid of the amine higher the rate of reaction.
(leading to increased concentrations of the intermediate ammonium enolate)
e.g.; Quinuclidine (highest pKa), DBU.
Improvement of reaction rate
Important landmarks
Hydrogen-bonding additives or solvents
help the proton-transfer step.
e.g.; MeOH/t-BuOH/H2O
Lewis acids with alcohol-based ligands
The Lewis acid-alcohol complex results in increased acidity of the
OH groups, which promotes proton-transfer events.
30
17. 31
XH
Y
`R
R
*
Three functional groups
Via the functional group manipulation develop opportunities in organic synthesis
Chiral center
For asymmetric version offers
challenge to develop efficient catalyst
Intra-molecular version
Offers challenges to design and synthesize novel class of substrates with
several combinations of activated olefinic and electrophilic groups thereby
leading to develop various cyclic frameworks of synthetic importance
X= O, NR
Y= Electron withdrawing group
Offers challenge to develop
novel activated alkenes,
electrophiles
and catalyst
18. 32
Pfizer, Pregabalin, Drugs Future, 2002, 27, 426
Me
H
Me
O
NC
+
DBU, DBP Me
Me
NC
OH
Me
Me
NC
OAc
Py
OEt
NC
Me
O
Me
KOH
O K
NC
Me
O
Me
O t-BuNH3
NC
O
Me
Me
HCl
t-BuNH2
Pd(OAc)2
Ph3P
CO, EtOH
Chiral (R,R)-Rh catalyst
H2
Chiral (R,R)-Rh catalyst
H2
NC NC O K
O
Me
Me
O
Me
Me
O t-BuNH3
sponge Ni catalyst
KOH, H2
OH
H2N
Me
O
Me
Pregabalin (Lyrica)
Used in: Fibromyalagia
spinal cord injury
Neuropathic pain
Baylis Hillman reaction
AcCl,/ Ac2O
(S)-3-(aminomethyl)-5-methylhexanoic acid
Synthesis for Pregabalin
19. Dunn, et al; Organic Process Research & Development, 2003, 3
73
,244
Synthesis of Sampatrilat
CO2But
+
O 3-Quinuclidinol (0.25 eq)
H2O, CH3CN,
HO
CO2But
Cl 2
CO But
2
SOCl (0.88eq)
Et3N (1.02eq)
Py (0.1 eq)
Ph
Et3N, 81%
N Ph
H
(S,S)
(0.66 eq)
H H
(1.6eq)
2
N
Ph
ButO C
Ph
CO2H
(1.1 eq)
LDA (2.2 eq)
THF -30 to 20 OC
CO2H
N
Ph
Ph
ButO2C
de > 98%
NH
CO2H
OH
HO2C
HN
NHSO2Me
O
H2N
O
Sampatrilat
Baylis Hillman Reaction
Vasopeptidase inhibitor
Inhibits the angiotensin
converting enzyme (ACE)
20. O
H
O N CHO MeOOC
+
O
H OH
O N COOMe
DABCO
88%
O
H
O N COOMe
DEAD, Ph3P
AcOH, THF
77%
COOMe
OAc OAc
Dry HCl
Et2O
99%
H3N
Cl
O N
H
O
N
N Ph
COOH
O
DCC, HOBT, DMAP, CHCl3, 79%
O N
H
O
N
O
N PhO
N
H
OMe
O
OAc
Baylis Hillman Reaction
Potential Antimalarial Therapeutic Agents
The antimalarial efficacy of compound is comparable to that of chloroquine with
IC50 6-8ng/mL against D-6
34
Zhu, S.; Hudson, T.H.; Kyle, D.E.; Lin, A.J.; J. Med. Chem. 2002, 45, 3491
Synthesis of Novel Pyrimidinyl Peptidomimetics
21. N
O
R1HN CHO
N Ph
+
COOMe DABCO
N
O
R1HN
N Ph
OH
COOMe
Baylis Hillman reaction
DEAD, Ph3P
4-(NO2)PhCOOH or
PhCOOH or
CH3COOH
N
O
R1HN
N Ph
COOMe
OR2 R1 = PhCH2OCO, R2 = 4-(NO2)PhCO
R1 = PhCH2OCO, R2 = PhCO
R1 = PhCH2OCO, R2 = CH3CO
Anti-malarial compound
35
Zhu, S.; Hudson, T.H.; Kyle, D.E.; Lin, A. J. J. Med. Chem. 2002, 45, 3491
Antimalarial Therapeutic Agents
22. H3C
O O
H
+
OCH3
OCH3
DABCO, 7 days, rt
90%
O
HO
NBS, (CH3)2S,
OoC to rt, 24 h, 92%
O
OCH3
Br
COOH
LiAlH4, THF
OH
CH2OH
CH3I, acetone
reflux 6h
50%
CH2OH
OCH3
K2CO3, 95%
CHO
OCH3
PCC, CH2Cl2
1.5 h, rt,90%
H
H
O Sn, (CH3CH2)2O, HOAc,
O
p-(TsOH), C6H6, reflux
9h, 70%
OCH3
Baylis Hillman reaction
36
J. Bermejo et al, J. Med. Chem. 2002, 45, 2358
Synthesis of Antiproliferative Agent
23. Simplicity of this reaction in the easy construction of the carbon-
carbon bond.
Conclusions
Morita Baylis Hillman adduct is an excellent source for various
stereochemical transformation methodologies.
Several natural products and biologically active molecules have also
been synthesized using Morita Baylis Hillman strategy.
37
25. References
1. Baylis, A. B.; Hillman, M. E. D. Ger. Pat. 2,155,113, (1972). Both Anthony B.
Baylis
and Melville E. D. Hillman were chemists at Celanese Corp. USA.
2. Basavaiah, D.; Rao, P. D.; Hyma, R. S. Tetrahedron 1996, 52, 8001-8062.
(Review).
3. Ciganek, E. Org. React. 1997, 51, 201-350. (Review).
4. Wang, L.-C.; Luis, A. L.; Agapiou, K.; Jang, H.-Y.; Krische, M. J. J. Am. Chem.
Soc.
2002, 124, 24022403.
5. Frank, S. A.; Mergott, D. J.; Roush, W. R. J. Am. Chem. Soc. 2002, 124, 2404-
2405.
6. Reddy, L. R.; Saravanan, P.; Corey, E. J. J. Am. Chem. Soc. 2004, 126, 6230-
6231.
7. Krishna, P. R.; Narsingam, M.; Kannan, V. Tetrahedron Lett. 2004, 45, 4773-
4775.
8. Sagar, R,; Pant, C. S.; Pathak, R.; Shaw, A. K. Tetrahedron 2004, 60, 11399-
11406.
9. Mi, X.; Luo, S.; Cheng, J.-P. J. Org. Chem. 2005, 70, 2338-2341.
10. Matsui, K.; Takizawa, S.; Sasai, H. J. Am. Chem. Soc. 2005, 127, 3680-3681.
11. Price, K. E.; Broadwater, S. J.; Jung, H. M.; McQuade, D. T. Org. Lett. 2005, 7,
147150. A novel mechanism involving a hemiacetal intermediate is proposed.
12. Limberakis, C. Morita–Baylis–Hillman Reaction. In Name Reactions for