Kwon
Strategies & Tactics
On the literature
• Cannot expect to read everything
• Read papers that are: A. interesting to you
B. most relevant to your research
• Read abstract, introduction, look at the figures and schemes, and conclusion
Multi-component reactions (MCR) (“one-pot process”)
R. W. Armstrong, Acc. Chem. Res., 1996, 29, 123
Example: Ugi four-component reaction:
R1
R4
Example: Tandem [4+2]/[3+2] cycloaddition of nitroalkenes
Me
N
On-Bu
H
CO2Me
O N O
TiCl2(Oi-Pr)2 MeO2C
CH2Cl2
–70 °C, 1 h
80%
H
Me
R5
R2
N
R3
C
R4
H
O N O
MeO2C
+
H
(87%)
H
H2/Raney-Ni
Me
H
R1
R2
R5
N
H
OH
Mechanism:
O
R3
O
R4
HO
+
H 2N
R2
O
–H2O
R4
O
R3
-C
R3
R2
N
R1
R2
HN
R1
N+
R5
R1
O
O
R3
R4
O
N
O
On-Bu
O
N
O
O
Ideal synthesis:
• High yields (reaction efficiency)
• Efficiency, fewest steps (“step economy”): P. A. Wender, Nature, 2009, 460, 197
• High selectivity (chemoselectivity, regioselectivity, diastereoselectivity, enantioselectivity)
• Experimental ease of the transformations
ex) High pressure Diels–Alder reaction (15 kbar) requires a special instrument
• Environmentally benign (“atom economy” and “green chemistry”)
• Ideally atoms of the substrates and reagents used for the reaction should appear in the
final product (e.g., Diels–Alder reaction, some catalysis)
B. M. Trost, ACIEE, 1995, 34, 259
• Domino, cascade, tandem reactions
L. F. Tietze, Chem. Rev., 1996, 96, 115
S. E. Denmark, Chem. Rev., 1996, 96, 137
• Minimize oxidation state adjustments (“redox economy”)
P. S Baran, ACIEE, 2009, 48, 2854
• Avoid protection/ deprotection (“protecting-group-free” synthesis)
P. S Baran, Nat. Chem., 2009, 1, 193
O
NH2
R3
O
Synthetic project requires a thorough knowledge of:
• Available synthetic methods
• Reaction mechanisms
• Commercially available starting materials
• Analytical tools (IR, UV, NMR, MS)
• Isolation techniques
O
Chem 244A
R1
R2
N
H
R5
H
B:
R3
O
N
C
R1
R2
O
R3
N
R5
H+
H
N
R1
C
R2
N+
R4
R5
On-Bu
H
(13%)
80–82%
O
N
HO
H
Me
H
1
Morris Dweck
Kwon
Strategies & Tactics
C.
A.
Strategies vs. Tactics
Types of Transformations
a. One group disconnection
Strategies for synthesis
Intellectual plan
Retrosynthetic analysis
Retrosynthesis
Antithesis
TM
Chem 244A
Tactics for synthesis
Operation that converts starting material
(SM) to the target molecule (TM)/product
(PD)
+
OH
(CH3CHO + EtMgBr)
OH
b. Two group disconnection
O
synthons
O
OH
The symbol “
” signifies a reverse
synthetic step and called “transform.”
B.
CO2Me
CO2Me
1. C–C bond cleavage or disconnection
2. functional group interconversions (FGI)
A transform effects molecular simplification by:
1. disconnecting molecular skeleton
2. removing functional groups, stereocenters
3. adding functional groups
b. Functional group interconversions (FGI)
• convert one functional group to another
• substitution, addition, elimination, reduction, oxidation
c. Retron: a structural subunit that signals the application of a particular disconnection
ex) beta-hydroxy ketone is a retron for an aldol transform
d. Synthons: idealized fragments resulting from C–C bond disconnection
e. Synthetic equivalents (SE): actual compounds used for the forward synthesis
OH
OH
O
O
O
aldol
H
H
A
H
Simmons–Smith
H
Diels–Alder
CHO
H
(O3, Me2S)
CHO
e. Antithetical rearrangement
O
(H2SO4 or PCl5)
NOH
O
NH
Beckmann
rearrangement
O
g. Functional group addition (FGA)
O
+
CO2Me
CO2Me
h. Functional group removal
O
B
TBSO
O
H
H
hydrogenation
CO2Me
d. Antithetical disconnection
(PdCl2, H2O, CuCl2, O2)
f. Partial retron: a basic retron that can be easily established by using well-known transforms
to form a retron
Example: The A ring of compounds A and B are partial retrons for the Diels–Alder transform
HB
CO2Me
Wacker ox.
and
HC
+
f. FGI
H
A
+ CH3CHO
c. Pericyclic disconnection
Terminology
a. Main transforms are:
O
O
OH
+
CO2Me
OMe
Danishefsky's diene
O
OH
2
H
H
Morris Dweck
*g. Carbonyl Desaturation: Where Does Catalysis Stand? ACS Catal. 2021, 11, 883–892.
Kwon
D.
Strategies & Tactics
Guiding Principles
f. explore feasibility and selectivity
The Chemical Abstracts Service (CAS) database: SciFinder Scholar
https://scifinder.cas.org/scifinder/view/scifinder/scifinderExplore.jsf
Beilstein: Reaxys Searchers; to download the search engine go to
https://www.reaxys.com/#/search/quick
Science Citation Index Expanded™
http://apps.webofknowledge.com/
a. exploit resident symmetry
SnBu3
Pd0
+
Stille
Br
McMurry
1. Chemoselectivity: selective reaction of one functional group in the presence of other functional
groups
CHO
(TiCl3, Zn-Cu, DME or TiCl3, LAH, DME,
)
O
b. generate symmetry by FGI
OH
H
Ph
K. C. Nicolaou, J. Am. Chem. Soc., 1982, 100, 5555
Endiandric acid D
CO2H
6p e-
H
8p e-
HO
E
OH
HO
C1–C2–C3–C4
vs. linear:
OH
OH
C1 C2 + C3
C1 + C2–C3–C4
OH
Me2N
HO
EtO
2. Regioselectivity: the preferential addition of the reagent at only one of two (or more) possible atoms
(sites)
OH
C4
disiamylborane
thexylborane
9-BBN
BH
C1 + C2 + C3
C4
H
2
3. Stereoselectivity: the predominant formation of one of several possible stereoisomeric products
A. Diastereoselectivity
O
+
Me2N
BH3ŸTHF
94:6
99:1
O
Ph
O
E
HO
d. multiple group disconnections are superior
O
O
EtO
OH
c. employ maximum convergency
convergent:
O
NaBH4
H
H
O
EtO
FGI
H
HO
Chem 244A
Ph
O
O
OH
O
Me2N
Ph
Br
+
Me2N
Ph
eq. H / axial H
e. minimize the use of FGA, FGI, and protecting groups
O
O
RO
O
RO
O
OH
RO
Claisen condensation
R'O
RO
LAH
O
O
93 : 7
3
O
H
L-selectride
8 : 92
BHLi
3
Aldol
Morris Dweck
Kwon
Strategies & Tactics
Chem 244A
Dissonant: Positive and negative charges are placed at carbons attached to the Group 1
B. Enantioselectivity
HO
O
O
HO
(+)-DET
TBHP
Ti(iPrO)4
EtO2C S OH
O
R'
R
R
O
EtO2C S OH
R'
Br
O
O
R
R'
• Stereospecific reaction: two stereochemically different substrates react to give two
stereochemically different product
O
O
g. Consonant/dissonant patterns
R'
R
Heteroatoms impart electrophilicity and nucleophilicity to the (carbon) atoms of the molecules.
1. Groups conferring electrophilic characters
O
The dissonant connectivity requires an “inversion of polarity (umpolung)” of a synthon.
h. “Umpolung” reversal of polarity
–OH, –OR, =O, =NR, –X, –NR2, –NH2
O
O
"acyl anion addition"
2. Groups conferring nucleophilic characters
–Li, –MgX, –CuX, –ZnX, –AlR3, –SiR3, –SnR3
3. Groups that exhibit ambivalent characters
1.
1,3-Dithianes (thioacetals): reversal of polarity of a carbonyl group
D. Seebach, ACIEE, 1979, 18, 239
Synthesis, 1977, 357
–BR2, –CR=CR2, –C≡CR, –NO2, ≡N, –SR, –S(O)R, –SO2R
Consonant: Positive charges are placed at carbons attached to the Group 1
2. Nitroalkanes
Henry rxn (Kamlet rxn): Nitro Aldol
O
CH3NO2 +
R
R
NaOH
R
R
NO2
OH
R
Ac2O
pyr
R
NO2
4
Morris Dweck
Kwon
Strategies & Tactics
* Nef rxn
Chem 244A
Stetter rxn mechanism
O
Ph
N
O
R
N
H
O
O
H+
R’
N
R
OH
HO
H+
OH
N
R
R’
H 2O
HO
R
R’
N
N
H+
R
S
O
N
R
Ph
R'
N
H
R
S
Ph
R'
S
N
:B
R'
R
H
S
OH
OH
OH
O
R’
OH
Ph
Ph
H+
OH
H
O
N
N
O
R
R’
O
H
R’
HNO
1/
2
H
R’
OH
O
R
O
N
Ph
:B
R
R'
R
S
O
R'
S
OH
O
N2O + 1/2 H2O
O
Example: J. A. Murry, D. E. Frantz, …, P. J. Reider, JACS, 2001, 123, 9696
3. Cyanohydrins
S
O
R
H
TMSCN
ZnI2
NC
R
OTMS
H
n-BuLi
or
LDA
OTMS E+
NC
NC
R
R
O
OTMS F- or H+
E
R
OH
XCHO
E
N
+
TolO2S
N
O
Ph
N
H
Et3N, CH2Cl2
35 – 60 °C
4. Benzoin condensation
O
(10 mol%)
R
N
H
N
Ph
Cy
O
O
CN
OH
OH
O
Ar
ArCHO
Ar
H
CN
Ar
H
Ar
NC
CN
Ar
Ar
OH
5. Stetter rxn
N
O
Ar
NC
Cy
6. α-Metalated vinyl ether or vinyl sulfide: acyl anion equivalents
Sulfur is more effective than oxygen in stabilizing an adjacent carbanion.
O
O
O
Ar
Ar
OH
OMe
ACIEE, 1976, 15, 639
or
t-BuLi, THF, TMEDA
–65 °C
n-BuLi
SPh
Li
t-BuLi, pentane
or
LDA, THF
OMe
Li
SPh
5
Morris Dweck