Chem 634 Ketone, Imine, and Related Reductions
Part 1
Announcements
Proposals due now.
No Office Hour tomorrow (10/7).
Problem Set 2 due Tues, 10/13.
Extra office hour: Mon, 10/12, 10:30-11:30 in 237 BRL.
Midterm 1 on Thurs, 10/15 in class.
Everything through oxidation chemistry will be included.
Normal office hour on Wed, 10/14, 10:30-12:00 in 220 BRL.
Announcements
Fall 2015 Seminar Series
219 Brown Laboratory
October 7, 2015, 4pm
Shedding Light on Metal Homeostasis:
Fluorescent Tools for the Study of Cellular Magnesium
Daniela Buccella Ph.D.
New York University
Department of Chemistry
http://www.nyu.edu/fas/dept/
chemistry/buccellagroup/
Magnesium is the most abundant divalent cation in mammalian cells, with multiple
roles that are essential for cellular function. Disrupted homeostasis of this metal has
been associated with various pathologies including age-related diseases, neurodegeneration, and cancer. However, detailed understanding of the mechanisms by which
intracellular Mg2+ concentrations are regulated and their role in human health is still
lacking, hampered by the paucity of efficient tools for the detection of this ion in the
complex environment of the cell. Fluorescence imaging has emerged as one of the
most promising tools to study intracellular cations, but current commercially available
fluorescent indicators do not offer the combination of selectivity and spatial resolution required to elucidate the many unanswered questions about cellular magnesium
homeostasis. Research in our group focuses on the development of molecular tools for
the study of Mg2+ by live-cell microscopy techniques, seeking to shed light on fundamental aspects of magnesium biology. We have developed new fluorescent indicators for the visualization of Mg2+ with improved selectivity and subcellular resolution,
which have enabled the study of magnesium dynamics in mitochondria and the
uncovering of Mg2+ fluctuations in early stages of apoptosis. Furthermore, our studies have revealed that complex binding schemes leading to the formation of ternary
complexes may cause common indicators to co-report on various intracellular species,
challenging the interpretation of fluorescent imaging experiments. In light of these
results, new approaches for the study of metal speciation in the cell will be discussed.
Nobel Prize in Physiology or Medicine (2015)…
… Goes to Chemistry!
Dr. William Campbell
Prof. Satoshi Ōmura
Prof. Youyou Tu
Drew University;
Merck Institute for Therapeutic
Research
Microbiology
Kitastao University, Tokyo
Bioorganic Chemistry
China Academy of Traditional
Chinese Medicine
Pharmaceutical Chemistry
“for their discoveries concerning a novel therapy against infections caused by
roundworm parasites”
“for her discoveries concerning a novel therapy against Malaria”
What are these “Contributions”?
Natural Products!
avermectin
from soil-dwelling bacteria
artemisinin
from Artemisia annua
Reducant Cheat Sheet
C=X reductants
comment/electophile
iminium ion acid chloride aldehyde/ketone
LiAlH4 (LAH)
Very strong, low solubility in tol
amine
ROH
ROH
NaAlH2(OCH2CH2OMe)2 (Red-Al)
Very strong, soluble
amine
––
ROH
LiAlH(OEt)3
Weaker than LAH
––
––
––
NaAlH(OtBu)3
Weaker yet
amine
slow to ROH
––
NaBH4
Moderate
amine
ROH
ROH
LiBH4
More reactive than Na verison
amine
––
ROH
NaBH(OAc)3
Weaker than NaBH4, more selective
amine
––
slow to ROH
NaCNBH3
even more so
amine
––
slow to ROH
LiBHEt3 (Super-Hydride)
Very strong reductant
––
ROH
ROH
(iBu)2AlH (DIBAL or DIBAL-H)
electrophilic
––
ROH
ROH
BH3•L (L = THF or DMS) or B2H6
electrophilic
––
––
ROH
H2/ cat
hydrogenation
amine
ROH or aldehyde
ROH
–– = not product or not commonly used combination
n/r = no reaction, ROH = alcohol, RHO = aldehyde
ester
amide
carboxylate
ROH
amine
ROH
ROH
amine
ROH
alcohol
RHO (3° amide)
––
slow to ROH slow to amine
––
slow to ROH
n/r
––
ROH
––
slow to ROH
n/r
slow to ROH
––
n/r
n/r
––
ROH
RHO (3° amide)
––
ROH or RHO amine or RHO
ROH
slow to ROH slow to amine
ROH (fast)
ROH
amine
––
nitrile
amine
amine
RHO
––
––
––
––
––
likely red.
RHO
––
amine
Adapted from Carey and Sunburg, 5th Ed.
A Closer Look At One Series
H
Al
LiAlH4
H
small, inorganic... not very soluable
upto 4 "H–"
H
H
H
H
NaAlH2(OCH2CH2OMe)2
"Red-Al"
+
AlH
H
O
HO
Me
Al-
MeO
O
H
H
OMe
O
more organic soluable, but a little
less reactive
H
H
LiAlH(OEt)3
+
AlH
H
AlHO
Me
Me
O
H
O
Me
O
weaker than LAH, but only 1 "H—"
Me
H
H
NaAlH(OtBu)3
+
AlH
H
H
Me
Me
Me
HO
Me
Me
Me
O
Me
Me
Me
O
Me
O
Me
Me
Al-
steric bulk makes it weake yet,
only 1 "H—"
General Mechanism (Nucleophilic)
w/ LAH
Li
H
Li
O
R
H
Al
H
H
O
R
R
w/ NaBH4
Na
R
O
R
AlH3
OH
H
H
R
R
H
R
Na
BH3
H
O
R
BH3
H
R
OH
H
R
H
R
metal ion activates carbonyl
four coordinate Al and B are nucleophilic anions
Examples of Nuc. Red. (Not Inclusive)
O
NMe2
LAH
NMe2
HO Me
LiBH4
MeO2C
CO2H
Me
OH
HO Me
HO
CO2H
O
N
Me
Bu
Me
O
LiAlH(OEt)3
then HCl
TFA
99% de
H
Bu
Me
99%ee
Refer to chart.
Electrophilic Reductants
Me
O
R
Carbonyl
activated by
Lewis Acid
Me
R
O
R
R
H
R
Al
Me
H
O
R
R
H
Al
Me
Three coordinate Al and B are
electrophilic
Al activated by
Lewis base
Me
H
R
Al
H+
Me
H
Me
OH
R
R
H
+
Me
Me
Me
Note: NOT "H" from Al-H that is the reductant!
Partial Reductions
O
O
OMe
O
N
Me
Me
DIBAL
-78 °C
BOC
H
O
N
Me
Me
BOC
note proximal
Lewis Base
O
R
OMe
N
Me
Weinreb
amide
DIBAL
R
O AlH
OMe
R
N
Me
good way to make aldehydes
H
O
R
H
Reduction of Nitriles
O
DIBAL
R C N
R
H
BH3
R
O
BH3
O
OH
R
H
B
H
O
H
O
R
H
+ HOBH2
Note: hydroboration competes when alkenes present!
Hydrogenations
Adam's cat.
2% PtO2
H2
O
Pr
H
R
OH
R
NH2
Raney Ni
R C N
O
R
H2
O
Pd/ BaSO4
Cl
R
poisoned cat.
(Rosemond Reduction)
H
Reductive Amination
Recall: Direct alkylation of amines often leads to competive overalkylation.
R NH2
R'X
R'
R NH
base
+
R'
R N
R'
+
R'
R N
X
R'
R'
Solution: Reductive Amination
Aldehyde or ketone
O
Recall
R
R'NH2
amine: 1° or 2°
H
+H
- H2O
H
R
NaHBR3
N
R'
H
iminium ion
Red: NaBH4 cheap
Na(CN)BH3 or NaHB(OAc)3 more selective
R'
H
N
R
Reductive Amidation
O
MeNH2
R
O
Cl
R
LAH
N
H
Me
harsh!
R
N
H
Me
Meerwein - Ponndorf - Verley (MPV) Reduction
OH
O
R
R
R'
H
Me
Me
R'
Al(OiPr)3
OR
O Al OR
OH
Me
R
R'
Me
R
Me
O
O
+
R'
H
Me
Me
Me
O
O
OR
Al
OR
Reduction of Ketone to Alkanes
Classical Conditions: All Very Harsh!
Wolfe-Kishner
H2N NH2 , NaOH
O
R
R'
H
H
R
R'
Clemmenson Reduction
Zn (Hg)
O
HCl
H
H
R
R'
R
R'
EtS
SEt
Raney Ni
H
H
R
R'
H2
R
R'
Also:
Tosyl Hydrazone Reduction
O
R
H2N NHTs
R'
N
-H2O
R
Ts
NH
R'
tosyl hydrazone
N
R
Ts
NH
R'
B
HN
NaBH3CN
HX
R
N
Me
- HO
R
H
NHTs
H
R'
BH4
R
NH
R'
-N2
H
N SO (tol)
2
N
H
H
H
R
R'
R
S
O sulfinic acid
Last step involves radical intermediates – high energy
Be Aware
O
R
H2NNHTs
R'
R
then
NaBH3CN
N
N
H
H
R'
R
allylic transposition
R'
Diasteroselective Reductions (and Additions)
O
Me
"H-"
H
Me
Me
Me
OH vs
Me
Me
small
OH
Me
H
Me
Me
axial
equat
LAH
92
8
NaBH4
80
20
7
93
Me
Me
very large
3
"L-Selectride"
Me
Me
Me
BHLi
O > 4 kcal/mol
Me MeMe
H
H
favored
H
H
O
Model for Small Reducing Agents: Torsional Strain
O
Me
Me
Me
H
H
O
H
H
H
H
HO
H
H
vs
H
H
δ−
H
torsional motion
results in eclipsing interaction
H
H
H
axial
H
H
O
H
OB
δ−
H
O
No torsional strain
H
equatorial
Favored for
small nucs.
OB
blue arrow = atomic motion of oxygen atom as carbon goes from sp2 to sp3
Model for Large Reductants
R3BH
Me
Me
Me
O
vs
Me
O
Me
Me
R3BH
Need to know how the nucleophiles approach carbonyl.
Burgi-Dunitz Angle
FMO's of C O
π*
π
C O
C O
110°
Approach of Nucleophiles
C
O
Nuc110°
Model for Large Reductants: Developing Diaxial Interactions
R3BH
O
Me
vs
Me
Me
Me
Me
R3B
Me
Me
Me
H H
H
O
Me
R3BH
O
Me
vs
O
Me
Me
R3B
H
favored
developing
1,3 diaxial interactions
OH
Me
H
Me
Me
major
Steric Interactions Can Override
Me
Me
O
Me
Me
H
Me
Me
Me
vs
OH
Me
Me
NaBH4
17
42
83
58
L-select.
0.2
99.8
LAH
all favor equatorial attack
Me
Me
Me
Me
O
H
> 4 kcal/mol
Me
Me
O
OH
H
Similar for Carbon Nucleophiles
Me
O
Me
Me
Nuc
Me
OH
Me
Me
Nuc =
H C C Li
EtMgBr
iPrMgBr
tBuMgBr
88
53
18
0
vs
OH
Me
Nuc
Me
Me
12
47
82
100
Acyclic Stereocontrol in Additions to Carbonyls
O
RL
H
R
HO
Nuc
RL
RM
Nuc
R
RM
HO
or
RL
Nuc
R
RM
More complex as there sigma bond rotation can occur!
O
RL
R
H
RM
Consider case where three substituents at alpha carbon all differ in size.
Felkin - Ahn model
O
RL
R
RM
Assumption: Will add away from largest substituent. Limits problem to
two conformations that must be considered. (Note you MUST get
stereochemistry correct in Newman projections.)
RL
RL
R
O
RM
H
vs
O
R
RM
H
Note these not lowest energy conformers, but most reactive conformers.
Felkin – Ahn Model
RL
RL
R
O
RM
H
vs
O
R
RM
H
RL
Think about FMO’s.
RL
R
O
RM
H
vs
R
O
RM
Nuc—
And Burgi-Dunitz Angle
H
Nuc—
disfavored
favored
Least sterically
demanding approach!
RL
HO
RL
Nuc
R
RM
RL
R
OH
RM
Nuc
H
R
HO
RM
H
Nuc
HO
RL
Nuc
R
RM
favored
Felkin – Ahn Model
Example:
O
Ph
H
H
Me
HO
0 °C
Ph
Me
LAH
74 : 26
L-sel.
99 : 1
Ph
H
Me
Me
Me
Ph
O
H
Me
H
HO
Me
Me
H
H
Note: Ratio (dr) implies favored diastereomer (shown) vs unfavored (not shown). It is very common to only
show one product and assume the reader understands the chemistry well enough to predict the other
product.
Yamamoto JACS, 1998, 110, 4475
Similar for Carbon Nucleophiles
O
Ph
MeLi
Me
Me
–78 °C
HO
Ph
Me
Me
Me
Ohno, JACS 1988, 110, 4826
Cram Chelation Control
O
BOMO
R
Me
H
R
Me
(98 : 2)
Not Felkin!
Me
Me
R
R
Me
–10 °C
Me
O
RO
BOMO
O
BOM =
M
HO
LAH
M
O
O
R
R
H
M
O
O
R
Lewis base
chelates
metal with
carbonyl
R
H
HO
RO
H
Nuc
Nuc
•  Lewis basic groups make good chelators.
•  Examples: BnO, MeO, BOMO, MOMO, NR2, etc.
Overman TL, 1982, 2355
Reetz, Acc. Chem. Res. 1993, 26, 462
Polar Felkin-Ahn
A values:
O
tBuPh
2SiO
LAH
R
Me
–10 °C
OH
H
tBuPh SiO
2
R
Me 95 : 2
Me = 1.7 kcal/mol
OSiMe3 = 0.74 kcal/mol
H
R' C H
H
Not Chelate!
Note: Silyl ethers are not good Lewis Bases (nO -> σ*Si-C)
R R
Si R
R' O
trans?!?
H
H
O
Me
Arguement: Low lying
OSiR3
OSiR3
H
H
Nuc
σ*C-OSiR3
O
stablizes developing
Me
σ Nuc–C
Nuc
Proposed TS
σ*C-OSiR3
At TS:
σ Nuc–C
σ*C-OSiR3
Occurs with highly electronegative alpha substituents that cannot chelate, such as
OSiR3, Cl, F, etc.
Summary of Felkin-Like Models
alpha stereocenter model steric only Felkin-­‐Ahn chela2ng Cram electronega2ve, but non-­‐chela2ng Polar Felkin