Selective Reductions of

Carbonyls and Alkenes

 Reductions – an overview
carbonyl reduction ester reduction

O OH O LAH OH
reductant
O HO

carboxylic acid reduction amide reduction

O OH O
BH3 LAH
OH N N

imine reduction/reductive amination Weinreb amide reduction

N HN O O
Na(CN)BH3 LAH
O
N H
then H2O

nitrile reduction reductive debenzylation

H H
N O H2 OH
DIBAL-H
O
then H2O catalyst
 Reductions – an overview
olefin hydrogenation Lindlar reduction

H
H2 H H2 H
catalyst H “poisoned”
catalyst

conjugate reduction reductive a-cleavage

O O O O X
2 SET 2 SET
X
H+ H

Birch reduction reductive dehalogenation 2 Cl–

Cl H
2 SET 4 SET
Cl H
2 H+ 2 H+

reductive desulfurization Mozingo reduction

S H2 H2 H H
H H S S
Raney Ni Raney Ni
 Common hydride reducing reagents

H
borane
BH3•SMe2 dimethylsulfde complex B Superhydride

Li

BH3•THF borane
tetrahydrofurane complex
H
B
L-Selectride
Me4NBH(OAc)3 tetramethylammonium
triacetoxy borohydride Li (racemate, mix of diastereomers)

H
Al DIBAL-H
Na(CN)BH3 sodium cyanoborohydride

MeO O H
NaBH4 sodium borohydride Na Al Red-Al
MeO O H

LiBH4 lithium borohydride LiAlH4 lithium aluminium hydride

Diastereoselective reductions of carbonyl compounds

Cyclic compounds often show excellent substrate control:

O OH
Me Me
NaBH4 [Reference]

O O

O HO
H NaBH4 H
O O
NH NHAc
[Reference]
O

MeO MeO

NaBH4
O H O H
H NMe H NMe [Reference]
O HO

codeinone codeine

this also works in the racemic series

 Diastereoselective reductions of aldols

OH O Me4N BH(OAc)3 OH OH
Evans-Saksena anti-reduction: anti 1,3-diol

OAc OAc OH OH OH
O O OH
Me4N BH(OAc)3 H 3O OH
OH O B OAc O B OAc H ≡
H H

intramolecular after ligand exchange

OH O Bu2BOMe, NaBH4 OH OH
Narasaka-Prasad syn-reduction: syn 1,3-diol

H H
O Bu2BOMe Bu NaBH4 OH OH
O BBu2 H 3O OH
OH O B OH ≡
O
O Bu

intermolecular (Fürst-Plattner)
 Enantioselective carbonyl reduction (stoichiometric)
example: Midland reduction of a prochiral ketone
(+)-α-pinene
‡
H
B
Me

Alpine borane D
D H O
B H
O chiral reagent O B
Me D

borinate

H2O2 , NaOH 97% ee

H [Reference]
D
OH

H
B
Me

99% ee
then H2O2 , NaOH [Reference]
O OH
 How to overcome poor substrate control
poor substrate control:

O O O

O O O
H Zn(BH)4 H H
H H + H
DME → H2O
AcO AcO OH AcO OH
O
dr = 1:1

[Reference]

solution: reagent control

using a chiral reagent
H
O
Al
O OEt

O O

O O
H (S)-BINAL-H H
H H dr > 99:1

AcO AcO OH
O [Reference]
the substrate and reagent need to be both enantiopure
 Enantioselective carbonyl reduction (catalytic)
example: Itsuno-Corey catalytic asymmetric reduction

H Ph Ph

O chiral catalyst
N B

O BH3
OH
5 mol%
90% ee
BH3•SMe2 [Reference]
100 mol%

H Ph Ph

O
N B
O OH
I 5 mol% I
> 99% ee [Reference]
BH3•THF
66 mol%
 Catalytic cycle of the Itsuno-Corey reduction

H Ph Ph

O
N B

≡
Ph
RS O
O B H
N B
H 2B RL Ph H H

HCl, MeOH
Ph Ph
O O
RS B
N B
HO RS N
Ph Ph
RL B O
B
H H RL H H
H H
RS
Ph O
O RL
B
N
Ph RS
B O
H H
H RL
 E.J.Corey

[1990 Nobel Prize in Chemistry]

The Torgov synthesis of estrone
[Reference]

a classical approach to estrone that is highly convergent

 2-naphthol
HO

1 1) H2, Raney Ni partial dearomatization

HO

2 2) CrO3, Ac2O protection of the phenolic hydroxy group and

oxidation of the p-benzylic position

AcO

3 3) KOH phenol deprotection

HO

6-hydroxytetralone a classic building block for estrone synthesis

 4 4) Grignard addition to the carbonyl
MgBr

OH
key step: nucleophilic addition of enolized
cyclopentadienone via para-quinone methide:
HO
O O

5 5) Triton B, xylene
t-BuOH
O
O O
O

N OH can also be achieved under acidic contitions,

O Triton B =
via a stabilized carbocation
HO

key step: acid catalyzed isomerization of the

6 6) TsOH exocyclic double bond, followed by nucleophilic
attack to a protonated carbonyl to yield A, then
deprotonation and dehydration:
Me O O

O
HO H
HO
Me O

OH
HO
 7 7) H2, Raney Ni selective hydrogenation

Me O

H
HO

8 8) HCl isomerization of benzylic olefin via

Me O Me O

H H

H H
HO HO

9 9) H2, Pd diastereoselective hydrogenation

Me O

H H
HO
estrone
 The Corey asymmetric variant

[Reference]

*
H

turns the classical Torgov approach into a short enantioselective synthesis

 Me O

O
MeO
H Ph Ph
O
1 1) BH cat. O key step: enantiotopos- and diastereo-
O N B face-selective Itsuno-Corey reduction
Me OH
PhNEt2

O
MeO

2 2) HCl, MeOH key step: Acid catalyzed isomerization

and cyclization, via:
Me OH Me OH

OH
MeO HO

99% ee (recryst.)
 O

3 3) O (IBX) alcohol oxidation

I
O
HO
Me O

MeO

4 4) H2, Pd/C, Et3SiH, selective hydrogenation, followed by

then TFA, TBAI protonation and hydride reduction via:

Me O

Me O
H H
MeO
H
MeO

Me O

H H
MeO
estrone methyl ether
 The List asymmetric variant

[Reference]

*
H
Me O Me O
H
enantiotopic
H H O
HO MeO
estrone

an even shorter variant using a very strong chiral Brœnsted acid

 O

Torgov intermediate
F5S
O
NO2 key step: alkene isomerization,
MeO SF5 enantiotopos-selective protonation,
nucleophilic attack, deprotonation,
SO2 and dehydration, via:
1 1) 5 mol% *
NH PhMe
Me O
SO2 O S S O
N
O O
MeO H
SF5
NO2 O
MeO
δ+
F5S
er > 99:1 (recyst.)
O

2 2) H2, Pd/C, Et3SiH, see Corey synthesis

then TFA, TBAI
Me O

H H
MeO

3 3) BBr3 demethylation, via:

Me O
Br
H
B
Br O
H H
CH3
HO
Br
(+)-estrone
 Heterogenous hydrogenation of alkenes

O O
Me Me
H2, Pd-C
[Reference]
O O
H

H H
Pd Pd Pd Pd
Pd Pd Pd Pd

Me H Me H
H2, PtO2
H H [Reference]
(Adam’s cat.)
H H
Me

These reactions are usually stereospecific syn additions from the less hindered side, but beware of in situ isomerization:

Me O Me O
H2, Pd-C
O O [Reference]
O H O H
 Lindlar reduction
One of the best ways to install (Z)-olefins. Deactivation (“poisoning”) of the catalysts prevents overreduction.

O O
H2
[Reference]
Lindlar-Pd
jasmone

O O
O O
H2
O O
TBSO
N [Reference]
O Ts O
Lindlar-Pd
NHBoc NHBoc
TBSO
OH OH
N
Ts

H2

O O [Reference]
Lindlar-Pd
quinoline
civetone
 Homogenous hydrogenation of alkenes

O H2 O
[Reference]
cat. Rh(PPh3)3Cl
(Wilkinson’s catalyst)

carvone

Me Me H Me
H
H2

O OTBS
[Reference]
O O OTBS cat. Rh(PPh3)3Cl O
Me Me
(Wilkinson’s catalyst)

Me Me

MeO MeO

O O O O
Me Me
HO HO
( )7 ( )7
H H2 H
O O
[Reference]
H cat. Rh(PPh3)3Cl H
HO ( )7 (Wilkinson’s catalyst)
HO ( )7
 A simplified catalytic cycle

H [M]

H-H H

metal dihydride
oxidation state +2

oxidative complexation
additon

[M] metal in low

alkene complex H [M]
oxidation state
H

reductive metal hydride migratory

elimimation intermediate insertion

H
H
H
[M]
H
 Substrate directed homogenous hydrogenations
diastereoselective and directed PF6
by the OH group:
cat.
Rh
Ph2P PPh2
Me Me

dr = 70:1 [Reference]
OH H2 OH
H

OH OH
cat. [Rh] , H2
+ A1,3-strain: OTBS OTBS dr = 19:1 [Reference]
Me Me Me

PCy3 PF6
Ir
Me
N H

[Reference]
diastereoface and Crabtree’s catalyst
HO H H
chemoselective: HO
H2
COOEt COOEt
 Enantioselective hydrogenations
The the classical Monsanto L-DOPA process was developed by a team led by W. S. Knowles [2001 Nobel prize in Chemistry]:

MeO P
cat.
BF4 MeO P
Rh

MeO COOMe (R, R)-DIPAMP MeO COOMe

94% ee
NHAc NHAc
AcO AcO
H2

HO COOH
L-DOPA
NH2
HO

[Reference]
 Asymmetric hydrogenations in medicinal chemistry
[Reference]
PCy2

Ph OMe
O cat. [Rh(nbd)(P-OP ligand)]BF4 O
(2.0 mol%) O
MeO NHBn MeO NHBn P O
20 bar H2 NHAc O
NHAc
lacosamide
99% ee

P-OP ligand

CF3 CF3
[RhCl(cod)]2 (0.15 mol%)
F N (S,R)-t-Bu-Josiphos (0.155 mol%) F N
N NH4Cl (0.15 mol%) N
N N N N
NH2 O 17 bar H2 NH2 O
F F
F Me F
sitagliptin
Pt-Bu2 95% ee
Fe PPh2 > 99.9% ee after crystallization
 Asymmetric hydrogenations in medicinal chemistry
[Reference]

1. KOH, Ni, H2
CN [Rh(cod)((S)-TCFP)]BF4 (0.0037 mol%) CN 2. AcOH
NH2
3.5 bar H2
CO2 NH3t-Bu CO2 NH3t-Bu CO2H
Me 98% ee (S) pregabalin
P P

(S)-TCFP

NHMe
CO2 CO2

NH3t-Bu [Rh(cod)((S)-PhanePhos]BF4 NH3t-Bu

(1.0 mol%),

9 bar H2
Cl Cl Cl
Cl PPh2 Cl Cl
90% ee sertraline

PPh2

(S)-PHANEPHOS
 Top 200 Pharmaceutical Products by Most prescribed and top selling drugs
[Njadarson Top Pharmaceuticals Posters]
Compiled and Produced by the Njardarson Group (The University of Arizona): Munaum H. Qure

1 Lisinopril 2 Atorvastatin 3 Levothyroxine 4 APAP/Hydrocodone 5 Amlodipine 6 Omeprazole 7 Metformin 8 Simvastatin 9 Gabapentin 10 Amoxicillin 11 Hydrochlorothiazide 12 Losartan 13
( Lisinopril ) ( Atorvastatin ) ( Levothyroxine ) ( Hydrocodone-Acetaminophen ) ( Amlodipine ) ( Omeprazole ) ( Metformin ) ( Simvastatin ) ( Gabapentin ) ( Amoxicillin ) ( Hydrochlorothiazide ) ( Losartan )

101,658K Scripts 97,942K Scripts 93,884K Scripts 82,093K Scripts 80,989K Scripts 71,265K Scripts 66,513K Scripts 59,106K Scripts 58,238K Scripts 56,071K Scripts 47,244K Scripts 46,607K Scripts
Antihypertensive Antihyperlipidermic Hypothyroidism Analgesic Antihypertensive Antiulcerants Antidiabetic Antihyperlipidemic Anticonvulsant Antibiotic Diuretic Antihypertensive

21 Metoprolol 22 Montelukast 23 Furosemide 24 Pantoprazole 25 APAP/Oxy 26 Escitalopram 27 Citalopram 28 Zolpidem 29 Pravastatin 30 Fluoxetine 31 Trazodone 32 Meloxicam 33
( Metoprolol ) ( Montelukast ) ( Furosemide ) ( Pantoprazole ) ( Oxycodone-Acetaminophen ) ( Escitalopram ) ( Citalopram ) ( Zolpidem ) ( Pravastatin ) ( Fluoxetine ) ( Trazodone ) ( Meloxicam )

37,066K Scripts 36,902K Scripts 36,536K Scripts 33,341K Scripts 31,510K Scripts 31,150K Scripts 30,883K Scripts 29,829K Scripts 29,620K Scripts 29,526K Scripts 28,873K Scripts 28,505K Scripts
Antihypertensive Anti-Asthmatic Diuretic Antiulcerant Narcotic Analgesic Antidepressant Antidepressant Sedative Antihyperlipidemic Antidepressant Antidepressant

41 Vitamin D2 42 Ventolin HFA 43 Clopidogrel 44 Lorazepam 45 Duloxetine 46 Cephalexin 47 Synthroid 48 49 Ranitidine 50 Bupropion XL 51 SMZ/TMP 52 Potassium Chloride 53
( Ergocalciferol ) ( Albuterol ) ( Clopidogrel ) ( Lorazepam ) ( Duloxetine ) ( Cephalexin ) ( Levothyroxine ) ( Ranitidine ) ( Bupropion ) ( Sulfamethoxazole-Trimethoprim ) ( Potassium Chloride )

24,163K Scripts 23,242K Scripts 23,041K Scripts 23,008K Scripts 21,875K Scripts 21,733K Scripts 21,552K Scripts 20,759K Scripts 20,753K Scripts 19,940K Scripts 19,928K Scripts 19,788K Scripts
Dietary Supplement Bronchodilator Anti-platelet agent Anxiolytic Antidepressant Antibacterial Hypothyroidism Antibiotic Antiulcerant Antidepressant Antibiotic Potassium Supplement

61 Naproxen 62 Methylprednisolone 63 Triamcinolone Acetonide 64 Spironolactone 65 Glimepiride 66 Amitriptyline 67 Quetiapine 68 69 Clonidine 70 Albuterol 71 Paroxetine 72 Diazepam 73
( Naproxen ) ( Methylprednisolone ) ( Triamcinolone Acetonide ) ( Spironolactone ) ( Glimepiride ) ( Amitriptyline ) ( Quetiapine ) ( Clonidine ) ( Salbutamol ) ( Paroxetine ) ( Diazepam )

16,884K Scripts 16,328K Scripts 15,278K Scripts 14,306K Scripts 13,768K Scripts 13,614K Scripts 13,560K Scripts 13,330K Scripts 13,282K Scripts 13,271K Scripts 13,205K Scripts 13,000K Scripts
Diuretic Antidiabetic Antidepressant Antipsychotic Antihyperlipidemic Antihypertensive Bronchodilator Antidepressant Anxiolytic

81 Vyvanse 82 Triamterene/HCTZ 83 Ondansetron ODT 84 Folic Acid 85 Tizanidine 86 Glipizide 87 Diclofenac 88 Estradiol 89 Alendronate 90 Advair Diskus 91 92 Lovastatin 93 L
( Lisdexamfetamine ) ( Triamterene-Hydrochlorothiazide ) ( Odansetron ) ( Folic acid ) ( Tizanidine ) ( Glipizide ) ( Diclofenac ) ( Estradiol ) ( Alendronic acid ) ( Fluticasone & Salmeterol ) ( Lovastatin )

11,366K Scripts 11,322K Scripts 11,177K Scripts 11,120K Scripts 11,102K Scripts 11,074K Scripts 11,005K Scripts 11,002K Scripts 10,846K Scripts 10,829K Scripts 10,733K Scripts 10,654K Scripts
Psychostimulant Diuretic Antiemetic Essential Vitamin Muscle Relaxant Antidiabetic Analgesic Hormone Replacement Antihypocalcemic Corticoid Antibacterial Antihyperlipidemic
 Asymmetric reduction of unactivated alkenes

[Reference]

AcO
Me
O

O C6F5
N “barfate” is
H2 (o-Tol)2P F5C6 B C6F5
Ir a noncoordinating
Ph C6F5 counterion
(1 mol%)

AcO
Me Me
Me
O >98% ee

vitamin E

This is another case of reagent control. The existing sterocenter is too remote to provide stereochemical bias.
 The Solvias synthesis of Metolachlor

[Reference]

MeO
MeO
O
Cl O O
Me N NH2
Cl
Cl

(S)-metolachlor

A catalytic asymmetric synthesis of a herbicide used in maize fields that is done on a very large scale.
 NH2

o-toluidine is a very cheap starting material

1) Al2Et6, ethylene, Friedel-Crafts-type ortho alkylation, directed by the

1)
amino group, presumably via:
high pressure

Al Al
NH2 HN HN

O
2) 2) cat. H2SO4, MeO imine formation

MeO

N
 3) 3) [Ir(cod)Cl]2, xyliphos key step: catalytic enantioselective hydrogenation
H2 (80 bar) AcOH, NaI, 50°C of the imine

Cl
Ir Ir [Ir(cod)Cl]2
Cl
MeO
100% conversion, 79% ee
Me NH Me 34 g Ir complex + 70 g xyliphos ligand +
Me P some acid + some iodide gives
10,000 kg of hydrogenated product in 4 h
Fe PPh2

xyliphos

4) 4) ClCOCH2Cl amide formation

MeO MeO
O O
Cl Cl
Me N Me N

(S)-metolachlor >10,000 tons / year made

2 atropisomers, both active
 Dissolving metal reduction of enones
These often lead to the thermodynamic product and are a good way to regioselectively generate enolates and enol ethers.

MeO MeO MeO

Me Li, NH3 Me H+ Me

O O O
O t-BuOH O then SET, O
O O O H
then H+

more stable [Reference]

radical anion conformer
OMe OMe

Me Me
Li, NH3
[Reference]
O then MeI, HMPTA O
H

‡
O Li, NH3 O Et3SiOTf
OTES

[Reference]
 Changing the chemo and diastereoselectivity

cat. PPh3
PPh3 Rh Cl Me
O PPh3 O Li, NH3 O

H2
t-BuOH

carvone

Me
Li, NH3 Pd-C

O t-BuOH HCOO– NH4+

O
O

thermodynamic product kinetic product

 The Shenvi reduction
Proceeds via hydrogen atom transfer (HAT) from a metal hydride formed in situ. Due to the intermediacy of
conformationally flexible radical intermediates, the thermodynamic product is formed.

O O 10 mol% Mn(dpm)3 O
Me Me Me
H2, Pd-C PhSiH3, TBHP
[Reference]
i-PrOH
H H

dr = 11:1 dr = 4:1

catalysts used: t-Bu hydride sources used:

t-Bu O t-Bu O H2
O O O O SiH3 Si
Mn(dpm)3 Mn Fe(acac)3 Fe O
O O O O
t-Bu O t-Bu O

t-Bu O H
oxidant used: O

“H”
conceptually:
H
Mn(dpm)3 (10 mol%)

i-PrOH, PhSiH3
H H
TBHP
“H” dr = 10:1
actual intermediate
 A catalytic cycle
driven by strength PhSiH2 OR
of Si-O bond
LnMnIII H

stoichiometric PhSiH3
metal hydride with
reductant weak M-H bond
LnMnII
formation of the
metal hydride HAT

t-Bu
OH
t-Bu O t-Bu
O O
Mn LnMnIII OR R = i-Pr, H alkyl radical intermediate
O O
t-Bu O t-Bu H

t-Bu OH O

Mn(dpm)3 t-Bu t-Bu

LnMnIII H
HAT
reoxidation
O
acetone + 1/ ethane
2

HO O LnMnII
H
stoichiometric H
oxidant
 The Shenvi reduction

O O O O
Me Me
Mn(dpm)3 (1 mol%)
i-PrOH, PhSiH3, TBHP
O O [Reference]
H
Me Me

O O

Me Me
MOMO Me
MOMO MOMO
Me H
OH Mn(dpm)3 (13 mol%) O Li, NH3 Me H
OH
[Reference]
Me Me
i-PrOH, PhSiH3 EtOH Me
Me Me
TBHP Me
O O
O
single isomer dr = 14:1

The alkyl radical intermediate can be fed into radical cyclizations:

10 mol% Co(dpm)2
COOEt
PhSiH3, TBHP COOEt COOEt [Reference]
COOEt +
COOEt COOEt
i-PrOH
4.5 : 1