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Lecture 14
2.1.1.1 Introduction
Lithium aluminum hydride (LAH) is a strong reducing agent with chemical formula
LiAlH4. It can reduce a variety of functional groups such as aldehydes, esters,
acids, ketones, nitriles, epoxides and azides. It vigorously reacts with water and
all the reactions are performed in polar aprotic solvents.
2.1.1.2 Preparation
It was first prepared by treating lithium hydride (LiH) with aluminum chloride
(AlCl3) (Scheme 1).
Scheme 1
Na + Al + 2H2 NaAlH4
Scheme 2
The aldehydes and ketones are reduced to give the corresponding alcohols
when treated with LAH (Scheme 3). For the reduction of aldehydes and ketones,
the reaction is generally performed in ether solvents at low temperature.
O OH
R H LiAlH4 R H
or or
O OH
R R' R R'
O OH
LiAlH4
Br Br
Me Me
Et2O, -78 C
Scheme 3
Mechanism
The hydride from LAH is transferred to the carbonyl group to form alkoxy anion
which then forms complex with aluminum (Scheme 4). Similarly, four hydride
atoms are replaced by four alkoxy groups and the aluminum complex thus
formed is then hydrolyzed by dilute acid to give the desired alcohol.
R R
O H O H R
O H H O H O H
H R H
O Al H R H H
H Al H O Al H O Al O
R H R H R R
H H H
H H H H H H O
R H
R
H R
OH H O H
H3O H
4 R H O Al O
H R O H
H H H
R
Scheme 4
The acids are often reduced with LAH to prepare the corresponding alcohols
(Scheme 5). The other comparable method for reduction of acid is using BH 3 as
a reducing agent. The three hydride ions are consumed for reducing one acid
group.
O
LiAlH4
R OH R OH
Me Me
O LiAlH4
OH Et2O OH
Scheme 5
The esters and amides are reduced to the corresponding alcohols and amines,
respectively, when treated with LAH (Scheme 6). Each molecule of ester or
amides consumes two molecules of hydride ions.
O
R'
R O R OH + R' OH
or LiAlH4 or
O
R'
R' R N
R N
R'
R'
Me Me
O O LiAlH4 HO OH
O O
Et2O O O
O O Me Me
Me Me
LiAlH4
NH NH
O OH THF
OH
Me Me
Scheme 6
The azides, nitriles and nitro compounds are reduced to the corresponding
amines in presence of LAH (Scheme 7). The aromatic nitro compounds do not
give the desired amines.
R N3
or
LiAlH4
R C N R NH2
or
R NO2
Scheme 7
The epoxides are reduced to the corresponding alcohols (Scheme 8). The
hydride ion is transferred to the less hindered side of the epoxides.
Me LiAlH Me
4
O OH
HO
O Me Me
LiAlH4
H O H O
Et2O/THF
O 0 C O
CO2Me
OH
Scheme 8
2.1.2.1 Introduction
Though LAH is a powerful reducing agent but is less selective. The reactivity and
selectivity can be modified by replacing the three hydride ion with alkoxy groups
such as tert-butoxy or ethoxy group. The resulting reagents are less reactive but
more selective than LAH.
2.1.2.2 Preparation
The lithium trialkoxyaluminum hydride can be prepared by treating LAH with the
alcohol and better to prepare in situ prior to use (Scheme 9).
3 t-BuOH LiAlH(Ot-Bu)3
LiAlH4 + or or + 3H2
3 EtOH LiAlH(OEt)3
Scheme 9
This is less reactive compared to LAH and reduces aldehydes and ketones to
alcohols and acid chlorides to aldehydes (Scheme 10). The other functional
groups such as acids, amides and nitriles do not react or react very slowly.
O O
LiAlH(Ot-Bu)3
Cl H
diglyme, -78 C
NC NC
Scheme 10
O
CN LiAlH(OEt)3 H
Et2O
Scheme 11
R NH2
R'
R NH2
R
R' N R
H R
R' O NO2
R' CN R
H2N
N R
O O O
or OH OH
R OR' R R' R H or
R'OH + R OH Red-Al R R' R H
O O
O R R
O NR'2
R O O
R Cl R OH
R OH R NR'2
R OH
Scheme 12
Examples:
OH OH OH OH
Reduction
+ +
Ether
TMS TMS TMS
TMS
LAH 19 49 32
SMEAH 100 0 0
OH OH
HOH2C
OH SMEAH OH
N Toluene N
t-Bu
30%
O Al O Al
O H Al
Me O SMEAH Me O
Me O C
Me THF Me Al
Me
O
OH
Al
O
Me
Me Me CH2OH
Me
Me
Me
Me O
O Me Me Al
Al O H3O
R' Me R H
R O Me H Me R'
R O
H
tetrahedral
intermediate
Scheme 13
The nitriles are selectively reduced to the corresponding aldehydes with one
equivalent of DIBAL-H at low temperature. The use of two equivalent of DIBAL-H
gives the corresponding primary amine.
Me Me
H H
CN CHO
DIBAL-H
CH2Cl2, -78 C
Me Me
Scheme 14
Examples:
O O
O ClH2C O
ClH2C DIBAL
iPrOH, PPTS
79%
PhH
CN CHO
80%
Problems
A. How will you carry out the following reduction reactions using aluminum hydride
based reagents?
CHO CH2OH
1. Ph Ph
CHO CH2OH
2. Ph Ph
O O
3. NMe2 H
4. CN CHO
5. CO2Me CHO
DIBAL-H OH
CO2Me
THF
Text Book
M. B. Smith, Organic Synthesis, 2nd Ed., McGraw Hill, New York, 2004.
Lecture 15
2.1.5 Borohydrides
Different borohydrides are available depending on the metal cations and ligands
such as sodium borohydride, lithium borohydride, zinc borohydride, lithium or
potassium trialkylborohydride and sodium cyanoborohydride. All the
borohydrides reduce aldehydes and ketones to the corresponding alcohols but
due to its counter cations and ligands it shows some special selectivity towards
some functional groups.
The sodium borohydride is an ideal reducing agent for the reduction of aldehydes
and ketones to give the corresponding alcohols (Scheme 1). Unconjugated
ketones and aldehydes are rapidly reduced, usually in preference to a
conjugated carbonyl group that may be present elsewhere in the molecules. The
reactions are performed in polar solvents such as THF, DME, diglyme, hydroxyl
solvent and water but the ethanol is the solvent of choice.
O O
O HO
NaBH4, EtOH/CH2Cl2
NH4Cl
S HS S
HS
Scheme 1
O OH
Me Me
NaBH4/CeCl3
CO2Me CO2Me
MeOH
OH OH
Me O Me Me O Me
91%
Scheme 2
Proposed Mechanism
Scheme 3
The esters react slowly and the carboxylic acids in normal condition do not react
but are reduced to alcohol in presence of catalytic amount of iodine in reflux
condition in THF (Scheme 4). This method provides effective route for the
CO2H NaBH4, I2 Ph OH
Ph
H NH2 THF, reflux H NH2
Scheme 4
Amides are not reduced directly by NaBH4, but if they are first converted to an
imimium salts that readily proceed the reduction to give an amine (Scheme 5).
O + Cl
Cl Cl Cl
N N NaBH4 N
POCl3
EtOH
Scheme 5
Examples:
O OH OH
MeOH
+
NaBH4 0 100
NaBH4/CeCl3 96 4
O OH
CO2Me Luche reduction CO2Me
CHO CHO
76%
O HO
Luche reduction
OTBS OTBS
O O
Me Me
77%
CO2Ph CO2Ph
Me Me
H H
CONMe2 LiBH4 CONMe2
CO2Me OH
Me Me
Scheme 6
The zinc borohydride is prepared from zinc chloride and NaBH 4 in ether. It is
most useful for the reduction of -unsaturated aldehydes and ketones to give
saturated alcohols (Scheme 7).
O OH OH
Zn(BH4)2
+
H3O+
96% 4%
Scheme 7
The presence of three alkyl groups in boron atom makes the hydride strongly
nucleophile and hence it is a strong reducing agent compared to other
borohydrides, and it can reduce the aldehydes and ketones even at -78 C
temperature. The commonly used trilakylborohydrides are lithium
triethylborohydride, Li(Et3BH), and lithium and potassium tri-sec-butylborohydride
(L- and K-Selectrides). The bulky L- and K-selectrides can reduce carbonyl
compound from less hindered side resulting selective products (Scheme 8).
H H
L-Selectride
OH
O
H THF, -78 C H H
H H
Et Et
H H
Scheme 8
Examples:
Me Me
Me Me
L-Selectride
THF OH
SO2 O
SO2
N(iPr)2
N(iPr)2
92%
OTBDMS OTBDMS
Me Me
L-Selectride
O O
H H ClCH2OMe OMe H H
Et2NH
MeO2C OTBDMS MeO2C OTBDMS
90%
OMe
CN OTBDMS K-Selectride CN
O OTBDMS
O
Me ClCH2OMe Me
Et2NH 60%
Other than the carbonyl groups, lithium triethylborohydride can reduce primary
bromides and tosylates to the corresponding hydrocarbons (Scheme 9). The
epoxides are also cleaved to give the alcohols and the hydride is transferred to
the less hindered side if epoxides. Lithium triethylborohydride is called super
hydride and an extremely powerful source of hydride.
OTs
Me
Li(Et3BH), THF
NaOH, H2O2
Scheme 9
Examples:
H
H
Super hydride N
N O
O HOH2C
MeO2C THF
O
O
97%
Super hydride
Me Me
Me N CO2Me Me N CH2OH
CO2Me CO2Me
90%
O O
CO2H
H
O + O
Et
Et Et
O
Source Yield (%) Ratio
DIBAL 64 25 75
Super hydride 83 85 15
L-Selectride 65 75 25
NaBH3CN is less reactive reducing agent than sodium borohydride due to the
presence of electron withdrawing cyano group. Reaction of NaBH4 with HCN
gives NaBH3CN, which is soluble in THF, MeOH, H2O, HMPA and DMF.
NaBH3CN cannot reduce the aldehydes or ketones in neutral condition but it
reduces the protonated aldehydes and ketones at around pH 3 (Scheme 10).
The iminium ion could be reduced to the corresponding amine with almost
quantitative yield (Scheme 11).
CO2Et H CO2Et
H
NaBH3CN H
O N
N pH ~4 OH
O O NaBH3CN O O
OHC HOH2C
MeOH, pH 4
NHCO2CH2Ph NHCO2CH2Ph
89%
Scheme 10
Ph Ph
N N
H NaBH3CN H
N N
N MeOH N
Bn Me Bn Me
Scheme 11
NHTs
N Me
CHO NaBH3CN
NH2NHTs
DMF, heat
Scheme 12
Scheme 31
Problems:
A. Complete the following reactions.
OH
N
1.
2. Br
O
H H
Ph O
2. N NaBH4
N EtOH
O Br
Me
H NaBH4
3. O N S
O THF
O
Text Book
M. B. Smith, Organic Synthesis, 2nd Ed., McGraw Hill, New York, 2004.
Lecture 16
2.2.1 Introduction
The solution of alkali metal in ammonia (at -33 C) can generate solvated
electrons and metal cations.
These solvated electrons can reduce conjugated double bonds, triple bonds and
aromatic compounds. Most of the organic compounds are not soluble in liquid
ammonia and, therefore, the compounds are dissolved in THF or Et2O and are
added to the dissolved metal solution.
Me Me
Na, (NH3)liquid
Me
Me
Scheme 1
Me Me
Li, (NH3)liquid
O Et2O O
H
then aq. NH4Cl Me Me
Me Me
cyperone
Me Me
Li, (NH3)liquid
O EtOH HO
H
Me Me Me Me
cyperone
Scheme 2
Mechanism
The solvated electron is transferred to the conjugated system to give the radical
anion which is protonated by added alcohol or ammonia and then the second
electron transfer generates the enolate anion which on protonation during work
up gives the desired carbonyl compound (Scheme 3).
O Li O OH OH Li O
Me Me Me Me Me
Li
aq. NH4Cl
Me
Scheme 3
Li, (NH3)liquid
EtOH
Scheme 4
X
X X
Birch reduction
or
Scheme 5
The aldehydes and esters groups are in the electron donation side because
these are reduced to the corresponding alcohols in Birch condition before the
reduction of aromatic ring (Scheme 6). The addition of one or two equivalent of
water or t-BuOH to the NH3 before the addition of metal can preserve the ester
group in Birch reduction.
O O
Scheme 6
Mechanism
The solvated electron accepts an electron and generates the radical anion which
then takes a proton from the alcohol and forms a radical intermediate (Scheme
7). The radical intermediate then takes another electron and converts to the
carbanion which on protonation gives the desired 1,4-cyclohexadiene derivatives.
The role of alcohol is to supply the proton because the NH3 is not sufficient acidic
to supply the proton to all the intermediate anion.
H H H H H H H H
- -
e ROH e ROH
H H H H H
Scheme 7
Examples:
O OMe O OMe
o
Et
K, NH3, t-BuOH, THP, -78 C
N N
CH2OH
CH2OH i. Li/NH
3
O
MeO ii. HO2C-CO2H,
H2O, t-BuOH
Lindlar R R'
catalyst
R R'
H2 Z alkene
Scheme 8
R R
R R
H H H H
Examples:
Br
Br N
Lindlar
N N3 Br O
Br O H H2, MeOH
O H2N N
O
H2N
Pr
CH2OH
H2
Pr
Lindlar catalyst
quinoline, MeOH
OH
O O
H2
O
O Lindlar catalyst
Me Me
O O
O
O
96% Me
Me
Me H2 Me
N N
CHO Lindlar catalyst
CHO
92%
The benzyl group and cyano group (alkyl nitrile) could be deprotected by
dissolved metal in ammonia (Scheme 9).
Me H Me H
Li, EtOH (7equiv)
H NH3, THF H
O BnO O HO
Ph Na, NH3 Ph
Ph CN Ph H
Ph Ph
Scheme 9
O
Na, EtOH
R OR' R OH + R' OH
H H
CO2Me CH2OH
Na, EtOH
COOH COOH
NH3
H H
Scheme 10
Proposed Mechanism
The carbonyl group of ester takes an electron and converts to the radical anion
which takes a proton from the alcohol and forms the radical intermediate. The
latter takes the second electron and a proton and undergoes elimination of an
alcohol to give aldehydes that further proceeds further reduction to give the
desired alcohol.
H
O O OH OH O
e EtOH e EtOH
R OR' R OR' R OR' R OR' R OR'
-HOR'
OH OH OH O O
EtOH e EtOH e
R H R H R H R H R H
Examples:
Na
EtO2C HOH2C
CO2Et CH2OH
EtOH
75%
Problems
Na, EtOH
1.
OH
Li-NH3-EtOH
2.
OMe
Na, EtOH
3.
H3O
Na-NH3-EtOH
4.
CO2H
Na-NH3-EtOH
5.
OEt
Na-NH3-EtOH
6.
Na, EtOH
7.
8. Na, EtOH
NOH
reflux
O
(EtO2)2SiHMe
9. Ph
Br KF
Text Book
M. B. Smith, Organic Synthesis, 2nd Ed., McGraw Hill, New York, 2004.
Lecture 17
2.3.1 Introduction
Hydrogen is the most abundant chemical element in the universe with atomic
number 1 and symbol H. It has three isotopes hydrogen 1H, deuterium 2D and
tritium 3T and the 1H is the most abundant (99.98%). The hydrogen 1H and
deuterium 2D are stable isotopes whereas the tritium 3T is a radioactive. In
organic chemistry, hydrogen is used to reduce a variety of functional groups but
the hydrogen gas itself can not reduce any functional groups without a catalyst.
Platinum oxide (PtO2) also known as Adams catalyst is generally used for the
platinum catalyzed hydrogenation reaction. Other catalysts such as Pd on
charcoal, Wilkinsons catalyst RhCl(PPh3)3, Crabtrees catalyst
[Ir(cod)(PChx3)(py)]PF6, Ru(OAc)2(BINAP), Raney nickel and Nickel boride (Ni2B)
are used. These reactions are performed in ethyl acetate, alcohols and acetic
acid as solvents.
Me Me
Me Me CO2H
CO2H
Pt, H2
AcOH
Me Me
O O
RhCl(PPh3)3
H2, toluene
Me Me Me
OAc OAc
Me Me
Pd-C, H2
O H OAc O H OAc
EtOH H
Me Me Me H Me
MeO2C MeO2C
O O
Ni2B, H2
MeOH Me
Me
Scheme 1
Et Et
P P
Et Et
(R,R)-DuPHOS
[(R,R)-Et-DuPHOS-Rh]+ CO2Me
CO2Me
NHAc
NHAc
99% ee
O OH
B-H
PPh2
O
PPh2
[Rh(COD)2]BF4 Me
Me 94% ee
(+)-BINAP
-78 oC (+)-BINAP
Scheme 2
OH
OH OH
OH Pt, H2
Scheme 3
Pd/BaSO4/quinoline
Pd/CaCO3/PbO
H2, MeOH
Me CO2H Me
CO2H
Scheme 4
CO2Et CO2Et
Ni, H2
100 atm., 50 C
PtO2, H2
CO2H CO2H
AcOH, 25 C
Scheme 5
The aromatic nitro compounds can be reduced to give the corresponding amines
when treated with molecular hydrogen in the presence of Pt, Pd or Ni catalyst
(Scheme 6). The reaction is generally performed in methanol, ethanol or ethyl
acetate at ambient temperature.
NO2 NH2
Pd/C, H2
EtOAc, rt
Scheme 6
O O
Cl Pd/BaSO4/quinoline H
H2
Proposed Mechanism
O H2 O O
R Cl R Pd Cl R H
Pd-BaSO4
Scheme 7
Examples:
O H2, Pd/C/BaSO4 O
Cl CCl3 H CCl3
quinoline, petroleium ether
50%
O
O H2, Pd/C
H
Cl
Pd/PPTA 48%
O O
H2, Pd-BaSO4
Cl H
quinoline, NaOH, xylene
O
O
H2, Pd-C, quinoline MeO H
MeO Cl
MeO
MeO NaOAc, toluene
OMe
OMe
O OH
Me [RhCl2(bipy)2]Cl 2H2O Me
Scheme 8
Ph2P
OH PPh2
O [(RhCl(COD)]2- N
(2S,4S)-BPPM O O CO2C(Me)3
O O
H2 87 ee (2S,4S)-BPPM
Scheme 9
The benzyl ethers, N-Cbz (Cbz = carboxy benzyl), and thioketal groups could be
removed by reaction with molecular hydrogen and Pd or nickel catalyst (Scheme
10). The benzyl ethers and N-Cbz are deprotected by Pd-catalyst and molecular
hydrogen whereas the thioketal groups are reduced to the corresponding alkanes
when treated with Raney nickel and molecular hydrogen.
NHCbz NH2
O O
O
O
O
H2, Pd/C, 0.01N HCl O
OBn
EtOAc-EtOH OH
OPBz
OPBz
Raney Ni
S S
H2
S S
Scheme 10
Problems
1.
2.
NC NC
3.
OH OH
4.
OH
CO2H CO2H
5.
OH OH
6.
7.
Text Book
M. B. Smith, Organic Synthesis, 2nd Ed., McGraw Hill, New York, 2004.
Lecture 18
Me
Me 60 C Me Me
N N Me 2 + N2
NC
Me CN
NC
AIBN
Bu H
Me Me Me Me
+ H Sn Bu Bu3Sn +
CN Bu CN
Bu
R + H Sn Bu Bu3Sn + R H
Bu
Scheme 1
O O
H H
Bu3SnH (1.2 equiv)
R' R'
Bu3SnH (1.2 equiv)
R R
N AIBN (0.05 equiv) N
H H
Br toluene, 110 C
Scheme 2
R
EtO2C CO2Et EtO2C R
O Me CO2Et
Me Bu3SnH-AIBN O
O Me Me
N Ph benzene, heat N O Me
Br
Ph Me
Ph
Ph
O O
NH Bu3SnH-AIBN NH
I benzene, heat
Scheme 3
S
NaH, CS2 Bu3SnH-AIBN
Me R Me
R OH R O S
MeI toluene, heat
Scheme 4
Mechanism
The tributyltin radical reacts with the sulfur atom to give a radical intermediate
which then cleaves to give the desired radical and reacts with TBTH to
regenerate the tributyltin radical and the product (Scheme 5).
S SnBu3
NaH, CS2 Me S
R OH R O S Me
MeI R O S
AIBN
Bu3SnH Bu3Sn
SnBu3
S
R Me R Me
O S
Bu3SnH
Scheme 5
Examples:
Me Me
TBTH, AIBN . Me
CH2I Me
Me CH2
Me
Me Me
Me
80%
.
IH2C .
O H3C
O OH O
TBTH, AIBN
CO2Et
CO2Et
PhH
CO2Et CO2Et
45%
Cu2+
NH2-NH2 HN=NH
H2O2
heat
HO2CN NCO2H HN NH + CO2
MeOH
O
heat SO3H
S NH-NH2
O HN NH +
Diglyme
Scheme 6
H H H H H H
N N N N
Examples:
CH2-OTBS CH2-OTBS
KO2CN=NCO2K
HO HO
O O O
O
91%
t-Bu t-Bu
HO CH2Br CH2Br
HO
KO2CN=NCO2K
HO HO
AcOH, MeOH
80%
O O
O O
KO2CN=NCO2K
Me Me
AcOH, MeOH
77%
OTHP OTHP
Cu(OAc)2/H2O2
EtOH/N2H4
2.4.3 Silanes
Silane hydrides can be used for the reduction of carbonyls and alkenes. Addition
of transition metal salts such as ZnCl2 or copper salts to the silane facilitates the
reduction (Scheme 7).
Me Me
Et3SiH
TFA
72%
(EtO)2SiHMe CH2OH
CHO Ph
Ph
KF
O O
Ph2SiH2
ZnCl2-Pd(PPh3)3
CHCl3
Scheme 7
O HO H
Ph2SiH2, L* Me
Me N N
H2O Ph H
Yield: 99% L* Me
Ee: 84%
Scheme 8
NO2 NO2
OH O
Al(OiPr)3
Cl COMe Cl CH(OH)Me
OH O
Mechanism
PrOi OiPr
Al Al(OiPr)2
O Al(OiPr)3 O O O O H+ OH
+
R i-PrO- H R
H H R
R
Scheme 9
Examples:
MeO O O
Al(OiPr)3 MeO
O O
O O toluene O
OH
OH 79% O
O OH
AlMe3
i-PrOH, toluene
82%
O OH
Cl AlMe3 Cl
i-PrOH, toluene
91%
Problems
diimide
OH
1.
OH diimide
2.
Bu3SnH
3.
N AIBN
H
Br
H
Bu3SnH
4. O
O AIBN, Toluene, Reflux
PhS H
Cl Bu3SnH O
O AIBN
Text Book
M. B. Smith, Organic Synthesis, 2nd Ed., McGraw Hill, New York, 2004.
Lecture 19
2.5.1 Photoreduction
O OH OH OH O
+ hv
Ph Ph +
Ph Ph Me Me Me Me
Ph Ph
O OH OH O
+ hv +
Ph Ph Me Me reflux Ph Ph Me Me
Scheme 1
O OH
OH O
hv
Me Me + Me Me + Me Me
Me Me
Me Me Me Me
Scheme 2
n, * n, * OH
O 1 O Intersystem 3 O OH
hv crossing (ISC) Me Me
Ph Ph n Ph Ph Ph Ph Ph Ph
*
dimerization
OH OH
Ph Ph
Ph Ph
Scheme 3
Scheme 4
O O OH
hv
Me Ph Me + Me + Ph
Ph
Norrish type II
OH
O Me
hv Ph
N
Ph Ph N
Ph
OH Me
O Me
hv Me Me
Me Me
O O
Scheme 5
hv R3N
+ R3N
H+
e-, H+
H H H H
dimerization
Scheme 6
The excited aromatic compounds could also be reduced by hydride source such
as sodium borohydride, lithium aluminum hydride of metal hydride (Scheme 7).
The reaction may undergo via the following sequences.
CN CN CN H H CN CN
hv NaBH4 H3O+
Scheme 7
2.5.2 Bio-reduction
The reductions of carbonyl groups have been studied most by using different bio-
reductants such as Bakers yeast or with reductase enzyme. For example, the
reductions of -ketoesters have been studied extensively (Scheme 8). The ethyl
acetoacetate could be reduced to give the corresponding 3-hydroxybutyrate. On
the other hand, 4-chloroacetoacetate when reduced with Bakers yeast, gives the
corresponding (S)-alcohol with opposite selectivity. Therefore, the
stereochemistry of the reduced product depends on the shape and size of the
prochiral starting substrates. It also says that the Bakers yeast has at least two
different active reducing sites.
O O Baker's yeast OH O
Me OEt Me OEt
H2O, sucrose, 30 C
O O Baker's yeast OH O
Cl Cl
OEt OEt
H2O, sucrose, 30 C
Scheme 8
The reduction with Bakers yeast is very much substrate dependant and it works
well with -keto substrates but it is less selective with other keto-functional
substrates. Therefore, it promoted further study on this subject for better results.
For example, a better result has been achieved with lyophilized whole cells of
Rhodococcus ruber DSM 44541, for asymmetric reduction of aryl ketones and
other unfunctional ketones with good enantiomeric excess (Scheme 9).
Me O Rhodococcus ruber Me OH
Scheme 9
O OH
G. candidum, NAD+
Me Me Me Me
secondary alcohol
O OH
Br G. candidum, NAD+ Br
Me Me
secondary alcohol
O OH
G. candidum, NAD+
CF3 CF3
secondary alcohol
Scheme 10
The reduction with isolated enzymes have also been studied and the advantage
of this protocol is that it reduces the effect of other interfering enzymes which are
present in a cell but the weak point is that the stability of isolated enzymes and
use of expensive specific co-factor such as NADP (Nicotinamide adenine
dinucleotide phosphate) (Scheme 11).
H2N H2N
O O OH O
+ enzyme
H R R' R R' +
O N O
N H
O O
O O
P O P O
OH OH O OH OH
O O P
O P O
O O O N
N
O NH2 O N NH2
N
N N N
HO O N HO O
PO3H PO3H
NADPH NADP+
formate dehydrogenase
CO2 HCOO-
Scheme 11
H H
O OH
HLADH
Scheme 12
Problems:
A What products would you expect from the following reactions?
O O
Baker's yest
1.
OEt
O
light
Ph
2.
O
light
3.
OH
O O
O OH
light Ph
Ph +
+
NH
NH2
Text Book
M. B. Smith, Organic Synthesis, 2nd Ed., McGraw Hill, New York, 2004.