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Structure, Mechanism and Reactivityof Hantzsch Esters
Jamie TuttleMacMillan LabGroup Meeting
08/25/04
Lead References:Lavilla, R. J. Chem. Soc., Perkin Trans., 2002, 1, 1141.
Stout, D. M. and Meyers, A. I. Chem. Rev., 1982, 82, 223.Kuthan, J. and Kurfürst, A. Ind. Eng. Chem. Prod. Res. Dev.,1982, 21, 191.
Eisner, U. and Kuthan, J. Chem. Rev., 1972, 1, 1.
A little background on the Hantzsch ester
NH
O
EtO
O
OEt
Me Me
HEH
! First discovered in 1882 by Arthur Hantzsch
! Derivatives exhibit important pharmacological properties such as
antihypertensive, antibiotic, antiinflammatory, and antifungal activity
! Other dihydropyridine derivatives are used as rocket fuel additives,
antioxidants, and photographic materials
! Closely related to NADH, a ubiquitous biological reductant found in the
biosphere
nefipidine
NH
O
MeO
O
OMe
Me Me
NO2
- Calcium antagonist vasodilator. Treats high blood pressure and angina.- Adalat (Bayer 1999) $1 bill. Procardia (Pfizer 1998) $822 mill.
Bioreductants and their inspired organoreductants
N
Me
S
HN
Chikashita, H. et al. J. Chem. Soc. Perkin Trans. 1 1987, 699
H H
H
Ph
OO
NH
N
NH
HN
O
OMe
Me
N
OH OH
O
NH2
O P
O
O
O P
O
O
O
OH OH
N
NN
N
H2N
NADH
! Reduced nicotinamide adenine dihydropyridine (NADH)
! Reduced flavin adenine mononucleotide (FADH) is the other major reductant
found in biology
R
isoalloxazine
R = AMP and D-Ribitol
! A non-biomimetic organoreductant
benzothiazoline
10-methylacridan
R. H. Garrett and C. M. Grisham, in Biochemistry, Saunders College Publishing 1995, p. 470-474
NH
O
NH2
nicotinamide
- usually used in conjuction with AlCl3 to reduce enones.
Some interesting enzymatic transformations
R. H. Garrett and C. M. Grisham, in Biochemistry, Saunders College Publishing 1995, p. 472-473
! Enzymes catalyze the following reactions to produce chiral products
! Most NADH biochemical transformations are reversible redox reactions
- Biosynthesis of UDP-galactose occurs via oxidation/reduction of UDP-glucose.
O
O
HO HO O-UDP
OH
O
HO HO O-UDP
OHOH
H
R' R''
R' R''
O
R' R''
OH
O
NADHUDP galactose-4-epimerase
NADHMalate dehydrogenaselactate dehyd.alcohol dehyd.
NADHglutamate dehyd.
R' R''
NH2
NAD+
NAD+
+ NH4+
Pertinent enzymatic transformations con't.
NADHisocitrate dehydrogenase6-phosphogluconate dehyd.
NADHaldehyhde dehyd.
NADHdihydrosteroid dehyd.
NADHdihydrofolate reductase
HOR''
R'
R' OH
O
R
R R
R
N
R
R R
HO OH
R'
R''
O
R' H
O
R
RR
R
NH
R
R R
NAD+
NAD+
NAD+
NAD+
CO2+
R. H. Garrett and C. M. Grisham, in Biochemistry, Saunders College Publishing 1995, p. 472-473.
General structure considerations
! Theoretically, 5 isomeric DHP forms can exist
NH
NH N N N
1 2 3 4 5
- Structures 1 and 2 are the most common. Presumably, the N lone pair delocalization into the pi system
stabilizes the structure. Observe, 5 sp2 hybridized centers in 1 and 2 versus 4 in 3-5.
! Substituent effects
- EWG's capable of resonance interaction (COR, CO2R, CN, NO2) in the 3,5 positions stabilize 1,4 DHP's by extending conjugation.- Conversely, electron donating groups (SPh, OPh) in the 3,5 position destabilize the molecule.- Nitrogen alkyl substitution, though possible to prepare, destabilizes 1,4 DHP's.- 2,6 alkyl substitution remains largely unexplored.
NH
12
3
4
5
1
35
1 2
3 34
Meyers, A. I. and Stout, D. M. Chem. Rev. 1982, 82, 223.Kuthan, J. and Kurfurst, A. Ind. Eng. Chem. Prod. Res. Dev. 1982, 21, 191.
~ >>>= ~=~=
Increasing susceptibility towards oxidation
2
4
6
! X-ray studies
- 4-unsubstituted Hantzsch esters adopt a planar conformation.- aryl and pyridyl substituents at the 4-position induce a puckered ("flat boat") configuration.
Hantzsch esters adopt two potential conformations
NHNHMe
Me
H
H
O
EtO
O
OEt
HO
EtOMe
Goldmann, S. et al. J. Med. Chem. 1990, 33, 1413.Fossheim, R. et al. J. Med. Chem. 1982, 25, 126.
Puckered conformation Planar Conformation
O OEt
Leustra, A. et al. Bull. Soc. Chi. Belg. 1979, 133.
Me
Three postulates aim to explain the reduction mechanism of 1,4 dihydropyridines
! The following mechanisms have been proposed:
I. Single step hydride transfer
II. Two step electron transfer-hydrogen atom abstraction
III. Three step electron transfer-proton transfer-electron transfer
! Data supporting each process were derived from nicotinamide analogues and
Hantzsch ester derivatives
! No unified mechanism has been established
Single-step hydride transfer
HEH + A+ HE+ + HA!+!+ !-
! Occurs in most Hantzsch ester reductions that proceed under thermal conditions
! General scheme
! Experimental results that support this mechanism
[HE....H....A]
NH
OEt
O
EtO
O
Me Me
NC R
BrCH3CN, dry, deaeratedRT, 7h, dark
R = CN, CO2Et
CN
90%, only isomer
Zhu, X. et al. J. Org. Chem. 1999, 64, 8980.
- Free energy calculations indicate the single electron transfer mechanism is less likely than hydride transfer by two-fold (for CN +158.17 kJ/mol vs. 87.47 kJ/mol).- Deuterated C-4 and N Hantzsch analogues were used to determine hydride source via NMR.
NMe Me
EtO
O
OEt
O
NMe Me
EtO
O
OEt
O
+ +H
vs.
H HH
CO2Et
Various studies support single-step hydride transfer
! Deuterated product detected by 1H and 19F NMR. Authors support hydride
transfer mechanism
NH
EtO
O
OEt
O
Me Me
D D
CF3
CO2H
O
O
CO2H
O
CF3
O D
D
+or
MeOH, reflux39h
38%
20%
pyridinium perchlorateMeOH, reflux24h
Norcross, B. E., Klinedinst, Jr., P. E., Westheimer, F. H. J. Amer. Chem. Sci. 1962, 84, 797.
NH
EtO
O
OEt
O
Me Me
R R
NH
EtO
O
OEt
O
Me Me
R= D or H
D Ph
0.1M ClCH2COOH0.1M NaOH KOH (30% aq)CH3CN, pH 3.0
BF4
! Kinetic isotope effect and thermodynamics support single step hydride transfer.
Cheng, J.-P. et al. Tet Lett. 2000, 41, 257.
- Deuterium KIE value of 4.16 indicates
direct hydride dissociation from C-4 is
rate limiting step.
- Presence of the bulky phenyl group
decreases reaction rate ~104 fold.
- Electrochemical experiments support
direct hydride transfer for both cases.
CN
CN
CO2Et
CN
CN
CN
CO2Et
CN
D
D4,4,-d2-HEHCH3CN, deaerated, dark24 h
! Thermodynamic and kinetic studies provide an arguement for this process.
Zhu, X. Q. et al. J. Chem. Soc., Perkin Trans. 2 2000, 1857.
94%
94%
! Deuterium regiochemistry determined by 1H NMR and MS.
Further evidence for a single-step hydride mechanism
or
- A KIE comparison of N-d and C-d,d Hantzsch derivatives gave values <1.4 and >5.2, respectively. Values above 2.0 indicate the C-H bond is being broken in the rate determining step. - Free energy changes of electron transfer were 167-178 kJ/mol vs hydride 75-90.5 kJ/mol.
alphacyanocinnamates
benzylidinemalononitriles
! Molecular electrostatic potential and HOMO/LUMO comparisons support a hydride attack
N
NC CN
O
Ph
CNNC
N
O
Ph
CNNC
NC CN
HEHEtOH
Garden, S. J. et al. J. Org. Chem. 2003, 68, 8815.
Two step transfer: 1 electron- 1 hydrogen
HEH + A+ HE+ + HA
! Occurs predominantly under photoexcited conditions or with strong oxidants
! General scheme
[HEH ....A ]
NH
EtO
O
OEt
O
MeMe
NC CO2Et
PhBr
+
NH
EtO
O
OEt
MeMe
+
NC CO2Et
PhBr
NC CO2Et
CH2Ph
EtO2C CN
CH2Ph
Br
NH
EtO
O
OEt
O
MeMe
NC CO2Et
MePh
EtO2C CN
MePh
Zhu, X.- Q. et al. J. Org. Chem. 1999, 64, 8980.
EZ70%30%
single isomer
- Only the Z isomer is reacted. - Deuterium studies indicate a proton is abstracted from C-4.
CH3CN, dry, deaeratedhv, 420 nm
1e-1H
O
! Evidence is found in specific cases
! Three NADH analogues are analyzed kinetically and thermodynamically
1 Electron, 1-Hydrogen evidence continues. . .
NH
N
OEt
O
N
NH2
O
O
O
EtO
Me Me
Ph
Me
Ph
30% CH3CN70% H2O (v/v)KCl
O
Ph
or
Cheng, J. - P. and Lu, Y. J. Phys. Org. Chem. 1997, 10, 577.
HEH
AcrH2
BNAH
HEH + Xn+ [HEH...Xn+] HAH Xn ]slow fast
HE+ + XnHe-
T
fast
- A slight endothermic electron transfer was followed by a large exothermic proton transfer.- HEH, despite being a poorer electron donor than BNAH (0.446V, 0.182V, respectively), reacts faster.- Failure of CF3COOD to deuterate the intermediate radical anion suggests electron and proton steps may overlap.
HT
! General scheme
Multi-step transfer: electron-proton-electron (e- - H+ - e-)
HEH + A [HEH ....A] [HE....AH] HE+ + HA
! Cheng returns with the same reductants and a different mechanistic postulate.
Cheng, J. - P. et al. Chem. Eur. J. 2003, 9, 871.
NH
NNH
Me Me
OEt
O
EtO
O
NH2
O
Me
NMe Me
OEt
O
EtO
O
Me
N
NMe Me
Me Me
(omitted 6 nicotinamide derivatives)
ClO4
CH3CN
- Uses titration calorimetry and electrochemistry to develop hypotheses.
- In this experiment, HEH can deliver a hydride or undergo the e- - H+ e- mechanism with equal probability.
- N-substituents on nicotinamide derivatives have a large effect. EWG's favor heterolytic bond cleavage,
EDG's favor homolytic bond cleavage.
NH
Me Me
OEt
O
EtO
O
2
NMe Me
OEt
O
EtO
O N
NMe Me
Me MeNH
NMe Me
Me Me
H
1e- 1H+ 1e-
An interesting effect of e- - H+ - e- on 4-substituted Hantzsch DHP's
! Creates a potential source of alkyl cations
Lee, K. - H. and Ko, K. - Y. Bull. Korean Chem. Soc. 2002, 23, 1505.
NH
EtO
OH R
OEt
O
MeMe NH
EtO
OH R
Ph
O
MeMe
Ph-I-OH + -OTs
NH
EtO
O
OEt
O
MeMe
R
NH
EtO
O
OEt
O
MeMe
H
PHI(OH)OTsCH2Cl2, RT1-3 mins.>90% yield +
- R+ - H+
N
EtO
O
OEt
O
MeMe
R
N
EtO
O
OEt
O
MeMe
H
SET
PHI(OH)OTs
or
Ph-I-OHNH
EtO
O
OEt
O
MeMe
H
SET
- -OTs or -OH
- -OTS or -OH
R C6H53-NO2C6H42-ClC6H44-MeOC6H4C6H5CH=CHMeCH=CHCH3C2H5C6H5CH2(CH3)2CH
Hantzsch DHP ester groups may play a role sterically and electronically
Houk, K. N. et al. J. Am. Chem. Soc. 1995, 117, 4100.Cheng, J. - P. and Lu, Y. J. Phys. Org. Chem. 1997, 10, 577.
N
O
NH2
R
H H
N
NH2
O
R
H H
Cis Trans
! Nicotinamide amides can exist in either a cis or trans geometry
7 kcal/mol
Cis = ground state Trans = reduction transition state
N
NH2
O
R
HbHa
N
R
HH
N
NH
O
R'
R''
OEt
! The carbonyl is slightly tilted towards the incoming electropositive substrate
! Electrostatic interaction of both carbonyl groups with electrophile
MeMe
O
EtO
O
Orbital overlap may provide a key for understanding Hantzsch DHP orientation during hydride delivery
HN
HN
NH
NH
=
=
- Houk's nicotinamide models indicate a favorable LUMO donor/LUMO receiver overlap that lowers the activation energy.
! Two interesting concepts arise when analyzing FMO's
NH
MeMe
EtO
O
OEt
O!
"
H H!
- Garden's HOMO coefficient calculations show H! = 0.2325 and H" = -0.001.
Garden, S. J. et al. J. Org. Chem. 2003, 68, 8815.Houk, K. N. et al. J. Am. Chem. Soc. 1995, 117, 4100.
! Based on these data, it may be possible to determine Hantzsch ester/substrate
overlap by analyzing LUMO/LUMO coefficients.
O
NH2
N
HN
=
=
NH
O
OEtEtO
O
Me Me
Hantzsch ester preparation
! Many methods provide reasonable routes leading to Hantzsch derivatives
! Cyclocondensation routes are the most efficient and predictable
NH
NH
! Reduction of pyridine derivatives has been used with mixed success
vs.
! Main methods of preparation (reactants will be discussed)
1) Warming the reagents in alcohol (usually EtOH).2) Using hexamethlyenetetramine in place of formaldehyde and ammonia.3) Utilization of NH4OAc and primary amine salts with acetic acid or pyridine as solvents
! General trends for varying certain substituents on the Hantzsch DHP
NR3 R3
R2
O
R2
O R1- If R1 = varied, while R2 = OR, Me, NH2, R3 = Me and R4 = H, then use method 1.
- If R1 = varied, while R2 = Me, NMe2, OEt, OMe, O-i-Pr, O-n-Bu, R3 = Me and R4 =
alkyl, aryl, then use method 1.
- If R2 = varied, while R1 = R4 = H and R3 = Me, then use method 2.
- If R3 = varied and R1 = varied, while R2 = Et and R4 = H, then use method 3.R4
Kuthan, J. and Kurfurst, A. Ind. Eng. Chem. Prod. Res. Dev. 1982, 21, 191.
Namesake Preparation is most efficient
! Best way to introduce diversity in R and R1 positions.
O
R H R1CO2Et
O
NH
EtO2C CO2Et
R1R1
NH3+
H CO2Et
R1O
NH3
enolateCO2Et
R1HO
O
R H
NH3R1O
OH
RCO2Et
Haldol
NH3
R1O
OH
RCO2Et CO2Et
R1O
enamine formation
R
H CO2Et
R1O
CO2Et
R1H2N
E1cb
12
EtO2C
R1 O
R
CO2Et
R1H2N
CO2EtEtO2C
R1
N
O
R1
R
conj. add'n.tautomerization
H1 2
CO2EtEtO2C
R1HO
R
NHR1
H HNH3
NH3
NH
EtO2C CO2Et
R1R1
Our Hero
R
Hantzsch, A. Ann. 1882, 215, 1.Li, J. J. Name Reactions, Ed. 2, Springer - Verlag, Berlin, 2003, 172-73.
R
Cyclization/condensation methods lead to a variety of Hantzsch derivatives
O
R2R1 R3 NH
X
R4
R3HN
X
R4N
R4
R1 R2
X
R3
X
R3
-R4NH2
-H2O
! Use of enamino ketones, esters and nitriles (X groups)
- Great way to introduce nitrile groups to the 3 and 5 positions.
+ +
! Use of 1,5 diketones
! Use of !-" unsaturated ketones
Me OEt
O O
O
H H
Et2NHMe Me
O
CO2Et
O
CO2Et NH
CO2Et
Me
EtO2C
Me
- The diester intermediate is not isolated.
NH4OAc/AcOH
Me
O
CO2Et
Me
- Can react with enamines or ketones to provide unsymmetrical products.
H2N Ph
OMe
NH3
NH
COPh
Me
EtO2C
Me
Me
Kuthan, J. and Kurfurst, A. Ind. Eng. Chem. Prod. Res. Dev. 1982, 21, 191.Eisner, U. and Kuthan J. Chem. Rev. 1072, 72, 1.
The advent of microwave technology has streamlined the synthesis
! Useful modifications of Hantzcsh's synthesis
4 NH3 6O
H H
+
- Hexamethylenetetramine provides a cheap and easily handled source of ammonia and formaldehyde.
- The advent of microwave technology has reduced reaction time to minutes. Many functional groups can tolerate these conditions.
NH
R2 R2
MeMe
R1
RHHHHHMeMeiPriPrPhPh
R2
CO2EtCO2MeCO2tBuCOCH3CNCO2EtCNCO2EtCNCO2EtCN
Barbry, D. et al. Molecules 2002, 7, 528.
R2
Me
O O
HR1
NH3
NH2
Me
R2O
HR1R2
Me
O
2
or
NH4OAcno solvent
NN
N
N
Hantzsch esters reduce imine derivatives
! Imine, both preformed and under reductive amination conditions
N
R H
R1
CH3COOH, RT, o/n
R R1 % yield
p-MeOPh p-MeOPh 90
Ph 2-Naphthyl 89
p-OHPh o-OMePh 79
Ph p-OHPh 95
Ph Ph 66
! Ketimine
HEH
HEHN
PhPh
Ph
HN
HR
R1
CH2Cl2, 0.2 M TFA, o/n NH
PhPh
Ph
60% yield
! Bisarylidene-ethylenediamines
! Enamines
N
R NCH3COOH, RT, o/n
HEH
R1 NH
RHN
R
R % yield
p-ClPh
Ph 45
50
N
CH2Cl2, 0.2 M TFA, o/nHEH
- (CH2)2 -
- (CH2)3 -
- CH2OCH2 -
R % yield
55
58
50
Singh, S. et al. J. Chem. Soc. Perkin Trans. 1, 1985, 437.
R
N
R
+
+
+
+
Other imine derivative examples
MeO
N
ClO4
! Steroid iminium gives a single isomer
HEH (1.2 eq)MeCN, 24 h, reflux
MeO
O
~ 70%H
Pandit, U. K. et al. J. Chem. Soc. Chem. Comm. 1974, 327.
Pandit, U. K. et al. J. Chem. Soc. Chem. Comm. 1975, 211.
! Steroid unsaturated iminium gives a single isomer
MeO
N
ClO4
HEH (1.2 eq)MeCN, 24 h, reflux
MeO
HN
~ 90%
! Reductions proceed with 2 eq.HEH and are run in CH3CN at RT. Yields are all
> 90%.
Effect of substitution on hydride regioselection with !-" unsaturated iminium salts
Nie-Sarink, M. J. and Pandit, U. K. Tet. Lett. 1979, 26, 2449.
Ph H
N
x
Ph H
N
Ph H
N
Ph Me
NH Me
H
ClO4 ClO4 ClO4 ClO4
XX X
1 2 3 4
substrate11
22222222
33
4
XCH2O
OCH3CH3
FHBr
CO2EtCNNO2
HBr
-----
ratioC=C:C=N
attack100:0100:0
77:2329:7128:7221:7910:900:1000:1000:100
100:0100:0
100:0
E1/2 (V)-0.75-0.66
-0.47-0.43-0.38-0.35-0.32-0.22-0.15+0.04
-0.59-0.49
-0.44
- E1/2 is a measure of the relative LUMO energy. Data shows that E1/2 values below -0.59 lead to C=C attack. E1/2 values above - 0.30 lead to iminium attack.- Aromatic substituents have a significant effect on regioselectivity.- Sterics are more important than FMO interactions as shown in 3(Br) and 4.
pKaamine11.278.33
5.345.084.654.633.862.461.741.00
4.633.86
4.8
! These substrates were shown earlier in a deuterium labeling experiment
Hantzsch esters effectively reduce electrophilic olefins
CO2H
CF3
O
O
HEH (1:1)MeOH, reflux
CF3
O
CO2H
O
Norcross, B. E., Klinedinst, Jr., P. E., Westheimer, F. H. J. Amer. Chem. Soc. 1962, 84, 797.
61.2%
83.5%
! The second step in these reactions proceeds using the crude reduced product
Pandit, U. K. et al. Bioorg. Chem. 1973, 2, 293.
Cl
O
1)HEH (1:1) dioxane, 85°C, N2
2) BnOH 1:1
Cl
O
Cl
O
"
"
O
O
O
O
O
MeO
O
O
Me
>70%
>70%
10%
Bn
OMeO
Bn
Me
2) BnOH 1:1
2) MeOH 1:1
Me
Nitro- and carbonyl alkene reductions! !-nitroalkene derivatives
Inoue, Y. et al. Bull. Chem. Soc. Jpn. 1988, 61, 3020
R1NO2
R2
HEH (1.3 eq)AcOH (0.18 eq)benzene, N2, 80°C, 15h R1
NO2
R2
R1
Ph
p-CH3Ph
m-CH3OPh
p-CH3OPh
p-ClPh
p-NO2Ph
Ph
m-CH3OPh
R2
H
H
H
H
H
H
CH3
CH3
yield100 (glc)959695 (glc)95977085- Benzoic (pKa = 4.21), formic (pKa = 3.75), and chloroacetic
(pKa = 2.87) acids also worked.- Dichloroacetic (pKa = 1.26) and trifluoroacetic (pKa = 0.3) did not.
HEH (1.3 eq)AcOH (0.18 eq)toluene, N2, 80°C, 15h
Ph O
O
Ph O
Me
O
Me
O O
Ph O
O
Ph O
Me
O
Me
O O
yield
76
83
54
35
B = trace
A = 13
A B
(Here used TFA)
! "-! unsaturated aldehydes and ketones
! Maleic anydride is reduced non-regioselectively
Various substrates
Pandit, U. K. et al. Bioorg. Chem. 1973, 2, 293.
O
O
O
MeOOMe
O
O
1) d2-HEH
dioxane, reflux
2) MeOH/HCl(g)
D
O
O
O
MeOOMe
O
O
1) d2-HEH
dioxane, reflux
2) MeOH/HCl(g)Me
MeOOMe
O
O
D Me
Me
D
(1:1)
! Stabilized sulfonium salts are reduced by N-methylated Hantzsch esters
SMe
Me
Ph
O
ClO4
Van Bergen, T. J. and Kellogg, R. M. J. Am. Chem. Soc. 1964, 98, 1962.
Ph
O
40%
- Best case shown.
N-MeHEHacetone, 60°C
N
EtO
O
OEt
O
MeMe
Me
N
EtO
O
OEt
O
MeMe
Me
N
EtO
O
OEt
O
Me
Me
Me
H+
! Preparation of cyclic compounds
Other interesting reductions
Zhu, X. -Q. et al. J. Org. Chem. 2001, 66, 344.
time (h) % yield
BrH2CCN
BrH2CCO2Et
CN
R
CN
R
R = CN, CO2Et
R = CN, CO2Et, SO2Ph
O
O
Br
CN
R
H
CN
CO2Et
H
HEH (2.0 eq)CH3CN, deaerated, darkAr
CN
CO2Et
Br CN
CO2ET
SO2Ph
O
O
R
CN
"
"
"
11-15
7-11 >90
>91
>9213-17
15
19
18
89
88
86
20 85
E
E
A brief look at Lewis acid catalyzed Hantzsch reactions
! Olefin reduction with SiO2
Ohno, A. et al. Tet. Lett. 1984, 25, 36.
O
O
HEH (1.5 eq)SiO2 0.5 gbenzene, 80°C, dark17 h
O
O
88%
67%
! Reductive amination using Sc(OTf)3 and LiClO4
Ohsawa, A. et al. Tet. Lett. 2002, 43, 3105.Ohno, A. et al. Tet. Lett. 1977, 52, 4593.
HEH (1 eq)Sc(OTf)3 (2 mol %)THF, Ar, RT, 24 h
NH2
OMe
O
H
O
+
O
H
N
OMe
99%
Me
O
OMe
O
NH2
HEH (1.5 eq)LiClO4 (2 eq)CH3CN, RT, 4d, dark+
MeOMe
O
NH 35%
A look at asymmetric Hantzsch variants
! Asymmetric versions
NMe Me
NH
O
Me
PhH
Me Me
EtO
O
Tanner, D. and Li, X. Tet. Lett. 1996, 37, 3275.
PhOMe
O
O
Mg(ClO4)2 (1.0 eq)
CH3CN, 20 days
PhOMe
OH
O
83% yield72% ee
Pr
NMe Me
NH
O
EtO
O
Pr
O
O
O
Ph
Mg
Me
N
NH
O
O O
H
O
O O
Me
Mg2+
N
HN
OO
O
OO
NH
OO
Kellogg, R. M. et al. J. Am. Chem. Soc. 1981, 103, 2091.
PhOEt
O
O
Mg(ClO4)2 (1.2 eq)
Me
1.2 eq
PhOMe
OH
O
80% yield86% ee
CH3CN, 1-2 days
NADH regeneration
! Most of the current approaches require the use of enzymes or whole cell lysates
Kroutil, W. et al. Curr. Op. Chem. Bio. 2004, 8, 120.van der Donk, W. A. and Zhao, H. Curr. Op. Chem. Bio. 2003, 14, 421.
! A reasonable possibility
Lo, H. C. and Fish, R. H. Angew. Chem. Int. Ed. 2002, 41, 478
Rh
N
N O
Rh
N
N H
Rh
N
N OH2
O
N
NH2
O
Bn
N
NH2
O
Bn
N N=
N N
NaHCO2
CO2
+
+
2+
Me
O
Me
OH
>93% ee, 90% yield
HLADHEnzyme
[Cp*Rh(bpy)(H)]+
Future Directions
! Preparation of fused ring systems
O
Br
N
NH
O
BnOMe
N
EtO
O
OEt
O
MeMe
R
R = H, Me
O
! Extending 3,5 ester alkyl chains may increase enantioselectivity
N
HN
O
R'
R''
NH
H
HO
O
Me
Me
! Develop a catalytic cycle
Conclusions
! Reduction mechanisms are highly dependent on substrates
! Effectively lowering the LUMO of electrophiles facilitates reduction with
Hantzsch esters
! A catalytic cycle may be created with careful selection of the second reductant
and hydride source
! Based on mechanistic postulates, enantioselectivity may be increased with
different Hantzsch derivatives
Recommended