Structure, Mechanism and Reactivity of Hantzsch Esters · Structure, Mechanism and Reactivity of Hantzsch Esters ... decreases reaction rate ~104 fold. ... HEH can deliver a hydride

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