Upload
vothien
View
221
Download
0
Embed Size (px)
Citation preview
Different Methods of Preparation of Chiral α-amino acids
RCOOH
O
O
R
RCHO + NH3 + HCN
RCOOH
NH2
H2
RCOOH
NH2
RCOOH
NH2
R+
N
R CO2R'
R''
N
OM
OR'
(racemates)
Kinetic Resolution Asymmetric Hydrogenation Reductive Amination
Aux *
Electrophilic Amination
Chemical or
Enzymatic MLx
Nu-
Enzym
e
Alkylation
R1CHO + R2NH2 + R3COOH + R4NC
Asymmetric Ugi Reaction
Asymmetric Strecker Reaction
Ring Openingof Aziridine
Duthaler, R. Tetrahedron. 1994, 50, 1539
Introduction to Strecker Reaction
Strecker, A. Ann. Chem. Pharm. 1850, 75, 27 Miller, S. L. Science, 1953, 117, 528
♦ Classical Strecker synthesis of α-amino acids
♦ Why Strecker reaction?
* Simple starting material, three components, efficient reaction. * Catalytic asymmetric Strecker reaction still a new and hot area. * Possibly the prebiotic process which produced amino acids on the primitive earth!
“A completely different compound was formed upon the bring together of the aldehyde- ammonia adduct and hydrocyanic acid in the presence of acids.”
In addition of chemical analysis of the new compound, characterized it physically: “The larger crystals of alanine are mother-of-pearl-shiny, hard and crunch between the teeth.”
-- Strecker, 1850
R COOH
NH2
R CN
NH2
HCNNH3R CHO + +
Strecker Reaction - An Outline
I. Mechanism study of Strecker reaction.
II. Asymmetric Strecker reaction using chiral auxiliaries
III. Catalytic asymmetric Strecker reaction
IV. Future work
V. Conclusions
Mechanism Study of Strecker Reaction
Ogata, Y.; Kawasaki, A. J. Chem. Soc. B 1971, 325-329. Stadnikoff, G. Ber. 1907, 40, 1014-19; J. Russ. Phys. Chem. Soc. 1914, 46, 1201-15. Snyesarev, A. P. J. Russ. Phys. Chem. Soc. 1914, 46, 217-23.
♦ Cyanohydrin pathway
♦ Imine pathway
R CHOHCN
R H
HO CN NH3
R H
H2N CN
cyanohydrin
R CHONH3
R H
NH HCN
R H
H2N CN
imine
♦ The argument began around early 20th century. -- Snyesarev vs. Stadnikov, 1907 - 1914
Mechanism Study of Strecker Reaction
Ogata, Y.; Kawasaki, A. J. Chem. Soc. B 1971, 325-329. Taillade, J.; Commeyras, A. Tetrahedron 1974, 30, 2493-2501
♦ Control experiments - intermediate criterion
♦ Suggested pathways in Strecker reaction
♦ Kinetic study also showed that in the presence of excess CN- the rate-determining step is imine formation.
Ph NH
CN
Ph
Ph NH
CN
Ph
Ph NH
CN
Ph
Ph NH2
Ph NH2
HCN
Ph CN
OH
HCN
Ph NPh
HCN
Ph CHO
Ph NH2
Ph CHO
Ph CHO
22 hrs(to reach equilibrium)
3 hrs
1 hr 1.5 hrs
<20%
100% !
22 hrs 60%+ +
Ar1 NH
Ar2CNHCN
Ar1 NAr2
Ar1 OH
CN
Ar2 NH2
HCN
Ar1 CHO
Ar1 CHO
+k1
k2
+
k2 > k1
Asymmetric Strecker Reaction - An Overview
Chiral Amino Acid
Carbohydateauxiliary
Chiral Auxiliary Based Synthesis
Catalytic Asymmetric Sythesis
Chiral amineauxiliary
Cyclic ketimineauxiliary
Guanidinecatalysts
Chiral Schiff basecatalysts
BINOL-basedcatalysts
Asymmetric Strecker Reaction Using Carbohydrate Auxiliary
Kunz, H.; Sager, W. Angew. Chem. Int. Ed. 1987, 26, 557-559. Kunz, H.; Sager, W.; Pfrengle, W.; Schanzenbach, D. Tetrahedron Lett. 1988, 29, 4397-4400.
♦ Preparation of carbohydrate templates
♦ Asymmetric Strecker Reaction Using Carbohydrate
O
OR
RO
OR
OR
ORMe3SiN3 O
OR
RO
OR
OR
N3O
OR
RO
OR
OR
NH2
R = Piv
SnCl4/CH2Cl2
H2/Raney Ni
O
OR
RO
OR
OR
NH2
O
OR
RO
OR
OR
N R'
H
R' CHO
Me3SiCN
O
OR
RO
OR
OR
N R'
H
O
OR
RO
OR
OR
HN R'
CNH
Me3SiCN O
OR
RO
OR
OR
HN CN
R'H
R' COOH
H3N H Cl
>90% quantitativeR:S = 7-13 : 1
ZnCl2/i-propanolor SnCl4/THF
HCl/HCOOH
ZnCl2,CHCl3
S : R = 3-9 : 1R = Piv
R = Piv
♦ Reversed Asymmetric Induction of Strecker Reaction:
Kunz, H.; Sager, W. Angew. Chem. Int. Ed. 1987, 26, 557-559. Kunz, H.; Sager, W.; Schanzenbach, D.; Decker, M. Liebigs Ann. Chem. 1991, 649-654.
Rationale of stereoselectivity in asymmetric Strecker reaction
Asymmetric Strecker Reaction Using Carbohydrate Auxiliary
O
OR
RO
OR
OR
N R'
H H
O
OR
RO
OR
O
N R'
H
O
Zn
ClCl
CN-
NOE
Conformation A Complex B
Ph NH2
Et RCHO
Ph N
Et
RR
C NC
EtH
R Ph
HCN
Fe
RCHO
CH3CHO
C2H5CHO
PhCH2CHO
SR COOH
NH2CN modified hemin-copolymer
EtOH, 20oC, 20 hrs
1) HCl
2) Pd(OH)2, H2
ee % Yield
92
96
99
57
46
41Hemin
Asymmetric Strecker Reaction Using Chiral Amine Auxiliary
Harada, K. Nature 1963, 200, 1201. Harada, K.; Saito, K. Tetrahedron Lett. 1989, 30, 4535-4538.
♦ First example of asymmetric Strecker reaction
♦ Asymmetric Strecker reaction using chiral amine and cyanide-modified hemin-copolymer
CH3CHO + HCN +Ph NH2
CH3
CH3OH Ph NH
CH3
CH3
CN
H3C COOH
NH2r.t. 5 days 1) HCl
2) Pd(OH)2, H2
(S) - Alanine(S) - methylbenzylamine17% yield, 90% ee
Vincent, S. P.; Schleyer, A.; Wong, C.-H. J. Org. Chem. 2000, 65, 4440-4443.
Asymmetric Strecker Reaction Using Chiral Amine Auxiliary
O
CHO
OBnPh NH2
(OBn)3HO CN
N
R H
H
CH3
PhTHF
CN
(S)
N
R HCN
(S)CH2Cl2
CH3H
Ph
PhHN R
CH3 CN
PhHN R
CH3 CN
(OBn)3
(S)
(R)
O
OBn
ACN
HN Ph
THF
Solvent
CH2Cl2
(OBn)3
O
OBn
COOH
NHBOC
1)
2)
*
1) MeOH, HCl2) LiOH, MeOH
*4) (BOC)2O
R/S of A Yield of A
1:3.5
7:1
82
69
C-gluco-alanine analogue
Felkin-Anh type 1,3-syn-stereoselectivity
Cram type 1,3,-trans-stereoselectivity
, Solvent3) H2, Pd/C
Asymmetric Strecker Reaction Using (R)-Phenylglycinol Auxiliary
Inaba, T.; Kozono, I.; Fujita, M.; Ogura, K. Bull. Chem. Soc. Jpn. 1992, 65, 2359-2365.
Ph NH2
OH
Ph NH
COOH
ROH
R
R COOH
NH2
Ph N COOMe
R
Ph NH
CN
ROH
S
HCl
R
R COOH
NH2
Ph NH
CN
ROH
R
+ RCHO1) KCN/NaHSO3
2) 80oC, MeOH
1) HCl
2) Separation
(R, S) : (R, R) = 4-6.7 : 1
1) SOCl2 - MeOH
2) Pb(OAc)4
(R = aryl)
Pd - HCOOH
(R = alkyl)
40-100%87-100%
41-66% over 3 steps, 79-99% ee
54-86%92-100% ee
+
Chakraborty, T. K.; Hussain, K. A.; Reddy, G. V. Tetrahedron 1995, 51, 9179-9190.
Asymmetric Strecker Reaction Using (R)-Phenylglycinol Auxiliary
R
Ph
i-Bu
t-Bu
Ph NH2
OH
PhCH2CH2
CHCl3
RCHOR N Ph
OHH
TMSCN
A
RHN Ph
OHCN
RHN Ph
OTMSCN
B
RHN Ph
OHCN
RHN Ph
OTMSCN0oC, 6-8 h
+
(S, R) Major (R, R) Minor
TBAF or 3N HCl
+
Diastereoselectivity(S, R)-A : (R, R)-B
Total Yield(A+B), %
p-MeO-Ph
82:18 92
90:10 95
54:46 87
84:16 95
88:12 92Chromatographyseparation
Asymmetric Strecker Reaction Using (R)-Phenylglycinol Auxiliary
Chakraborty, T. K.; Hussain, K. A.; Reddy, G. V. Tetrahedron 1995, 51, 9179-9190. Hosangadi, B.; Dave, R. Tetrahedron Lett. 1999, 11295.
♦ Removal of chiral auxiliary
♦ Rationale of diastereoselectivity
CN-
R
H HH O H
RN
OH
PhH
CN- re-face attack
(S, R) Major Isomer
re-face attack
Pb(OAc)4
RHN Ph
OHCN
Ph N Ph
CN
HN Ph
OHCO2Me
NH2
CO2H
Ph NH2-HCl
CO2HCH2Cl2/CH3OH0oC, 5min
Methanolic HCl
rt, 5h
Conc. HCl
reflux, 3h
1) Pb(OAc)4
2) Dil. HCl
70% in 3 steps
(S, R) Major Isomer
R = i-Pr or Ph
yield not reported
i-Pr i-Pr
Ma, D.; Tian, H.; Zou, G. J. Org. Chem. 1999, 64, 120-125.
Synthesis of α,α-Disubstituted Amino Acids Using (R)-Phenylglycinol Auxiliary
Br
Ar Me
O
MeO2C
Me
O
HN
Ph
O
Ph NH2
OH
SAr Me
CbzN
Ph
MeO2C
OH
Ar Me
N
Ph
OH
RMeO2C Me
CbzN
Ph
Ar
OH
HO2C
Me
HO2C NH2
Ar Me
NHO
Ph
CbzCl
Ar Me
HN
Ph
MeO2COH
toluene, reflux+
1) TMSCN, MeOH
2) HCl/MeOH
Unseparable isomers, 73%
+
58% 23%
Pd(OAc)2/dppp/Et3NCO/EtOH/DMSO
100%
1) NaOH/MeOH2) Pb(OAc)4
3) 3N HCl, reflux4) propylene oxide 47%
(S)-αM4CPG
* Antagonist of metabotropic glutamate receptor
Ar =
Ma, D.; Ding, K. Org. Lett. 2000, 2, 2515-2517.
♦ Synthesis of α,α-disubstituted amino acid -- the idea
Synthesis of α,α-Disubstituted Amino Acids Using (R)-Phenylglycinol Auxiliary
RCHOTMSCN
Ph NH2
OH
O
N
R''
O
R Ph
RHN Ph
OHCN
O
N
R''
O
R'PhR
R NH2
CO2H
CO2H
NH2R'
R
(S, R) major isomer + minor isomer
1) Pb(OAc)4
2) HCl
1) HCl/MeOH2) Heat3) R''X
Diastereoselectivealkylation, or aldolcondensation?
Ma, D.; Ding, K. Org. Lett. 2000, 2, 2515-2517.
Synthesis of α,α-Disubstituted Amino Acids Using (R)-Phenylglycinol Auxiliary
CH3CHOPh NH2
OH
BrCH2CO2Me
BnBr
EtI
n-PrCHO
O
N
Bn
O
H3C Ph
NO
-O
RPh
Bn
S
S
S
RCO2H
NH2E
H3C
O
N
Bn
O
EPhH3C
1) , KCN
2) HCl/MeOH then PTSA toluene, reflux3) BnBr/K2CO3 (66% yield)
1) NaHMDS, -78oC
2) Electrophile
Electophile Yield dr of C5
5
Configuration of C-5
87 > 200:1
90
50
80
> 200:1
> 200:1
8:1 (E = (S)-CH(OH)Pr)
1) Hydrolysis2) Pd/C, H2
62-80%
E
E
Favored
Disfavored
Sakamuri, S.; Kozikowski, A. P. Chem. Commun. 2001, 475-476.
Application of (R)-Phenylglycinol Auxiliary in Total Synthesis
NHAc
OH
N
CHO
OMe
N
OMe
HN
OHCO2Me
PhN
OMe
NHBOC
CO2Me
N
OMe
HN
OHCN
Ph
NHNMe
O
OH
OMe
MeOH
1) (R)-phenylglycinol, CHCl3
2) Me3SiCN3) TBAF
66% for 3 steps4:1 dr
HCl in ether
81%
7-methoxybenzolactam-V8Intermediate of potent activator of protein kinase C
1) Pb(OAc)4
2) Pd(OH)2/C, H23) BOC2O, Et3N
44% for 3 steps
Vedejs, E.; Kongkittingam, C. J. Org. Chem. 2001, 66, 7355-7364. Reddy, R.; Jaquith, J.; Neelagiri, V.; Saleh-Hanna, S.; Durst, T. Org. Lett. ASAP, Feb 2, 2002
Application of (R)-Phenylglycinol Auxiliary in Total Synthesis
N
CH3
O
H
N
NN
O
O
CH3
H
OH
O
NH CH3
CH3
HN
CN
OH
Ph
NH2
NH2
O
HNOH
Ph
NH2
O
ind
1) Sc(OTf)3,(R)-phenylglycinolCH2Cl2, rt ind
81%81:11 dr
2) Bu3SnCN
1) H2O2, K2CO3
DMSO, MeOH ind
ind =
Pd(OH)2/C, H2MeOH, rt
ind
72%
95%
(-)-Hemiasterlin cytotoxin and mitosis inhibitor
2) separation
Asymmetric Strecker Reaction Using Chiral Cyclic Ketimine
Moon, S.-H.; Ohfune, Y. J. Am. Chem. Soc. 1994, 116, 7405-7406.
♦ Asymmetric Strecker reaction using chiral cyclic ketimine -- the idea
X
Y OH
O
R CO2H
NH2
O
NX R
Y O
HCN
R CO2H
NH2
O
HNX R
Y O
HNCX NH2
CO2H
OHY
X CO2HNH2
OHY
X = alkyl or aryl, Y = H or alkyl or aryl
*
*or use:
Asymmetric Strecker Reaction Using Chiral Cyclic Ketimine
Moon, S.-H.; Ohfune, Y. J. Am. Chem. Soc. 1994, 116, 7405-7406.
♦ Preparation of intermediate C and D
NH
O
Ph
HO
HO
HN
CNH
PhO
N S O
BocHN HCH2Ph
NC-
NH2
O
Ph
HO O N
Ph
HCO2MeH
NCNaCN
O O
H2N HCH2Ph
R
O
OMe OMe
CSA
O
HN H
PhO
NH
O
Ph
HO
H
NC-
CN
1) dl-acetoin, toluene (84%)2) TFA, CH2Cl2
A R = MeB R = H
i-propanol(96% in 2 steps)
C:D = 4:1
5
5
5
5
5
6
6
6
6
6
(5S, 6S) - CKinetically favored
(5S, 6R) - DThermodynamicaly favored
TFA, rt, 5hC:D = 1:9
,
E
Moon, S.-H.; Ohfune, Y. J. Am. Chem. Soc. 1994, 116, 7405-7406.
Asymmetric Strecker Reaction Using Chiral Cyclic Ketimine
O
HN
CNH
PhO
O
NMe
Me O
NCCH2Ph Me NH2
CO2H
OHHMe
5 6
(5S, 6S) - C
t-BuOCl, Et2Othen Et3N
exo/endo = 2.4:1
1) Con. HCl
2) Dowex 50W*4(1N NH3)
1c 84%
♦ Four enantiomers and diastereomers of α-methylthreonine and two enaniomers of α-methylserine were synthesized using the same methodology.
HO2C NH2
Me
OHRH
O O
NH2 CH2PhH
R
O
HO2C NH2
Me
OHHMe
Me NH2
CO2H
OHHR
O O
NH2 HCH2Ph
R
O
Me NH2
CO2H
OHMeH
1a R = Me2a R = H
1c R = Me8b R = H
1b 1d
A R = MeB R = H
ent - A R = Meent - B R = H
α-methylthreonineα-methylserine
♦ Removal of phenylalanyl moiety and preparation of amino acid.
Namba, K.; Shinada, T.; Teramoto, T.; Ohfune, Y. J. Am. Chem. Soc. 2000, 122, 10708-10709.
Asymmetric Strecker Reaction Using Chiral Cyclic Ketimine - Application in Total Synthesis
♦ Total synthesis of Manzacidin A and C -- idea and retrosynthesis
HN N
OR2R1
O
HNC
HOCO2H
NH2 NH2
H
CN
N
NH
Ph O
H
NH
Br
O
NHN
O
CO2HH
6
R1 = CH2Ph, R2 = H orR1 = H, R2 = CH2Ph
1a Manzacidin A 1b Manzacidin C (6S isomer of 1a)
* Isolated from marine sponges, only preliminary biological tests due to availability
Asymmetric Strecker Reaction Using Chiral Cyclic Ketimine - Application in Total Synthesis
Namba, K.; Shinada, T.; Teramoto, T.; Ohfune, Y. J. Am. Chem. Soc. 2000, 122, 10708-10709.
OH
NH2
H
HNN
OHPhH2C
O
HNC
NN
OPhH2C
O
HNC
HO2C
NH2 NH2
OHH
BocHNN
OHPhH2C
O
H
O
NH
Br
O
NHN
O
CO2HH
NN
OHPhH2C
O
H
1a Manzacidin A
6
1) Et3N, Boc-L-Phe-OSu
2) p-TsOH, 2,2-dimethoxypropane3) PdCl2, CuCl, O2 (66%)
TMSOTf, 2,6-lutidine
TMSCN, ZnCl2, 2-PrOH, rt, 18h
(81%, single isomer)
O3, MeOH
(94%)
Conc. HCl
* 1b Manzacidin C (6S isomer of 1a) was synthesized using same methodology.
Asymmetric Strecker Reaction - Halfway Overview
Chiral Amino Acid
Carbohydateauxiliary
Chiral Auxiliary Based Synthesis
Catalytic Asymmetric Sythesis
Chiral amineauxiliary
Cyclic ketimineauxiliary
Guanidinecatalysts
Chiral Schiff basecatalysts
BINOL-basedcatalysts
Catalytic Asymmetric Strecker Reaction Using Chiral Guanidine Catalyst
Iyer, M. S.; Gigstad, K. M.; Namdev, N. D.; Lipton, M. J. Am. Chem. Soc. 1996, 118, 4910-4911.
♦ Pros: The first successful example of catalytic asymmetric Strecker reaction Good for some aromatic imines Low catalyst loading ♦ Cons: Narrow substrate range
R
NCHPh2
MeOH SR CN
NHPh22 equiv HCN, 2 mol% ANH
HN
O
O
HN NH2
NH
Lipton's Cyclic Dipeptide catalyst A
Entry R Temp (oC) Yield (%) ee (%)1 C6H5 -25 97 >992 p-ClC6H4 -75 97 >993 p-OMeC6H4 -75 90 964 m-NO2C6H4 -75 71 <105 3-pyridyl -75 86 <106 i-Pr -75 81 <107 t-Bu -75 80 17
Corey, E. J.; Grogan, M. J. Org. Lett. 1999, 1, 157-160.
N
N NH
Corey's bicyclic guanidine catalyst A
Catalytic Asymmetric Strecker Reaction Using Chiral Guanidine Catalyst
♦ Pros: Improved results for some aliphatic imines ♦ Cons: Narrow substrate range ee not so great
R
NCHPh2
R CN
NHPh2
toluene(0.2M), 20h
2 equiv HCN, 0.1 equiv A
(R) - product when R = Aryl(S) - product when R = Alkyl
*
Entry R Temp (oC) Yield (%) ee (%)1 C6H5 -40 96 862 p-ClC6H4 -20 88 813 p-MeOC6H4 -40 99 844 o-CH3C6H4 -20 88 505 i-Pr -40 ~95% 846 n-Hex -40 ~95% 63
Mechanism of Strecker Reaction Catalyzed by Chiral Guanidine
♦ Catalytic cycle of Guanidine catalyzed Strecker reaction
♦ Pre-transition-state assemblies for the Strecker reactions of N-benzhydryl benzaldimine (above) and N-benzhydryl pivalaldimine (below).
Corey, E. J.; Grogan, M. J. Org. Lett. 1999, 1, 157-160.
NN
H NHHNH
CN
CN
NN
H NHH
H
N
N
NH
NPh Ph
Ar
NPh2HC
N
N NPh Ph
H
Ar
NPh2HC
H
C
N
Ar
HNCHPh2
CNH A
H C N
N
NH
NPh Ph
H
C
N
A-HCN complexPre-TS assembly
Sigman, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120, 5315-5316.
R H
N
R CN
NCF3
O1) 1.2 equiv HCN5 mol% A, 15htoluene, -70oC
2) TFAA
N N
t-Bu
t-Bu t-Bu
t-BuO O
Al
Cl
Jacobsen's chiral (salen)Al(III) complex A
Catalytic Asymmetric Strecker Reaction Using Chiral(Salen) AI(III) Complex
♦ Pros: Good results for some aromatic imines ♦ Cons: Narrow substrate range
Entry R Yield (%) ee (%)1 C6H5 91 952 p-ClC6H4 92 813 p-OMeC6H4 93 914 2-Naphthyl 93 995 cyclohexyl 77 576 t-Bu 69 37
Asymmetric Strecker Reaction Using Chiral Schiff Base Catalyst
Sigman, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120, 4901-4902.
R R'
N N
OM
R''
R R'
N N
O
M
R''
Linker 1 amino acid Linker 2
NH
HN
O
O
NH
O
NH
N
R2iPr
R2
t-But-Bu
HO
HN
NH
S
NH
N
OMet-Bu
HO
Ph
O
NH
HN
O
O
NH
O
NH
N
R2R1
R2
R4R3
HO
O
NH
S
NH
N
R2R1
R2
Xt-Bu
HO
5
12 Metal ionsLibrary Size: 12 compoundsBest result: no metal ion (19% ee)
5
4 amino acids, 2 diamines6 salicylaldehydesLibrary Size: 48 compoundsBest result: Leucine, (R, R)-diamine,3-t-butyl substituted aldehyde(55% ee)
11 amino acids, 3 diamines4 salicylaldehydesLibrary Size: 132 compoundsBest result: t-Leucine, cyclohexyldiamine, X = 5-OMe(91% ee)
Library 1 Library 2
Library 3
Jacobsen's Schiff Base catalyst A
R H
N
R CN
NCF3
O1) 2 equiv HCN 2 mol% A, 24h toluene, -70oC
2) TFAA
Sigman, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120, 4901-4902.
Asymmetric Strecker Reaction Using Chiral Schiff Base Catalyst
♦ Pros: Good results for most aromatic and aliphatic imines Low catalyst loading ♦ Cons: No mechanism proposed
Entry R Yield (%) ee (%)1 C6H5 78 912 p-BrC6H4 65 863 p-MeOC6H4 92 914 2-Naphthyl 88 885 cyclohexyl 77 836 t-Bu 70 85
HN
NH
S
NH
N
OMet-Bu
HO
Ph
O
Jacobsen's Schiff Base catalyst A
Sigman, M. S.; Vachal, P.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2000, 39, 1279-1281.
R H
NR'
R CN
NR'
CF3
O1) HCN, 2 mol% B, 20h toluene, -70oC
2) TFAA
Asymmetric Strecker Reaction Using Chiral Schiff Base Catalyst
♦ Pros: Good results for most imines Low catalyst loading ♦ Cons: No mechanism proposed
Entry R R’ Yield (%) ee (%)1 C6H5 allyl 74 952 o-BrC6H4 allyl 88 953 m-BrC6H4 allyl 87 904 p-BrC6H4 allyl 89 895 p-OCH3C6H4 allyl 98 956 o-OCH3C6H4 allyl 93 777 t-Bu allyl 75 95(91)8 t-Bu benzyl 88 96(93)9 CH3(CH2)4 benzyl 69 78
HN
NH
X
NH
N
t-Bu
R2t-Bu
HO
R1
O
A: R1 = polystyrene, X = S, R2 = OCO(tBu)B: R1 = Ph, X = O, R2 = OCO(tBu)
Asymmetric Strecker Reaction Using Chiral Schiff Base Catalyst
Sigman, M. S.; Vachal, P.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2000, 39, 1279-1281.
♦ Catalytic asymmetric Strecker reaction using polymer-supported catalyst -- Easy to remove, no loss of reactivity after recycle, but displays slightly lower enantioselectivity,
♦ Removal of protecting group and synthesis of D-tert-leucine
H
N Ph
CN
NH
O
Ph
1) HCN, 4 mol% A, 15h toluene, -78oC
2) Ac2O, formic acid
Cycle Yield (%) ee (%)
1 97 92 5 97 9210 98 93
CN
NH
O
Ph
COOH
NH
O
Ph
COOH
NH2 HCl
Recrystalized> 99% ee
65% H2SO4
45oC, 20h
1) Conc. HCl, 70oC, 12h
2) H2, Pd/C, MeOH
99% yieldD-tert-leucine, >$100/gquant. yield, >99% ee(84% yield from imine)
Vachal, P.; Jacobsen, E. N. Org. Lett. 2000, 2, 867-870.
R CH3
N Ph
R CN
NHBnH3CHCN, 2 mol% B
toluene, -75oC
Synthesis of Quaternary Amino Acids Using Chiral Schiff Base Catalyst
♦ Pros: Good results for some aromatic imines. ♦ Cons: Low ee for some substrates.
Entry R t (h) Yield (%) ee (%)1 C6H5 24 97 902 o-BrC6H4 90 45 423 m-BrC6H4 60 97 914 p-BrC6H4 80 quant 935 p-CH3OC6H4 60 98 887 t-Bu 15 98 708 C6H5CH2CH2 17 98 41
HN
NH
X
NH
N
t-Bu
R2t-Bu
HO
R1
O
A: R1 = polystyrene, X = S, R2 = OCO(tBu)B: R1 = Ph, X = O, R2 = OCO(tBu)
Krueger, C. A.; Kuntz, K. W.; Dzierba, C. D.; Wirschun, W. G.; Gleason, J. D.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 1999, 121, 4284-4285.
R N
Ph
Ph R NH
Ph
Ph
CN10 mol% Ligand A, 10 mol% Ti(OiPr)4
2 equiv TMSCN, 1.5 equiv i-PrOHtoluene, 20h, 4oC
Asymmetric Strecker Reaction Using Chiral Schiff Base Catalyst
♦ Pros: Good results for most imines. ♦ Cons: High catalyst loading
Entry R X Yield (%) ee (%)1 C6H5 X = 5-OMe 82 972 o-ClC6H4 X = 3,5-DiCl 85 933 o-BrC6H4 X = 3,5-DiCl 93 944 p-CH3OC6H4 X = 3,5-DiCl 99 945 2-naphthyl X = 5-OMe 80 937 t-Bu X = 3,5-DiBr 97 85
X
AA1
OH
N
O
HN
O
NH
O
OMe
O
AA2
Schiff base
Snapper & Hoveyda's Schiff base Ligand A
Porter, J. R.; Wirschun, W. G.; Kuntz, K. W.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2000, 122, 2657-2658.
N
Ph
PhR NH
Ph
Ph
CN
R
10 mol% Ligand A, 10 mol% Ti(OiPr)4
2 equiv TMSCN, 1.5 equiv i-PrOHtoluene, 24h
Synthesis of Unsaturated α-Amino Acids Using Chiral Schiff Base Catalyst
♦ Pros: Good results for most imines. ♦ Cons: Hydrolysis of product difficult.
NH
Ph
Ph
CN
R HCl NH
Ph
PhR
H2N O
NHBocR
HO OHOAc, MeOH 1) TFA, Et3SiH
2) HCl, MeOH3) NaOH, (Boc)2O, dioxane
♦ Conversion of aminonitriles to Boc-protected amino acids.
Entry R X Yield (%) ee (%)1 C6H5 X = 1-naphthyl 80 842 o-MeOC6H4 X = 1-naphthyl 61 783 p-NH2C6H4 X = 3,5-DiBr 93 764 Me X = 3,5-DiBr 84 855 Me-CH=CH- X = 5-OMe 95 89
Josephsohn, N. S.; Kuntz, K. W.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2001, 123, 11594-11599.
Proposed Mechanism of Chiral Schiff Base Catalyzed Strecker Reaction
♦ Proposed Mechanism of Schiff base catalyzed Strecker reaction (Above)
♦ Suggested transition-state of Strecker reaction by molecular modeling and calculation (Below)
OTi
N
OOiPr)2
XPh NP
X
X
OTi
N
OOiPr)2NPTMS
NC
Ph
NC N(H)P
Ph
I II
III
OTi
N
OOiPr)2NP
Ph
TMSCN
N
O TiO
HN
H
NH
Me
Me
O
O
O O
HNC
N
H
H
Ar
Takamura, M.; Hamashima, Y.; Usuda, H.; Kanai, M.; Shibasaki, M. Angew. Chem., Int. Ed. 2000, 39, 1650-1652. Nogami, H.; Matsunaga, S.; Kanai, M.; Shibasaki, M. Tetrahedron Lett. 2001, 42, 279-283.
R H
N
R CN
HN
9 mol% A, 2 equiv TMSCN
0.2 equiv PhOH, CH2Cl2, -40oC
P
P
OPhPh
Ph
OPh
O
OAlCl
Shibasaki's bifunctional catalyst A
Asymmetric Strecker Reaction Using Bifunctional Catalyst
♦ Pros: Good results for most imines. ♦ Cons: Polymer-supported bifunctional catalyst works not well.
Entry R Yield (%) ee (%)1 C6H5 92 952 p-ClC6H4 92 953 trans-CH3(CH2)3CH=CH2 66 864 n-Hexyl 80 805 t-Bu 97 78
Takamura, M.; Hamashima, Y.; Usuda, H.; Kanai, M.; Shibasaki, M. Angew. Chem., Int. Ed. 2000, 39, 1650-1652. Nogami, H.; Matsunaga, S.; Kanai, M.; Shibasaki, M. Tetrahedron Lett. 2001, 42, 279-283.
Asymmetric Strecker Reaction Using Bifunctional Catalyst
♦ Conversion of aminonitriles to amino acid derivatives.
♦ Strecker reaction using polymer-supported bifunctional catalyst
P
P
OPhPh
Ph
OPh
O
OAlCl
O
Shibasaki's bifunctional catalyst A
3
= JandaJEL
Ph H
NFlu
Ph CN
HNFlu
10 mol% A 4 equiv TMSCN
1.1 equiv tBuOH CH2Cl2, -50oC
Cycle Time(h) Yield (%) ee (%)
1 60 98 87 3 44 78 83 5 204 83 77
Ph CN
HNFlu
Ph CONH2
HNFlu
Ph CONH2
NH2HCl(g), HCO2H
rt, 1h, (100%)
1) DDQ/THF, 3oC, 1h2) 1N HCl, 3oC, 5min
3) Amberlyst A-21/MeOH (91% in 3 steps) 98% ee
93% ee100% ee
95% ee recryst.(90%)
Proposed Mechanism of Strecker Reaction Catalyzed by Bifunctional Catalyst
Takamura, M.; Hamashima, Y.; Usuda, H.; Kanai, M.; Shibasaki, M. Angew. Chem., Int. Ed. 2000, 39, 1650-1652.
P
P
OPhPh
O
OAl
Cl
O
PhPh
(CH3)3Si
N
R
PNC H
N
R
PNC H
TMS
N
R
PNC H
H
II
B
C
I
RN
H P
TMSCN
P
P
OPhPh
O
OAlCl
O
PhPh(CH3)3Si
CN
NH
R
P
catalyst A
PhOHand/or HCN
+ PhOTMSand/or TMSCN
+
Ishitani, H.; Komiyama, S.; Kobayashi, S. Angew. Chem., Int. Ed. 1998, 37, 3186-3188.
Asymmetric Strecker Reaction Using Chiral Zirconium Catalyst
N
HO
R H
+ Bu3SnCN HN
HO
R CN
10 mol% A
toluene/benzene-65oC to 0oC, 12h
♦ Pros: Catalysts commercially available, good for most aromatic imines. ♦ Cons: Not so good for aliphatic imines.
Entry R Yield (%) ee (%)1 C6H5 92 912 p-ClC6H4 90 883 o-MeOC6H4 96 894 p-MeOC6H4 97 765 C6H5(CH2)2 55 836 iBu 79 837 C8H17 72 84
Br
Br
O
O
Zr
Br
Br
O
O
Zr
Br
O
O
Br
OtBu
L
L
OtBu
L = NMI Kobayashi's Chiral Zirconium Catalyst A
Ishitani, H.; Komiyama, S.; Hasegawa, Y.; Kobayashi, S. J. Am. Chem. Soc. 2000, 122, 762-766.
Catalytic Three-Component Strecker Reaction Using Chiral Zirconium Catalyst
♦ Pros: First catalytic three-component Strecker reaction; Good results for most imines; Low catalyst loading Catalysts commercially available. ♦ Cons: Still need protecting group; No mechanism discussion.
H2N
HO
X
HN
HO
R CNX
+ + HCN1-5 mol% A
CH2Cl2, -45oC, 12hRCHO
Entry R X Yield (%) ee (%)1 C6H5 H 80 862 C6H5(CH2)2 CH3 85 943 C8H17 CH3 83 904 cyclohexyl CH3 95 945 iBu CH3 94 916 tBu CH3 quant 88
Catalytic Three-Component Strecker Reaction Using Chiral Zirconium Catalyst
Ishitani, H.; Komiyama, S.; Hasegawa, Y.; Kobayashi, S. J. Am. Chem. Soc. 2000, 122, 762-766.
HN
HO
CN
HN
MeO
CONH2
CAN NH2
CONH2
1) MeI/K2CO3
2) H2O2/OH-
94% in 2 steps63%
leucinamide
♦ Conversion of aminonitriles to amino acid derivatives.
♦ Synthesis of D-pipecolic acid methyl ester.
TBSO CHO
H2N
HO
HOCN
HN
H3CO
CO2CH3
N
H3CO
TBSOCN
HN
HO
CO2CH3
NH
4+ HCN
2.5 mol% A
CH2Cl2, -45oC, 12h(80%, 91% ee)
+1) CH3I, K2CO3 acetone, rt
2) TBAF/THF (66%)
4
1) CBr4, PPh3/CH2Cl2
2) sat. HCl(g)/CH3OH, reflux (45%)
CAN, TFAA
4CH3OH-H2O, 0oC (88%)
D-pipecolic acidmethyl ester
Attempted Application of Catalytic Asymmetric Strecker Reaction
Vedejs, E.; Kongkittingam, C. J. Org. Chem. 2001, 66, 7355-7364.
N
H
CH3
N
HO
+ Bu3SnCN
N
NN
O
O
CH3
H
OH
O
H
CH3
H CH3
XCAN
N
H
CH3
HN
HO
CN
N
H
CH3
HN
H3CO
CONH2
(-)-Hemiasterlin
10 mol% A
toluene/benzene-65oC to 0oC, 12h( > 80%, 77:23 er)
1) MeI/K2CO3
2) H2O2/NaOH, Bu4NHSO4 (> 49%)
Asymmetric Strecker Reaction - Future Work
♦ Further development of chiral auxiliary methods, more applications in total synthesis.
♦ Development of more practical asymmetric catalytic systems toward commercial process. - higher yield & ee; higher turnover; easier separation… ...
♦ Better understanding of mechanism of catalytic asymmetric process.
♦ Successful application of catalytic asymmetric process in synthesis of large molecules.
Asymmetric Strecker Reaction - Conclusions
♦ 150 years after discovery of Strecker reaction, asymmetric Strecker reaction has been a real highlight in synthesis of α-amino acids.
♦ Catalytic asymmetric Strecker reaction achieved great advance in last 5 years. Although an efficient method for preparation of simple amino acids, its application in synthesis of large molecules and commercial production still needs further development.
♦ After 20 years’ development, Strecker reaction using chiral auxiliaries has been proved an efficient method for the preparation of simple amino acids and total synthesis of large molecules.