Additions: Conjugate Introduction
Nuc EWG
EWG
Nuc
Chiral Acceptor
R' EWG
Chiral Donnor
OM * R' Inherent Chirality R
Chiral Additives/Ligands
R Cu- +M
* R
*
Inherent Chirality O *
Chiral Reagent *
Chiral Auxiliary
R'M + Chiral Catalysts
Chiral Auxiliary
Review: Merino Eur. J. Org. Chem. 1998, 2051. Leonard Comtemporary Org. Synthesis, 1994, 387. Rossiter Chem. Rev. 1992, 771.
1
Conjugate Additions: Soft Nucleophiles
Organocopper Reagent
Copper-Catalyzed Grignard Reagents RMgX + 25 mol% CuX
Heteronucleophile
Nitrogen R2NH
Review: Erdik, Tetrahedron 1984, 40, 641. Et2O/THF
Monoalkylcopper reagents
RLi
+
CuX
RCu
N3 Sulfur RSH Alcohol ROH (oxymercuration) PhOH
-LiX RCu: -Unreactive, explosive, polymer and insoluble RCuLA : -More reactive, displays unique reactivity and selectivity patterns Review:NakamuraTetrahedron 1989, 45, 349. Also: JACS 2000, 1826. Homocuprate reagents (Gilman-Cuprates) RLi + CuX Et2O/THF -LiX CuX = CuI, CuBr, CuBrSMe2 -reactive againts a wide variety of electrophiles: the most widely used. -Stable <0C (generally -78C), low basicity -Higher order homocuprates: R3Cu2Li, R3CuLi2, R5Cu3Li RTM + CuR Et2O/THF RTCu(R)M RCu RLi R2CuLi
Carbon Nucleophile
Cyanide CN Enolate (Michael)
Mixed Homocuprate reagents -RT = transferable ligand -R = Dummy ligand: C
EWG
EWG
CR, CH2S(O)Me, 2-Thienyl, CH2S(O)2Me, Mesityl
X
EWG
2
Review on dummy ligands: Hamon and Levisalles, Tetrahedron 1989, 45, 489.
Conjugate Additions: Heterocuprates
RTM + CuZ Et2O/THF RTCu(Z)M RM + RTM + CuZ RT(R)Cu(Z)M2
-RT = transferable ligand -CuZ (usually commercially available) = CuCN, CuSPh, CuOt-Bu, CuPPh2, CuN(C6H11)2, CuP(t-Bu)2
-RT = transferable ligand -CuZ (usually commercially available) = CuCN, CuSPh, CuOt-Bu, CuPPh2, CuN(C6H11)2, CuP(t-Bu)2 -R = Dummy ligand 2-Thienyl N-Pyrrolyl N-Imidazolyl Combined Stability of Heterocuprates with the reactivity of Homocuprates.
From Functionnalized Organocopper Reagents (Knochel Reagents) Knochel, P.; Singer, R. D. Chem. Rev. 1993, 93, 2117; Lipshutz, B. H. Acc. Chem. Res. 1997, 30, 277. Zn CuCN2LiCl FG-RCu(CN)ZnI
FG-RI
FG-RZnI
3
Conjugate Additions: Relative Stereocontrol
Cyclic Systems
Facial Selectivity dictated by steric effects Classic Case: Prostanglandin's Synthesis C5H11 OMEM Cp2Zr(H)Cl C5H11 OMEM 1. MeLi 2. Li[ZnMe3] Ph O 1. TBSO cat Me2Cu(CN)Li2 R' 2.OHC(CH2)5CO2Me O OH (CH2)5CO2Me TBSO C5H11 OMEM
4
Acyclic Systems
Tomioka TL 1985, 3031. R1 CO2R2 1. Ph(MeS)2CLi 2. MeI R1 CO2R2 SMe Me
Zr(Cl)Cp2
Lipshutz JACS 1994, 11689. C5H11
ZnMe2Li OMEM
MeS
* R
EWG
Felkin-Anh Rule Review: Mengel, A.; Reiser, O. Chem. Rev. 1999, 1191.
Anti Addition
Importance of the Reagents and Reaction Conditions
Sato J. Am. Chem. Soc. 1999, 3640; Angew. Chem., Int. Edit. 1998, 2099. O O + R1 Enone Yield 77% 91% 73% 84% 78% 87% 25% 45% R1 cis:trans >99:1 >99:1 9:1 50:1 3:1 50:1 4:1 1:3 [Ph2Cu(CN)Li2] [(CH2=CH)2Cu(CN)Li2] 80% 75% 1:32 1:19 [s-Bu2Cu(CN)Li2] [t-Bu2Cu(CN)Li2] --92% <1:50 <1:50 cis R2 R1 trans Yield 83% 92% R2 cis:trans 1:32 1:50 O
Cyanocupratea [MeCu(CN)Li] [n-BuCu(CN)Li] [n-BuCu(CN)MgBr] [s-BuCu(CN)Li] [t-BuCu(CN)Li]
Cyanocuprateb [Me2Cu(CN)Li2] [n-Bu2Cu(CN)Li2]
O
TBSO
2
Cu(CN)Li
[PhCu(CN)Li] [CH2=CHCu(CN)Li] O [n-BuCu(CN)Li] Me O [n-BuCu(CN)Li] BnO
95%
<1:99
80%
>50:1
[n-Bu2Cu(CN)Li2]
87%
1:9
5
Effect of the Reagent Structure
O TBSO OCu R R CN 2Li+ TBS R2Cu(CN)Li2 TBSO RCu(CN)Li O R Cu CN OLi
B O H R OTBS O O
B H
TBSO
R
TBSO
R R
OTBS
O
O DBU / DCM rt, 98% R
O DBU / DFM R 100C, 74%
6
Conjugate Additions to Chiral Electrophiles
Yamamoto Chem. Commun. 1987, 1572. JACS 1988, 617. Nu Ph Me CO2Et Nuc Ph Me Felkin-product (anti) CO2Et + Ph Me anti-Felkin-product (syn) Ratio anti:syn 7:1 2.3:1 4:1 7:1 1:2.3 1:2 1:3.8 Nu CO2Et
Entry 1 2 3 4 5 6 7
E/Z-alkene E E E E Z Z Z
Nucleophile BuCuBF3 Bu2CuLiBF3 Bu2Cu(CN)Li2BF3 Me3CuLi2BF3 Bu2CuLiBF3 Bu2Cu(CN)Li2BF3 Me3CuLi2BF3
Yield 82% 90% 29% 46% 89% 26% 67%
Felkin with E-alkene and anti-Felkin with Z-alkenes
7
Proposed Transition Structures
E-Alkene
Nuc CO2Et H H Ph Felkin Felkin-product (anti)
Z-Alkene
Nuc H EtO2C Me H H
H Me
Ph Felkin
H anti-Felkin-product (syn) EtO2C H Ph Me H Nuc
1,3-Allylic Strain
8
Conjugate Additions to Chiral Electrophiles
Yamamoto Chem. Commun. 1987, 1572. Nu Ph Me CO2Et CO2Et Nuc Ph Me CO2Et CO2Et + Ph Me Nu CO2Et CO2Et
Felkin-product (anti)
anti-Felkin-product (syn) Ratio anti:syn 1:2.1 2.8:1 1:1.6 1:18 3.8:1 1.5:1 1.6:1 24:1
Entry 1 2 3 4 5 6 7 8
Nucleophile Bu2CuLiBF3 BuCuBF3 Me3CuLi2BF3 Bu2CuLi MeCuBF3 MeMgBr Me4AlLi AllylSnBu3
Yield 67% 90% 90% 87% 95% 89% 88% 93%
Trisubstituted alkenes show the same tendency than Z-alkenes
9
Important Factors to Consider
Important Factors: -Cuprate's electron-donating ability (oxidation potential) : Me2CuLi >> Me2Cu(CN)Li2 > MeCu > MeCu(CN)Li -Michael acceptor's electron-accepting ability (reduction potential): Ph Me Me -1.33 V NO2 > Me CN -1.43 V Ph CN > Me CN -1.68 V Ph CO2Et > Me CO2Et <-2.0V Ph CO2Et
Michael acceptor with low reduction potentials + RCu or RCuCNLi (lower electron-donating ability): Normal Felkin-Ahn TS : anti-product is the major isomer Nuc H Me CO2Et H H Ph Felkin Michael acceptor with high reduction potentials + R2CuL or R2CuCNLi2 (higher electron-donating ability): -complex TS : syn-product is the major isomer Ph EWG Me EWG H R CuLn anti-Felkin-product (syn) Felkin-product (anti)
"acute" angle of attack (suggested by ab initio calculations)
10
Conjugate Addition to Chiral Electrophiles
Yamamoto J. Am. Chem. Soc. 1992, 7652. Nu Me OR CO2Et Nuc Me OR CO2Et Felkin-product (anti) Ratio anti:syn 1:1.4 1:1.5 2.6:1 15:1 2.6:1 19:1 2.2:1 19:1 12:1 2:1 2.7:1 12:1 + Me OR Nu CO2Et anti-Felkin-product (syn)
Entry 1 2 3 4 5 6 7 8 9 10 11 12
OR OBn OBn OBn OBn OBn OBn OBn OBn OBn OTBS OTBS OTBS
Nucleophile (Methallyl)2CuLi MethallylCu (Vinyl)2CuLi (Vinyl)2CuLiBF3 (Vinyl)2Cu(CN)Li2 (Vinyl)2Cu(CN)Li2BF3 MeCuBF3 MeCu(CN)LiBF3 BuCuBF3 MeCuBF3 Me2CuLiBF3 Me2Cu(CN)Li2BF3
Yield 87% 99% 99% 58% 83% 66% 60% 62% 64% 6% 26% 55%
Nature of the cuprate reagent is important (entry 1 and 3) Nature of OR does not interfere (entry 9 and 12): no chelation vs non-chelation control
11
Conjugate Addition to Chiral Electrophiles
Nu Me OR CO2Et Nuc Me OR CO2Et Felkin-product (anti) OR OBn OBn OBn OBn OBn OBn OBn OBn OBn OTBS OTBS OTBS OTBS Nucleophile (Methallyl)2CuLi MethallylCu (Vinyl)2CuLi (Vinyl)2CuLiBF3 (Vinyl)2Cu(CN)Li2 (Vinyl)2Cu(CN)Li2BF3 MeCuBF3 MeCu(CN)LiBF3 BuCuBF3 MeCuBF3 Me2CuLiBF3 MeCu(CN)LiBF3 Me2Cu(CN)Li2BF3 Ratio anti:syn 1:4 1:4.5 >99:1 1.1:1 24:1 1:3.4 1:3.5 1:2.8 1:3.5 1:6 1:7 1:5 1:5 + Me OR CO2Et anti-Felkin-product (syn) Yield 99% 45% 82% 63% 58% 64% 30% 45% 56% 2% 12% 17% 36% Nu
Entry 1 2 3 4 5 6 7 8 9 10 11 12 13
Z-Alkenes are syn-selective, excepted for the addition of vinylcuprate The influence of of BF3 is very important but not well understood. Low yields are observec with -silyloxy ,-unsaturated esters.
12
Conjugate Addititon to Chiral Electrophiles
Nu Me OBn CO2Et CO2Et Nuc Me CO2Et + Me Nu CO2Et
OBn CO2Et Felkin-product (anti) Ratio anti:syn 1:13 1:32 1:9 1:12 1:5 1:24 1:13 1:3
OBn CO2Et anti-Felkin-product (syn) Ratio anti:syn 1:2.2 1:3.5 1:1.6 1:1.6 1:2.3 1:1.9 1:2.4 1:2.2
Entry 1 2 3 4 5 6 7 8
Nucleophile MethallylCu MethallylCuBF3 (Methallyl)2CuLi (Methallyl)2CuLiBF3 (Methallyl)Cu(CN)Li (Methallyl)Cu(CN)LiBF3 (Methallyl)2Cu(CN)Li2 (Methallyl)2Cu(CN)Li2BF3
Yield 99% 86% 79% 99% 88% 95% 99% 87%
Entry 9 10 11 12 13 14 15 16
Nucleophile (Vinyl)Cu (Vinyl)CuBF3 (Vinyl)2CuLi (Vinyl)2CuLiBF3 (Vinyl)Cu(CN)Li (Vinyl)Cu(CN)LiBF3 (Vinyl)2Cu(CN)Li2 (Vinyl)2Cu(CN)Li2BF3
Yield 45% 72% 91% 91% 88% 83% 94% 96%
The syn isomer is major with trisubstituted alkenes using vinyl and methallyl cuprates. The best results were observed with low order cuprates and BF3
13
Conjugate Addition to Chiral Electrophiles
Nu Me OR CO2Et CO2Et Nuc Me CO2Et + Me Nu CO2Et
OR CO2Et Felkin-product (anti) OR OBn OBn OBn OBn OBn OBn OBn OTBS OTBS OTBS OTBS OTBS Nucleophile MeCu MeCuBF3 Me2CuLi BuCu BuCuBF3 Bu2CuLi Bu2CuLiBF3 MeCu MeCuBF3 Me2CuLi MeCu(CN)Li MeCu(CN)LiBF3 Ratio anti:syn 1:8 1:16 1:1.7 1:2.3 1:19 1:2.1 1:4.3 1:6 1:5 1:1.6 1:12 1:10
OR CO2Et anti-Felkin-product (syn) Yield 58% 54% 75% 75% 52% 63% 51% 92% 98% 89% 92% 94%
Entry 1 2 3 4 5 6 7 8 9 10 11 12
Good Selectivities with low order cuprates More reactive substrates: good yield with -silyloxy ,-unsaturated esters. Nature of OR does not interfere (entry 2 and 9): no chelation vs non-chelation control
14
Conjugate Addition to Chiral Electrophiles
Nu R OR Y X Nuc (Nu) R X + R
Nu X
OR Y Felkin-product (anti)
OR Y anti-Felkin-product (syn)
Reagent Substrate E-Alkene Z-Alkene Trisubstituted (vinyl)CuLn anti anti (syn)* syn (alkyl)CuLn anti syn syn (methallyl)CuLn syn syn syn
*syn-selectivity was observed in a certain case.
-Cuprate's electron-donating ability (oxidation potential): Methallyl >> n-butyl > vinyl
15
Proposed Transition Structures
Disubstituted Alkenes + RCu or RCuCNLi (lower electron-donating ability): Felkin-Anh TS : ratio is dependant of the geometry of the alkenes E-Alkenes Nuc H RO CO2Et H H R Felkin Felkin-product (anti) EtO2C H H R OR H Nuc anti-Felkin-product (syn) Z-Alkenes
1,3-Allylic Strain
Disubstituted alkenes + methallyl cuprates and trisubstituted alkenes -complex TS : syn-product is the major isomer R EWG RO EWG H R CuLn anti-Felkin-product (syn)
"acute" angle of attack (suggested by ab initio calculations)
OR is the "medium size" group : steric effects are more important than stereoelectronic effects.
16
Conjugate Addition of Lithium Amides
Yamamoto J. Org. Chem. 1997, 6274. NR1R2 Me OR CO2t-Bu R1R2NLi Me CO2t-Bu + Me NR1R2 CO2t-Bu
OR Felkin-product (anti) Entry 1 2 3 4 5 6 OR OTBS OTBDPS OTIPS OCPh3 OTIPS OMe Lithium Amides LiNBnTMS LiNBnTMS LiNBnTMS LiNBnTMS LiNBn2 LiNBn2
OR anti-Felkin-product (syn) Ratio anti:syn 1:1.2 1:8 1:9 <1:99 2.3:1 1:1.7 Yield 91% 99% 95% 79% 77% 83%
Nuc H R CO2Et H H OR Felkin syn-isomer Chelation control interfer when LiNBn2 is used
17
Directed Cuprate Delivery
Breit, B. Angew. Chem., Int. Edit. 1998, 525; Tetrahedron 2000, 2833. R22Cu EWG PPh2 O R1 Me E-enoate (R1) i-Pr i-Pr i-Pr EtO2C Me2CuLi Me TrOH2C Me2CuLi Me PivOH2C Me2CuLi O O N i-Pr Me O Me 60% 5.7:1 71% 6:1 68% 19:1 O O OEt 1. R22CuLi 2. H+ 61-93%yield Cuprate Me2CuLi n-Bu2CuLi (CH2CH)2CuLi R1 Me Yield 93% 68% 61% R2 O O O OEt anti ratio (anti:syn) 19:1 19:1 4:1 PPh2 H O R D
Me2CuLi
75%
19:1
18
Chiral Auxiliaries for Conjugate Addition Reactions
O O 75-96% de 75-96% yield Oppolzer Helv. Chim. Acta 1980, 63, 2015. OppolzerTL 1983, 4971. R1 RCu Li O O O R1, R2 = Alkyl, aryl 72-88% de 66-91% yield Suemune TL 1990, 4751 Tet. Asym. 1991, 389
R Dumas and d'Angelo JOC 1994, 500; JOC 1996, 2293. O
O PhCHNH2 / MeOH 20C, 14-15 kbar
R O
O 55-84% y.
BnHN
H Naph.
Ph O 60% de
Naph. O 98% de Ph O Naph. O 93% de O 18% de O 18% de
O 20% de
MeO
Ph Ph O 16% de O 10% de
19
O >99% de
O 97% de
Chiral Auxiliaries for Conjugate Addition Reactions
Hruby JOC 1993, 7565. O O N R1 O R2 R3MgBr CuBr/Me2S O O N R1 O R3 R2 85-96% y.
R1 = Bn, 10% de R1 = Ph, 98% de with aryl grignard 48-86% de with alkyl grignard
Williams Tet. Lett. 1998, 8593 O O N R1 R2MgBr EtMgBr i-PrMgBr PhMgBr MgBr BrMg O R2MgBr CuBr/Me2S BF3OEt2 O O N S R1 R1 = Bn Yield 78% 99% 66% 74% 90% de 53% (R) 62% (R) 54% (R) 97% (S) 15% Yield 89% 99% 65% 85% 95% R1 = Ph de 67% (S) 81% (S) 98% (S) 97% (S) 97% (S) O R2 S major if R1 = Ph R major if R1 = Bn
TBDPSO --MgBr --95% 99% (S)
20
Chiral Auxiliaries (Nucleophiles)
O R * Nuc Nuc O R
OLi Ph O Me +
MeO2C XcO Me Me
O CO2Me 86% de
Proposed TS: -E-Enolate -s-trans-E-enone O
H
Me H O OXc
Corey, Tet. Lett. 1985, 26, 5025.
Li
Enders Tet. Lett. 1983, 24, 6015. Tet. Lett. 1986, 27, 3491. Chem. Ber. 1987, 120, 1223. Chem. Ber. 1993, 126, 1929. MeO LiN R1 R2 N CH2OMe R3 CO2Me R2 R3 O R1 Li N H R1 H R2 NXc XcN N R3 CO2Me 98% de
21
Chiral Auxiliaries (Nucleophiles)
d'Angelo TL 1994, 9705. JOC 1996, 61, 4361. Tet. Asym. 1995, 79 Me O CO2Me H Ph N CO2Me 1. EWG O CO2Me EWG 2. H3O+ Me O CO2Me H Ph N CO2Me 1. Me 2. H3O+ CO2Me O CO2Me CO2Me Me >95% de and ee 90-98% ee Me H Ph E R HN CO2Me H H
Christoffers. Angew. Chem., Int. Edit. 2000, 2752. Eur. J. Org. Chem. 2000, 701. Chem. Eur. J. 2001, 1014. O i-Pr CO2Me H2N O NEt2 NEt2 NH CO2Me O Me Cu(OAc)2 H2O (2.5 mol%) O
O
i-Pr
CO2Me
COMe
86% y. 98% ee
22
Catalytic Asymmetric Conjugate Addition Reactions
R-M
transmetalation step
Ln*CuXn
OMX
Ln*CuXn-1R + MX
O
R
addition + catalyst regeneration
MX O complexation CuLn*Xn-1 R
Dynamic ligand-exchange processes : formation of a highly reactive and selective catalyst by self-assembly
23
Nickel-Catalyzed Grignard Addition
Hoveyda J. Am. Chem. Soc. 1998, 7649. Ph2 P NiCl2 P Ph2
Me
Me
MeO
OMe RMgX (3 equiv) (S,S)-(chiraphos)NiCl2 (5 mol%) PPh3 (10 mol%)
O
(S,S)-(chiraphos)NiCl2
R
Grignard Reagent EtMgBr n-BuMgBr i-BuMgBr PhMgBr PhCH2CH2MgBr
Yield 90% 85% 63% 67% 81%
ee 85% 85% 70% 83% 84%
Without the phosphine, less than 10% ee was observed 15-53% ee were obtained with cyclopentenylacetal.
24
Phosphoramidite Ligands for Conjugate Addition
Feringa Angew. Chem. Int. Ed. Engl. 1996, 35, 2374-2376.
O O
i-Pr P N i-Pr 6.5 mol%
O
Cu(OTf)2, 3 mol% / Tolune, -15 C + Et2Zn (1.5 equiv)
O
78% y.; 63% ee O O
+
Et2Zn (1.5 equiv)
76% y.; 81% ee O Ph Ph + Et2Zn (1.5 equiv) Et -50 C Ph * O Ph
25
88% y.; 90% ee
Catalytic Asymmetric Conjugate Addition
Feringa Angew. Chem., Int. Edit. 1997, 2620.
O O
P
N
Me Me
4 mol% O Cu(OTf)2, 2 mol% / Heptane, -30C O
+
R2Zn (1.1 equiv) R
Me2Zn 68% y. >98% ee Ph Hep2Zn 95% y. 95% ee AcO i-Pr2Zn 95% y. 94% ee 2 77% y. 95% ee 2 Zn 53% y. 95% ee
EtO 2 OEt 91% y. 97% ee Zn
Zn
PivO 87% y. 93% ee
2
Zn
26
Catalytic Asymmetric Conjugate Addition
Feringa Angew. Chem., Int. Edit. 1997, 2620.
O O
P
N
Me Me
4 mol% Cu(OTf)2, 2 mol% / Heptane, -30C
O O
O
O
O
R R 10% ee R1 R1 R1 = H, Me, Ph >98% ee
R 84-88% ee >98% ee
R 97% ee
R
27
Catalytic Asymmetric Conjugate Addition
Feringa et al. Org. Let. 1999, 1, 623.
O O
P
N
Me Me
4 mol% O Cu(OTf)2, 2 mol% / Heptane, -30C + R2 R1 Et2Zn (1.2 equiv) Et R2 R1 O
O
O
O
O
O
MeO
Me OMe
MeO
Et OMe
Me
Et OMe
Bn
Et OMe
Et O 99 : 1 (cis:trans) 65% ee (cis)
28
99% ee
97% ee
9 : 1(cis:trans) 97% ee (cis)
32 : 1 (cis:trans) 93% ee (cis)
Catalytic Asymmetric Conjugate Addition: Kinetic Resolution
O O
P
N
Me Me
0.10 mol% O Cu(OTf)2, 0.05 mol% Toluene, -30C Me 33% y. >99% ee O O
+ Me
Et2Zn (0.55 equiv)
+ Me Et >95% trans:cis
Using n-Bu2Zn: O O O
Me 54% conv. >99% ee s >200
i-Pr 53% conv. 99% ee s >200
TMS 52% conv. >99% ee s >200
29
Catalytic Asymmetric Conjugate Addition
R O O P N Me Me
NO2
Et2Zn (1.2 equiv) Cu(OTf)2 (0.5-2 mol%) Toluene, -30 C R
Et NO2
Et 1-4 mol% NO2 Ph 90% conv. 48% ee
Et NO2 Cyc 100% y. 94% ee Et Et NO2 NO2 O O 79%y. 10 : 1 dr, 92% ee
(MeO)2CH
100% conv. 86% ee
30
Catalytic Asymmetric Conjugate Addition
Hoveyda J. Am. Chem. Soc. 2001, 123, 755-756. N O PPh2 H N O Bn 2.4 mol% O NHBu O
Cu(OTf)2, 1 mol% / Toluene, -30C R2Zn (3.0 equiv) Substrate Dialkylzinc (3.0 equiv.) Et2Zn O Bu2Zn i-Pr2Zn Zn
2
R Yield 78% 92% 90% 56% ee 97% 98% 79% >98%
OAc O Et2Zn Bu2Zn Zn
2
72% 64% 55%
>98% >98% >98%
O
OAc
Et2Zn
56%
97%
31
Catalytic Asymmetric Conjugate Addition
Hoveyda J. Am. Chem. Soc. 2001, 123, 755-756. H N O Bn 2.4 mol% O NHBu O
N O PPh2
Cu(OTf)2, 1 mol% / Toluene, -30C n Substrate O R2Zn (3.0 equiv) Dialkylzinc (3.0 equiv.) Me2Zn Et2Zn Bu2Zn i-Pr2Zn Zn
2
n Yield 71% 98% 93% 98% 76%
R ee >98% 98% 95% 72% 95%
OAc O Me2Zn Et2Zn Bu2Zn i-Pr2Zn 80% 98% 81% 78% >98% 98% 95% 62%
32
Catalytic Asymmetric Conjugate Addition
PPh2 PPh2 Rh O O O (acac)Rh(C2H4)2 Ph2P PPh2 and 31P NMR Elemental analysis
1H
Rh O
O + PhB(OH)2 1.4 equiv 2.5 equiv 5.0 equiv (acac)Rh(C2H4)2 / (S)-binap 3 mol% Dioxane/H2O (10/1), 100 C, 16 h 64% y. 97% ee 93% y. 97% ee >99% y. 97%ee
O
Ph
Hayashi and Miyaura, JACS, 1998, 120, 5579-5580.
33
Catalytic Asymmetric Conjugate Addition
OB(OH)2 R-B(OH)2 R
O Ph2P
PPh2
Ph2P
PPh2
Rh Ln R R
Rh Ln O
O Ph2P P R Rh P O R PPh2
Rh Ln
34
Catalytic Asymmetric Conjugate Addition
O + RB(OH)2 (acac)Rh(C2H4)2 / (S)-binap 3 mol% Dioxane/H2O, 100C, 16h R >99% y. 97% ee 70%y. 99% ee 97% y. 96% ee 94% y. 96% ee 88% y. 94% ee 76% y. 91% ee O
4-MePhB(OH)2 (5.0 equiv) 4-CF3PhB(OH)2 (2.5 equiv) 3-MeOPhB(OH)2 (5.0 equiv) 3-ClPhB(OH)2 (5.0 equiv) B(OH)2 (2.5 equiv) B(OH)2 (5.0 equiv)
t-Bu
O
O
O
O
PhB(OH)2 (1.4 equiv) 93% y. 97% ee
i-Pr PhB(OH)2 (5.0 equiv) 82% y. 97% ee
PhB(OH)2 (1.4 equiv) 51% y. 93% ee
n-pentyl PhB(OH)2 (2.5 equiv) 88% y. 92% ee
35
Catalytic Asymmetric Conjugate Addition
O Oi-Pr + LiArB(OMe)3 (2.5 equiv) (acac)Rh(C2H4)2 / (S)-binap 3 mol% Dioxane/H2O, 100 C, 3 h 4-ClC6H4 4-MeC6H4 4-CF3C6H4 3-MeOC6H4 2-naphtyl Ar O Oi-Pr 95% y. 97% ee 88% y. 97% ee 98% y. 96% ee 83% y. 94% ee 96% y. 93% ee
O O + ArB(OH)2 (5.0 equiv) (acac)Rh(C2H4)2 / (S)-binap 3 mol% Dioxane/H2O, 100 C, 3 h O
O
Ar
Ph 4-ClC6H4 4-MeC6H4 4-CF3C6H4 3-MeOC6H4 2-naphtyl
94% y. 98% ee 95% y. 97% ee 91% y. 97% ee 75% y. 97% ee 91% y. 98% ee 93% y. 98% ee
Ar NO2 + ArB(OH)2 (5.0 equiv) NO2 (acac)Rh(C2H4)2 / (S)-binap 3 mol% Dioxane/H2O, 100 C, 3 h 71-90% y. 98-99%ee 3:1 8:1 cis:trans NaHCO3 EtOH,
Ar NO2
9:1 49:1 trans:cis
36
Catalytic Asymmetric Conjugate Addition
O + cat. 10 mol% RO2C CO2R DME, rt, 72 h CO2R CO2R O O La O HO BnO2C Me 84% yield CO2Bn 98% ee O 94% yield >99% ee (R = Me) O
air-stable
96% yield >99% ee (85 h) R = Me
O
O 97% yield >99% ee (85 h) R = Me 82% yield 99% ee (96 h) R = Me
O ee's are lower with acyclic ketones
37
Catalytic Asymmetric Conjugate Addition
Corey, Tetrahedron Lett. 1998, 5347. Br H N O O R1 + Ph N Ph O Ot-Bu (10 mol%) N CsOHH2O, CH2Cl2, -78C CO2t-Bu COR1 N H Ph Ph
Acceptor EtCO MeO2C NC (Base : KOH) O
yield 85% 85%
ee 91% 95%
85%
91%
88%
99%
38
Catalytic Asymmetric Conjugate Addition
Br H N O + MeO (2 equiv) KOH (50 mol%) Toluene, -10C MeO 72% y. 80% ee O (10 mol%) N H OH
O
O
OBn N N O + Cl CH3NO2 (10 equiv) H (10 mol%)
Br
O
NO2
CsF (10 equiv) Toluene, -40C
Cl 89% y. 70% ee 95% ee after recristallization39
Catalytic Asymmetric Conjugate Addition
Br H N N H OH Ar1 O Ar2 (1.1 equiv.) Ar3 OTMS KOH (50 mol%) Toluene, -20C O Ar1 Ar2 79%-94% y. 91-95% ee 2-Me-C6H4 O 4-MeO-C6H4 92% y. 94% ee 4-F-C6H4 O Ph O Ar3 O
(10 mol%) Ph O 4-F-C6H4 85% y., 95% ee Ph O 4-F-C6H4 O Ph
79% y., 92% ee
Me O Ar1 Ar2 (1.1 equiv.) Ph OTMS Ar1 KOH (50 mol%) Toluene, -20C O Ar2
3 : 1 to 20 : 1 (anti:syn) O Ph Me 65-86% y. 92-99% ee + Ar1 O Ar2 O Ph
Me 9-22% y. 81-95% ee
40
Catalytic Asymmetric Conjugate Addition: Azide
Jacobsen J. Am. Chem. Soc. 1999, 8959. H N Al t-Bu O N H R O Ph O Me O (5 mol%) t-Bu t-Bu HN3 (6.6 equiv) Toluene,CH2Cl2, -40C R N3 t-Bu O N H O Ph N H
R Me Et n-Pr i-Pr t-Bu CH2Ph CH2OBn Ph
yield 96% 97% 97% 98% 99% 97% 93% 60%
ee 96% 97% 95% 97% 97% 95% 96% 58%
41
Catalytic Asymmetric Conjugate Addition: Azide
Miller Angew. Chem., Int. Edit. 2000, 3635. O N O N H O NBn N (2.5 mol%) NBOC t-Bu O HN Me R Me Et C6H11 i-Pr yield 97% 91% 79% 84% 84% ee 63% 71% 85% 82% 71% O R TMSN3 (3.8 equiv) RCO2H (1.0 equiv.) Toluene, 25C O N O N3 R
N BOCHN
O O N
O Me TMSN3 (3.8 equiv) RCO2H (1.0 equiv.) Toluene, 25C O
O N
O
N3 Me
85% y. 45% ee
42
Catalytic Asymmetric Conjugate Reduction
CN
TBSOH2C Me R CO2Et
H H (1.2 mol%) CH2OTBS Me CoCl2 (1 mol%) NaBH4 (2 equiv) EtOH/DMF, 23C R CO2Et
H
R = PhCH2CH2 Me2C=CHCH2CH2 Me2CH Me R CONHMe
94-96% ee
Me CoCl2 (1 mol%) NaBH4 (1 equiv) EtOH/diglyme, 23C R CONHMe
R = PhCH2CH2 cyclohexyl Ph Me Ph CONHMe
96-99% y. 92-99% ee
Me CoCl2 (1 mol%) NaBH4 (1 equiv) EtOH/diglyme, 23C Ph CONHMe 96% y. 97% ee
43
Catalytic Asymmetric Conjugate Reduction
P(p-tol)2 P(p-tol)2 (10 mol%) R1 R2 CO2Et CuCl (5 mol%) NaOt-Bu (5 mol%) / toluene, 23C PMHS (4 equiv) Me3Si O Me Si O H SiMe3 n R2 R1 CO2Et 84-98% y. 83-92% ee
Me Ph CO2Et Cyc
Me CO2Et Ph
Et CO2Et
Et Ph (From Z-alkene) Et CO2Et Me
Me CO2Et 6 Et
Et Ph CO2Et Ph
Et CO2Et (From Z-alkene)
CO2Et (From Z-alkene)
CO2Et
44
Nucleophilic Addition to Imines: General Strategies
O R H OH R R' + R OH R'
R'M External chiral ligand
Excellent electrophiles
Major Breakthrough: Ligand-accelerated dialkylzinc addition R2M R M N R1 R2 HN R1 R2
N R
R1
H
R
Imines are less electrophilic: more nucleophilic reagents are needed (highly basic). Imines are more Lewis basics: Lewis acids activate imines but high turnovers can be a problem. Solution: R1 is an electron-withdrawing group (Ar, SOR, SO2R, POR2, etc)
1
Chiral Auxiliaries for Nucleophilic Additions to Imines
1. Nuc 2. Cleavage R2 Ph H N OTBDMS Me N H Me HN RCuBF3 RLi H BnO O O NHBn c-C6H11CH2MgBr CeCl3, 75% BnO O O NBn c-C6H11CH2CuBF3 52% BnO O O Matsumoto Chelation Felkin
2
NH2 Residual Functionality
*
N
R1
1. Nuc 2. Cleavage R2 Ph Bu + Me HN 80 : 20 (Felkin) OTBDMS + Me HN 95-98 : 0-5 (52-93%) 10-20 : 80-90 (41-71) R Bu
NH2
*
R2 Ph Me
Nuc
H
Nuc
Bu2CuLiBF3 80%
Me HN OTBDMS R
N R2
*
R1
Pr
Pr
Pr
H
R3
Yamamoto Bn
Bn
Bn
NHBn
Chiral Auxiliaries for Nucleophilic Additions to Imines
N R2
*
R1 R
NBn2 H NPG
R1Li or R1Li, CeCl3 PG = Bn R1MgX PG = Ts R
NBn2 R1 NPG + R
NBn2 R1 NPG
PG = Bn ds 64->90% (syn) PG = Ts ds 78->90% (anti) Reetz
H
R3
Also PG = (O)Bn (nitrone), NMe2, NR2
Me N Ph Ph N
N
R1 N H O O
NMe2 H NR1 O H O O N Bn
S
Me
OTr Alexakis (amino aldehydes) Thiam, Chastrette Utimoto Cativiela
3
Aldonitrones: Good Electrophilic Precursors
H N O BocN O Ph BnMgCl BocN O Bn(HO)N Bn + BocN O Ph Bn(HO)N Bn H R NucBnMgCl, Et2AlCl TiCl2 or Cu(Oac)2, Zn AcOH, H2O Ph BnHN Bn BocN O BocN O Ph 95 : 5 (90% yield) 6 : 94 (89% yield) OR C N H O Bn
Ph
Bn
Favored (anti-Felkin)
OR H2, Pd(OH)2 O Bn H2N Bn N R C H H Nuc-
Disfavored (Felkin)
With Et2AlCl: chelate formation involving O of nitrone and C=O of Boc group
O
N
Bn
R'
H
HO
N
Bn
O N R Ph N
O
R
N
Zn(OTf)2 (cat.) i-Pr|NEt
R
88% ee
Ph
4
Chiral Auxiliaries for the Nucleophilic Addition to Imines: Imines Derived from Chiral Amines
N R2 Chiral Amines Me R N Ph R N Me N Me R N OH R R N O Ph Me N R Ar PivO PivO PivO H R H O OPiv O N R N O N Ph O Several steps are required to regenerate the auxiliary Nucleophilic reagents are quite limited
5
R1
1. Nuc 2. Cleavage R2 N-Sulfinyl aldimines O
NH2
*
H
Nuc Chiral Oxime Ethers O R R = Me, Et, Pr, i-Pr Ph R N O OPG Chiral nitrones
Chiral Hydrazones OH Ph
N R
S
R R
N
H
R = p-Tol N Me N OH N R N N OMe Cleavage leads to the destruction of the chiral auxiliary O S t-Bu
OR'
H
H
Addition to C=N: -Hydroxyamines-derived Auxiliaries
R R N OH R N R OPG R1 R3 R2 N O
Takahashi/Pridgen/Fugisawa/Higashiyama
ArCHO H2N OH 73-90% R
N H
OH
BnMgX or BnLi 35-90% R HN Bn OH
NaIO4, MeNH2 R
NH2 Bn
ds: >98%
H N R1 Ph H N O BnMgCl 87% HN Bn ds: >98% O Ph OH H2, Pd-C AcOH, 95% or Pb(OAc)4 NH2 Bn
6
Addition to C=N: RAMP- and SAMP Chiral Auxiliaries
N R
N OMe
N R
N OMe
H
H
O R1 H R1
NH2 R2
H2N
N OMe
HN OMe recycle
H2, Ra-Ni MeOH 47-84%
N R1
N OMe
R2Li, THF or Et2O -78 C, 73-98%
HN R1
N R2 OMe
H
Alternative deprotection: a. RCOCl b. Li, NH3
7
Hua/Yang/Ellman Chiral Auxiliaries
O N R S S p-Tol R N O S t-Bu
H
H O S S LiNH2 NH3, THF -78 C O S NH2
VO(acac)2 (0.0025 equiv) S 30% H2O2 H N t-Bu R1 Et Et Et i-Pr i-Pr i-Pr Ph Ph Ph R2 Me i-Pr Ph Me Et Ph Me Et i-Pr yield (dr) 96% (93:7) 97% (92:8) 100% (96:4) 99% (98:2) 100% (97:3) 97% (89:11) 96% (97:3) 96% (92:8) 29% (97:3) ClH3N OH (0.0025 equiv) t-Bu O R2 R1 HCl MeOH S N H OH CHCl3
88%, 91% ee
88%, 91% ee R1CHO, MgSO4 CH2Cl2
R2 R2MgBr R1 CH2Cl2
O S N
H R1
RS (H) t-Bu O S M N R2
8
RL
Ellman's Auxiliary: Synthesis of ,-Dibranched Amines
O O S RS NH2 RL O S N RS RL R3Li, Me3Al toluene O S N H
RS
R RL
Ti(OEt)4, THF 60-75 C
61-93% yield 89:11 to 99:1 RS Me Me Bu Bu Me Me RL i-Pr Ph i-Pr Ph i-Bu Bu yield (dr) 84% (1 isomer) 87% (1 isomer) 66% (1 isomer) 77% (1 isomer 88% (6:1) 77% (5:1) t-Bu O S M N R2 RS (H) RL
9
N-(tert-Butylsulfinyl)-imine: Synthesis of -Trifluoromethyl--branched Amines
O O S H NH2 R O S N H R TMSCF3, O S N H CF3 R 75-95% yield 90:10 to >99:1
Ti(OEt)4, THF 60-75 C
General Mechanism: F TMSCF3 + Ph Si Ph F Ph NBu4
Ph3SiF
CF3 Me Si Me Me F O S N H R TMSF CF3 H R NBu4 t-Bu N O
TBAT (DeShong)
CF3 H2N R
4N HCl MeOH
O S N H
CF3 NH4Cl R
O S N
CF3 R
Prakash, G. K. S.; Mandal, M.; Olah, G. A. Angew. Chem. Int. Ed. 2001, 40, 589-590
10
Addition of Arylboronic Acids
N R1
S
R2B(OH)2 (2 equiv) Rh(acac)(coe)2 (5 mol%) O dppbenz (5.5 mol%) dioxane, 70 C coe: cyclooctene dppbenz: 1,2-diphenylphosphinobenzene HN R1
S R2
O
H
70-96% yield 96:4 to 99:1
R1 4-MeC6H4 PhCH2CH2 PhCH2CH2 PhCH2CH2 PhCH2CH2 Ph Ph Ph
R2 Ph Ph 4-MeOC6H4 4-CF3C6H4 3-acetylC6H4 4-MeOC6H4 4-CF3C6H4 4-ClC6H4
yield (%) (dr) 96 (97:3) 86 (96:4) 70 (96:4) 73 (96:4) 80 (98:2) 76 (98:2) 71 (98:2) 93 (99:1)
11
Background: C=N Nucleophilic Additions
Cat. 1-8 mol% R1 H R1 = Aryl; R2 N Ts Cu(OTf)2 R2Zn (2 equiv) PhMe, 0 oC = Et: 79-99% yield; 90-94% ee Tomioka, K. et al. JACS 2000, 122, 12055; CL 2002, 8. R1 R2 H N Ts SmI2 THF-HMPA Reflux, 5 h R1 R2 (84 %) t-Bu O NH2 Bn N PPh2 Bn
H R1 R1 N OMe = Aryl or alkyl; R2
Cat. 10 mol% Zr(Oi-Pr)4 HOi-Pr R2Zn (3-10 equiv) PhMe, 0 oC
R2 PhI(OAc)2 (4 equiv) R1 N H MeOH, RT, 1 h OMe R1
R2 NH2 OH (65 %) N O
H N
O NHBu Ph
= Me, Et, Oct, t-isoamyl: 38-98% yield; 81- >98% ee
Hoveyda, A. H.; Snapper, M. L. et al. JACS 2001, 123, 984; JACS 2001,123, 10409.
R1 H
N H
O
Cat. 2-5 mol% R2Zn (3 equiv) PhMe, -15 to 20 oC
R1 R2
H N H
O
HCl, MeOH 50 oC, 1.5 h
R1 R2
NH2
R1 = Aryl; R2 = Et, Me, Ph: 90-99% yield; 70-97% ee
(95 %)
OH
N Ph
12
Brse, S. et al. JACS 2002,124, 5940; ACIE 2002, 41, 3692.
MethylDuPHOS MonoxideCu Catalyzed Reactions
Boezio, A. A.; Charette, A. B. J. Am. Chem. Soc. 2003, 125, 1692-1693. P N P Ar Me-DuPHOS
Boezio, A. A.; Pytkowicz, J.; Ct, A.; Charette, A. B. J. Am. Chem. Soc. 2003, 125, 14260-14261. O N Ar P O P
HN
O PPh2 H Me-DuPHOS (5 mol%) Cu(OTf)2 (5 mol%) R2Zn (2 equiv) Toluene, 0 C, 48 h Ar HN
O PPh2 >80% 85-96% ee R
O Me-DuPHOS MO (3 mol%) Cu(OTf)2 (5 mol%) R2Zn (2 equiv) Toluene, 0 C to rt Ar HN PPh2 R R = Me, Et, i-Pr, Bu, R-FG 91-96% 94-98% ee
PPh2 H
Ct, A.; Boezio, A. A.; Charette, A. B. Proc. Natl. Acad. Sci. U. S. A. 2004, 101, 5405-5410. O PPh2 SO2Tol Me-DuPHOS MO (3 mol%) Cu(OTf)2 (5 mol%) R2Zn (2.5 equiv) Toluene, 0 C to rt O N K2CO3, CH3CN Ar PPh2 H HN R1 O PPh2 R R = Me, Et, i-Pr, Bu, R-FG 78-98% 90-98% ee
Me-DuPHOS MO (BozPHOS)
R1
Me-DuPHOS MO (3 mol%) Cu(OTf)2 (5 mol%) R2Zn (2 equiv) Toluene, 0 C to rt
13
Catalytic Asymmetric Addition of Organozinc to C=N
O N Ph P Ph Ph Et2Zn CuOTf or Cu(OTf)2 (cat.) R3P Ph NHP(O)Ph2 >95% conversion Et
H
Et Zn Et + CuOTf EtZn NP(O)Ph2 Et L Et Cu L + EtZnOTf O L Cu N NP(O)Ph2 Et Ph P 4 Et2Zn + 2 Cu(OTf)2
Ph
2 Et-Cu + 4 EtZnOTf Ph Ph
EtZnOTf
EtH
H
Ph
Copper-catalyzed dialkylzinc conjugate addition: Alexakis, A. J. Am. Chem. Soc. 1991, 113, 6332. Feringa, B. L. Angew. Chem. Int. Ed. Engl. 1996, 2374
14
Organostannane Addition to N-Sulfonylimines: Diarylmethylamine Synthesis
Hayashi J. Am. Chem. Soc. 2000, 122, 976-977 N Aryl group R2 H SO2R + ArSnMe3 Rh(acac)(C2H4)2 (3 mol%) (R)-MOP (6 mol%) LiF, dioxane, 110 C 12 h Ar = Ph, 4-MeOC6H4, 4-CF3C6H4 N PPh2 Me OMe Me (R)-Ar*-MOP Ph HN SO2R Ph 77% yield 93% ee Ph SO2R H HN R2 SO2R 82-96% ee Ar
R = 4-NO2C6H4 2 optimal ligands:
PPh2 OMe
(R)-MeOMOP
BINAP gave low conversions (<10%) but high ee. Much lower yield with less nucleophilic p-CF3 stannane. p-NO2benzenesulfonyl group is cleaved with PhSH, K2CO3 Compatible with esters, halides, CF3.
15
Arylation of Imines: Rh-Catalyzed Organotitanium Addition
O SO2R H (S)-SegPHOS (3 mol %) [RhCl(C2H4)2]2 (1.5 mol %) Ar2Ti(OiPr)3 (1.2 equiv) THF, 20 C, 5 h Ar1 SO2R Ar2 O O O (S)-SegPHOS PPh2 PPh2
N Ar1
HN
R = 2,4,6-(i-Pr)3C6H2-
O HN p-CF3C6H4 S O Ph p-CF3C6H4
O HN S O Ph p-CF3C6H4 HN SO2R R= Ph
99%, 76% ee SO2R Ph p-FC6H4
97%, 88% ee SO2R Ph p-MeOC6H4
98%, 93% ee SO2R Ph m-MeOC6H4 SO2R HN Ph o-MeC6H4 SO2R Ph
HN p-ClC6H4
HN
HN
HN
95%, 94% ee
99%, 92% ee
98%, 92% ee
99%, 86% ee
99%, 89% ee
HN 1-Naphthyl
SO2R Ph Ph
HN
SO2R p-FC6H4 Ph
HN
SO2R m-MeO-C6H4 Ph
HN
SO2R p-MeO-C6H4
99%, 96% ee
96%, 93% ee
86%, 90% ee
97%, 88% ee
16
Arylation of Imines: Rh-Catalyzed Organotitanium Addition
17
Arylation of Imines: Rh-Catalyzed Boronic Acid Addition
N Ar1 Ts Ligand (3 mol %) Rh(acac)(C2H4)2 (3 mol %) (Ar2BO)3 (1.7 equiv) n-PrOH, 60-100 C, 1-3 h Ar1 HN Ts Ar2 N PPh2 O NHBoc
H
HN Ph
Ts
HN p-MeC6H4
Ts
HN m-MeC6H4
Ts
HN o-MeC6H4
Ts
HN 1-Naphthyl
Ts
p-PhC6H4
p-PhC6H4
p-PhC6H4
p-PhC6H4
p-PhC6H4
83%, 66% ee Ts
86%, 72% ee Ts
90%, 76% ee
97%, 86% ee Ts
88%, 92% ee Ts
HN o-TMSC6H4
HN o-TMSC6H4
HN o-TMSC6H4
HN o-TMSC6H4
p-PhC6H4
p-MeOC6H4
p-ClC6H4
m-ClC6H4
98%, 92% ee Functionnalization H HN Ts
84%, 88% ee
97%, 90% ee
99%, 94% ee
CsF DMF/H2O (10:1) reflux, 25 h 74% R
TMS HN
Ts ICl, CH2Cl2 0 C, 15 min 99% R
I
HN
Ts
R R = Cl
18
R = Ph
Arylation of Imines: Rh-Catalyzed Boronic Acid Addition
(R,R)-Ph-bod* (3 mol %) [RhCl(C2H4)2]2 (3 mol %) (Ar2BO)3 (1.2 equiv) KOH (20 mol%), H2O (1 equiv) 1,4-Dioxane, 60 C, 6 h Ar1
N Ar1
Ts
HN
Ts Ar2 Ph (R,R)-Ph-bod*
Ph
H
HN p-Cl-Ph
Ts
HN p-CF3-Ph
Ts
HN p-MeO-Ph 96%, 99% ee
Ts
HN p-Me2N-Ph 94%, 98% ee
Ts
HN o-MeO-Ph
Ts
Ph
Ph
Ph
Ph
Ph
96%, 98% ee 96%, 98% ee PG = NS, Ligand = Ph-bnd* HN 1-Naphthyl 95%, 98% ee 94%, ee 96% PG = NS, Ligand = Ph-bnd* Ts
97%, 95% ee
98%, 99% ee
98%, 99% ee PG = NS, Ligand = Ph-bnd* HN 2-Furyl Ts HN Ph Ts HN Ph Ts HN Ph Ts
Ph
Ph
p-Cl-Ph
p-MeO-Ph
o-Me-Ph
99%, 99% ee
99%, 99% ee
97%, 96% ee
96%, 99% ee
96%, 99% ee 94%, 98% ee PG = NS, Ligand = Ph-bnd* PG = NS, Ligand = Ph-bnd*
19
Arylation of Imines: Rh-Catalyzed Boronic Acid Addition
(R,R)-Ph-bnd* (3 mol %) [RhCl(C2H4)2]2 (3 mol %) (Ar2BO)3 (1.2 equiv) KOH (20 mol%), H2O (1 equiv) 1,4-Dioxane, 60 C, 6 h Ar1 Ph HN Ns Ph Ar2 (R,R)-Ph-bnd*
N Ar1
Ns
H
NH p-ClC6H4
Ns
NH p-MeOC6H4
Ns
NH 1-Naphthyl
Ns
NH Ph
Ns
NH Ph
Ns
Ph
Ph
Ph
p-Cl-Ph
p-MeO-Ph 94%, 98% ee
96%, 98% ee
98%, 99% ee
94%, 96% ee
96%, 99% ee
Deprotection O HN S O
NO2
PhSH (2 equiv) K2CO3 (5 equiv) DMF, rt, 4 h 96% No racemization
NH2
Cl
Cl
20
Arylation of Imines: Rh-Catalyzed Boronic Acid Addition
21
Arylation of Imines: Rh-Catalyzed Boronic Acid Addition
O N Ph P (R,R)-DeguPHOS (5.5 mol %) Rh(acac)(coe)2 (5 mol %) ArB(OH)2 (2 equiv) Et3N (1 equiv), MS 3A 1,4-Dioxane, 70 C, 24 h Ph O HN P PPh2 Ph Ph BnN PPh2 (R,R)-DeguPHOS
Ph Ph
H
Ar
coe = c-octene To avoid hydrolysis of the imine, Et3N and MS 3A were added.
O HN Ph P
Ph Ph Ph Cl HN
O P
Ph Ph Ph CF3 HN
O P
Ph Ph Ph OMe HN
O P
Ph Ph O
97%, 94% ee
87%, 88% ee
93%, 93% ee
93%, 88% ee
22
Arylation of Imines: Rh-Catalyzed Boronic Acid Addition
O N Ar1 S Ligand (2.5-7.5 mol %) Rh(acac)(C2H4)2 (1-3 mol %) Ar2B(OH) (1.3 equiv) Acetone, 40C, 4 h
2
N O
O HN Ar1 S Ar2
N O
O O
H P N
H
OMe HN p-ClC6H4 SO2NMe2 Ph p-FC6H4 HN SO2NMe2 Ph HN p-CF3C6H4 SO2NMe2 Ph p-MeOC6H4 HN SO2NMe2 Ph p-MeC6H4 HN SO2NMe2 Ph
95%, 95% ee SO2NMe2 Ph
81%, 93% ee SO2NMe2 Ph
98%, 94% ee SO2NMe2 Ph
72%, 90% ee SO2NMe2 p-MeOC6H4 97%, 92% ee Ph
77%, 92% ee SO2NMe2 p-MeC6H4
HN m-FC6H4
HN o-MeC6H4
HN 2-Thiphenyl
HN Ph
HN
81%, 93% ee Deprotection
91%, 87% ee
81%, 91% ee
81%, 94% ee
O - Inexpensive - Low-molecular-weight - Easy to remove HN p-ClC6H4 S
N O
H2N NH2 W, 200W, 2 h 96% no racemization p-ClC6H4
NH2 Ph
Ph
23
Arylation of Imines: Mechanism of Rh-Catalyzed Boronic Acid Addition
P* Rh P* O O
Ar2-B(OH)2 (HO)2B Ar1 N SO2NMe2 P* Ar2 Rh Ar2 P* Ar2-B(OH) P* Rh OH Ar2-B(OH)2 P* Ar1
2
N
SO2NMe2 H
Ar2 P* Rh N P* SO2NMe2 Ar1
H2O P* Rh HN Ar1 SO2NMe2 Ar2 P*
Ar2 N Ar1 H SO2NMe2
24
Vinylation of Imines: Ni-Catalyzed Organoborane Addition
R1 N Ar H OTMS R2 (2 equiv) Ligand (5 mol %) Ni(cod)2 (5 mol %) Et3B (3 equiv) MeOAc/MeOH, rt, 12 h Ar R2 HN OTMS Et R1 Fe P
Ph
HN Ph
OTMS Et n-Pr n-Pr p-CF3C6H4
HN
OTMS Et n-Pr n-Pr p-MeOC6H4
HN
OTMS Et n-Pr n-Pr o-Tol
HN
OTMS Et n-Pr n-Pr
85%, 89% ee
91%, 85% ee
75%, 82% ee
74%, 85% ee
HN 2-Naphthyl
OTMS Et n-Pr n-Pr c-Hex
HN
OTMS Et Et Et Ph
HN
OTMS Et Ph Me Ph
HN
OTMS Et 2-Naphthyl Me 42%, 70% ee (regio 85:15)
25
90%, 73% ee
53%, 51% ee
45%, 85% ee (regio 80:20)
Vinylation of Imines: Ni-Catalyzed Organoborane Addition
Deprotection and enrichment HN Ph n-Pr 89% ee OTMS Et n-Pr 1. TBAF, THF 0 C 2. H5IO6, MeNH2 MeOH/H2O (1:1) Ph n-Pr 73%, 89% ee O NH2 Et n-Pr Maleic acid Et2O Recrystallization O O OH Ph n-Pr 71%, >99% ee NH3 Et n-Pr
26
Vinylation of Imines: Rh-Catalyzed Reductive Coupling of Alkynes
27
Enantioselective Addition to C=N: Allylmetal Reagents
N R R' M HN
*
R'
H
R Precursor to the synthesis of - or -amino acids Me TsN O Ph O N Zn N O
BiPc2 Itsuno Low ee 63-73% ee at best
B
Itsuno R' = TMS, arylimines 92% ee
Nakamura
O N Ph Zn N
O PdCl 2 Ph Hanessian Yamamoto 60-80% ee
X O Zr O X Ot-Bu R1 Kobayashi
28
Ot-Bu H
CH2OH SnBu3
Enantioselective Addition to C=N: Allylmetal Reagents
O N Li i-Pr R3 R1 R2 N Ph ZnL2 Me ZnL2 SiMe2Ph ZnL2 Ph X N X = OMe 90% (95% ee) 96% (98% ee) 74% (98% ee) R3 R4 R2 R5 i-Pr N H 54% (90% ee) 44% (95% ee) R3 = Me i-Pr R1 N Zn N O O N N N N ZnBr R1 R2 R3 N O O N Zn N i-Pr R H R O N R' HN * R' * R3
R2 R1
H
X X=H
95% (68% ee)
72% (95% ee)
54% (88% ee)
48% (90% ee) 42% (99% ee) R3 = Me
29
Enantioselective Addition to C=N: Allylmetal Reagents
O N N R5O2C OBn R4 + Ph Zn R3 R5O2C R1 R2 N Ph HN
*
O
R'
*
R3
R2 R1 62-90% yield 74-93% ee
Phenylglycinol derived semicorrin Glyoxylates and pyruvates as electrophiles
NHOBn COOt-Bu 82% yield 93% ee
Me
NHOBn COOt-Bu 74% yield 92% ee NHOBn COOt-Bu
Ph
NHOBn COOt-Bu 90% yield 87% ee Me NHOBn
t-BuOOC
NHOBn COOt-Bu 89% yield 74% ee
COOt-Bu 72% yield 91% ee
30
62% yield 94% ee
Chiral Catalyst for the Allylation of Imines
Kobayashi ACIEE 2001, 40, 1896. X = Br, Cl X O Zr HO O X N Ar H H H CH2OH H Me SnBu3 Ar Me syn:anti >95 : 5 Tethers for binding to catalyst NHAr CH2OH 87-95% ee 71-84% yield CH2OH SnBu3 Ar Ot-Bu NHAr CH2OH Ot-Bu
31
Allylation of Imines
Lou, S.; Moquist, P. N.; Schaus, S. E. J. Am. Chem. Soc. 2007, 129, 15398-15404.
32
Allylation of Imines
Lou, S.; Moquist, P. N.; Schaus, S. E. J. Am. Chem. Soc. 2007, 129, 15398-15404. 33
Mannich Reaction: Background
O R1 R2 H N R4 R2 N + R4 O Cl R2 + R4 H R2 H R3 R3 + (R)H O H + R3 H N R4 (R)H R4 R3 N R4 N R4 O R1 R2 R3
R3 OH R1 R2 R1 R3 N
(R)H
H O R1 R2 NHR3 R4 -amino carbonyl
OSiR3 R1 R2
Lewis Acid
N
Organic Base
O N
R3 -lactam R4 O R1
O R1 + R2 R
O + H R3
H N
Catalyst R4
R2 N R4 R3
-amino carbonyl
R
34
Diastereoselective Mannich - Chiral Auxiliaries
H. Waldmann Angew. Chem. Int. Ed. 1999, 38, 184 MeO O O N Ar Sunji; V. Tetrahedron 1997, 689 t-Bu Me + N OMe Palomo; C. ACIE 2000, 1063 1. LDA, THF, -78 C O OTMS O 2. p-TolO2S NHPG R - p-TolSO2H NPG R
35
(H) Me (H) Me N t-Bu O
OTMS OMe
MeO
O O N Ar ROOC N t-Bu H Me (H) Me (H) Me O 50-82%, >99:1 ds
+ Cl
Me O Me N AlCl4 THF, -78 C t-Bu Me N O
O Me
51 % y 82 % ee
NHPG R 54 - 94 % y 92 - >99 % de
TMSO
Xc
Mannich-Type Reaction: Chiral Lewis Acid (Metal Catalysts)
Metal-catalyzed NR1 Tomioka, Kobayashi R2 H OTMS + NR1 Sodeoka, Lectka RO O H O R3 RO Chiral Lewis acid NHR1 O R3 R2 NHR1 O R3
Ph MeO
Ph O OMe O Zr O O
Ar P
Ar Ar AgOTf P
Ar CuClO4
Tomioka (lithium enolate)
P Ar
P Ar Ar Lectka
Ar
Kobayashi
Sodeoka
36
Kobayashi's Chiral Zirconium Catalyst
HO OTMS + R1 Br O Zr O Br O Br Ph 4-ClC6H4 1-naphthyl 2-furyl c-C6H11 O H Y Br R1 Ph 4-ClC6H4 1-naphthyl Yield (Y = OMe) 70 86 quant. H2C=C(OTMS)SEt 78 88 quant. 89 56 88 86 >98 89 80 ee 87 83 92 Chiral catalyst (5-10 mol%) NH NMI (5-30 mol%) CH2Cl2, -45 C R1 O Y OH
N
Ceric ammonium nitrate to convert the aniline into NH2 group.
37
Kobayashi's Chiral Zirconium Catalyst: Amino Alcohol Synthesis
HO PGO + H Y DMI (5-30 mol%) CH2Cl2, -45 C Br O Zr O DMI Br DMI = 1,2-dimethylimidazole Ph Br O Ph 4-ClC6H4 1-naphthyl 1-furyl R1 OPG Br O DMI R1 Yield syn:anti ee OTMS Chiral catalyst (5-10 mol%) NH O Y OH
N R1
(E)-TBSOCH=C(OTMS)Oi-Pr quant. 73 65 68 96:4 92:8 >99:1 92:8 95 98 91 98
(Z)-BnOCH=C(OTMS)OR 91 (R = PMP) 6:94 8:92 8:92 13:87 18:82 80 91 96 80 92
4-ClC6H4 72 (R = PMP) 1-naphthyl 80 (R = c-C6H11) 2-furyl c-C6H11 68 (R = PMP) 41 (R = c-C6H11)
Ceric ammonium nitrate to convert the aniline into NH2 group.
38
Mannich Reaction of N-Acylimino Esters
Kobayashi Org. Lett. 2002, 143-145. O O EtO N O R1 + R4 R4 OR3 R2 Ph NH -Nap TfO Cu OTf Ph O HN -Nap (10 mol%) R4 R4 CH2Cl2, 18 h R1 EtO NH O R2
R4 = H; R3 = TMS; R2 = Ph: 92% yield; 94% ee
High ee when R4 = H, Me; R2 = Ar, OMe, SEt
O R1 EtO O NH O Ph
O 1. K-Selectride 2. LiBEt3H HO HPA-12 (specific inhibitor of sphingomyelin)
39
NH
OH
Lectka's Chiral Lewis Acid: Enol Silanes as Nucleophiles
NTs O OEt H + R R Ar P Ar CuClO4 P Ar Ar = 4-MeC6H4 Ar Ph 4-ClC6H4 2-naphthyl 4-MeOC6H4 t-Bu 4-Me2NC6H4 4-FC6H4 4-CF3C6H4 PhOH, HBr/AcOH to cleave the tosyl protective group Chiral catalyst is also very effective in ene reactions of -imino esters PhOH, HBr/AcOH to cleave the tosyl protective group NHPG O O OEt R PG 4-MeO-2,6-Me2C6H2SO2 4-NO2C6H5SO2Me3SiCH2CH2SO2Deprotection conditions 9 : 1 TEA/MSA, PhSMe PhSH, K2CO3 CsF, DMF
40
OTMS
Chiral catalyst (2-10 mol%) THF or CH2Cl2 0 to -80 C Yield 91 93 91 90 65 91 91 75
NHTs O O OEt ee 98 95 92 98 90 92 96 89 R
Mannich Reaction of Imino Esters: Ethyl Pyruvate as Nucleophile
Jorgensen ACIE 2001, 2995. O RO2C R R = H, Me, Bn Ph 5 mol% Manipulation (sensitivity of Ts group) O O EtO2C R = Me, Bn R NHTs CO2Et 1. L-selectride 2. PTSA 70-92% R CO2Et TsHN O 1. (Boc)2O DMAP (cat.) 2. Mg, MeOH 70% O BocHN O R CO2Et + EtO O N Cu (OTf)2 N Ph O NTs CH2Cl2, 40 C Me Me O RO2C R 89->98% ee >10:1 (syn:anti) >70% yield O NHTs CO2Et
41
Electrophilic Aromatic Substitution with "Iminium" Intermediates
Jorgensen ACIE 2000, 39, 4114 O EtO O Ph3P=NCOOMe H EtO O N H O OMe Ar-H (R)-Tol-BINAP CuPF6 (5 mol%) THF, -78 C O OEt EtO O 75% (93% ee) O HN EtO O 63% (97% ee) N Me OEt EtO O 82% (87% ee) HN O OEt EtO O 44% (52% ee) HN O 88% (86% ee) O OEt O EtO 75% (92% ee) N Me N Me O NMe2 HN HN OEt EtO O MeO 68% (72% ee) O OEt HN LA* EtO O N H O OMe Ar-H EtO O HN Ar O OMe
Ph P
O Ph HN
O OEt
CuPF6 P Ph Ph
EtO
NMe2
N
NMe2
42
Henry Reaction (Nitroaldol)
Jorgensen ACIE 2001, 2992. JACS 2001, 5843
N EtO O
C6H4OMe NEt3, 0 C or rt + R NO2 O N Ph TfO Cu OTf N Ph Me Me O EtO O
NHAr NO2 R
syn:anti 50:50 to 95:5 ee syn: 74-99% anti: 77-98%
Modest ratios: R = Ph, Me Good ratios: R = Et, Pent, Bn
43
Mannich-Type Reaction: Organic Chiral Catalyst
"Organic Catalyst" H N
O CO2H
O N
N H List Barbas
MeO benzoylquinine Lectka
44
Organic Catalysis: Three-component Mannich Reaction
List J. Am. Chem. Soc. 2000, 122, 9336-9337. OMe CHO O + + DMSO, 50% NO2 OMe 94% ee NO2 NH2 L-Proline (35 mol%) O HN
N
COOH +
MeO
N H
O2N (Z)-imine (Corey TL 1991, 5287)
45
Organic Catalysis: Three-component Mannich Reaction
List J. Am. Chem. Soc. 2000, 122, 9336-9337. OMe NH2 O + RCHO + DMSO, 50% OMe OHC 35%, 96% ee R L-Proline (35 mol%) O HN
90%, 93% ee OHC OHC OHC OHC OBn 74%, 73% ee 82%, 75% ee
56%, 70% ee
46
Enantioselective Synthesis of -Keto--amino Acids
O PMP + R' R" (20 vol%) H CO2Et
Barbas, C. F. J. Am. Chem. Soc. 2002, 124, 1842 Barbas, C. F. J. Am. Chem. Soc. 2002, 124, 1866
N
(L)-Proline (20 mol%) Dioxane 2-24h, rt R'
O
HN (S) R"
PMP
(S) CO2Et
O H R (1.5 eq)
PMP + H
N CO2Et
(L)-Proline (5 mol%) Dioxane 2-24h, rt H
O
HN (S)
PMP
Entry O (1)
R HN PMP CO2R 1a (R=Et) 1b (R=iPr) O HN PMP CO2R PMP CO2R 3
Yield
dr
ee
(S) CO2Et
1a: 82% 86% 1b: 85%
-
95% 99% 97%
R ee >95%, dr>10:1
(2)
72%
>19:1
>99%
Entry (1) (2) (3) (4) (5) (6) (7)
R i-Pr Me Et n-Bu n-Pent
Yield 81% 72% 57% 81% 81% 89% 71%
dr >10:1 (19:1) 1.1:1 (3:1) 1.5:1 (7:1) 3:1 (>19:1) >19:1 (>19:1) >19:1 (>19:1) >19:1 (>19:1)
ee 93% 99% 99% 99% >99% 99% >99%
Product
O
2 HN
1
(3) 47% >19:1 >99%
2
O HN
PMP CO2R
3 4 5 6
(4) 4 O (5) 5 HN
81%
>19:1
>99%
PMP CO2R
79%
>19:1
>99%
O (6)
HN
PMP CO2R 77% 61%
7
F O (7) OH
6 HN PMP CO2R 7 62% >19:1 99%
47
Enantioselective Synthesis of -Lactams
Lectka J. Am. Chem. Soc. 2000, 122, 7831-7832. O R Cl R benzoylquinine (BQ) (10 mol%) H O C + BQHCl NMe2 NMe2 + O O H N C (1.1 equiv) R O N H + BQ Me2N H NMe2 Cl
MeO Ts Ts N EtOOC R O H COOEt N BQ C O
R
H
36-65% yield 95-99% ee 99:1 dr R = Ph (96% ee), Et (99% ee), OPh (99% ee), OAc (98% ee), OBn (95% ee)
48
Classical Strecker Synthesis
General reaction:
NH2 RCHO + NH3 + HCN R
*
H3O+ R
NH2
*
CN
COOH
Strecker, A. Liebigs Ann. Chem. 1850, 75, 27 Aldimine intermediate. Synthesis of natural and non-natural amino acids.
Important for high ee: must be cleavable PG
N R1
TMSCN or HCN Catalyst R
NHPG
*
H
CN
49
Chiral Ligands for the Strecker Reaction
Organic Catalysts O HN NH O N H Corey Lipton t-Bu OMe Jacobsen H N NH N O N HO NH2 Ph H N S N H N H R2 N O N H X N H
N HO
t-Bu
OCOt-Bu
Chiral Lewis acids Ph Ph P
t-Bu N X OH O
H N
O N H Ot-Bu OMe O t-Bu N Al O t-Bu Cl O t-Bu t-Bu N
O
Br
Br
O Cl Al O Br P
OH OH
OH OH
Ti(Oi-Pr)4
Br Zr(Ot-Bu)4 1:1:0.5-1
Jacobsen O
Ph Ph Shibasaki
Kobayashi
50
Jacobsen's (Salen)Al(III) Catalyst for Asymmetric Strecker Synthesis: Results Using Aldimines
N R N Al t-Bu O t-Bu Cl O t-Bu t-Bu entry a b c d e f g h i
a
1. Cat. (5 mol%), 1,2 eq HCN toluene, -70 C, 15h H 2. TFAA
O CF3 R N CN
N R Ph p-MeOPh p-MePh p-ClPh p-BrPh 1-naphtyl 2-naphtyl cyclohexyl t-Bu yielda(%) 91 93 99 92 93 95 93 (55)c 77 69 eeb(%) 95 91 94 81 79 93 93 (>99)c 57 37
Easily prepared Stable
Isolated yield. b Determined by GC or HPLC using commercial chiral columns. c After recrystallization from hexanes.
Sigman, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120, 5315.
51
Jacobsen's (Salen)Al(III) Catalyst for Asymmetric Strecker Synthesis: Nitrile Hydrolysis and Deprotection
N H
1) 1,2 eq HCN, 7 (2 mol%) toluene, -70C, 15h 2) MeOH/HCl , reflux , 8h
HN CO2Me
78% yield, 92% ee
dimethylbarbituric acid 5 mol% Pd(PPh3)4, rt CH2Cl2, 3h
NH2HCl Recrystallized 60% yield, >99% ee CO2Me
52
Catalytic Enantioselective Strecker Synthesis: Jacobsen's Schiff Base Catalyst
1) cat. (2 mol%) toluene, -78 C, 24h, HCN F3C H 2) TFAA R entry Ph H N O S N H N H 1 2 N HO 3 4 5 t-Bu OMe
a b
O N CN yielda(%) 78 92 65 88 70 77 eeb(%) 91 70 86 88 85 83
N R
R Ph p-OMePh p-BrPh 2-naphtyl t-Bu cyclohexyl
6
Isolated yield. Determined by GC or HPLC using commercial chiral columns. Catalyst improved version for alkyl-substituted imines. Catalyst contains 4 substructures that were optimized from parallel synthetic libraries on solid support Metals were not necessary (Lipton) Sigman, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120, 4901.
53
Jacobsen's Improved Schiff Base Catalyst
N R R1 + HCN H 2) TFAA R entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 R Ph t-Bu p-OMePh m-OMePh o-OMePh p-MePh m-MePh o-MePh p-BrPh m-BrPh o-BrPh p-t-BuPh t-Bu cyclohexyl cyclohexyl 1-cyclohexenyl t-BuCH2 pentyl i-Pr cyclopropyl cyclooctyl R1 allyl allyl allyl allyl allyl allyl allyl allyl allyl allyl allyl allyl benzyl benzyl allyl benzyl benzyl benzyl benzyl benzyl allyl CN yield (%) 74 75 98 99 93 99 97 96 89 87 88b 89 88 85 88 90 85 69 74 89 65 eea(%) 95 95 (91) 95 93 77 95 96 95 89 90 95 97 96 (93) 87 86 91 (87) 90 (87) 78 79 91 90 1) 1 or 2 (2 mol%) toluene , -70oC , 20h F3C O N R1
X R2 O 1: R2=Ph X=O 2: R2=polystyrene X=S N H N H
N HO
t-Bu
OCOt-Bu
Sigman, M. S.; Vachal, P.; Jacobsen, E. N. Angew. Chem. Int. Ed. 2000, 39, 1279
a
Values in parentheses were obtained with resin-bound catalyst 2
b Reaction
time was 36h.
54
Jacobsen's Improved Schiff Base Catalyst
Z-imines: 1) cat (2 mol%) toluene, -70 C, 20h N + HCN 2) TFAA CN O 88% yield, 91% ee Same sense of stereoinduction as the acyclic E-imines. Resin-bound catalyst: No loss of catalyst reactivity or product enantioselectivity after ten catalyst recycles (entry 13 of precedent table). Hydrolysis-deprotection sequence: 1) 3 (4 mol%) toluene, -78 C Ph 15h H + HCN or TMSCN/MeOH Recrystallised >99% ee 99% yield 2) Ac2O formic acid O H N CN Ph 65% (w/v) H2SO4 45C, 20h H O N Ph N CF3
N
1) HCl conc. 70 C, 12h
NH2HCl COOH
2) H2, Pd/C COOH MeOH
>99% ee, quantitative yield, 84% from imine
55
Catalytic Enantioselective Strecker Synthesis: Snapper and Hoveyda's Ti-Tripeptide Schiff Base Catalyst
t-Bu N Ph R N Ph X OH O 1 H N O N H Ot-Bu OMe O 10 mol% R N H Ph CN Ph
Ti(Oi-Pr)4 (10 mol%), TMSCN (2 eq) i-PrOH(1,5 eq) added over 20h, toluene, 4 C Without i-PrOH
With i-PrOH conv. (%), ee (%)a 99, 97 96, 93 99, 94 100, 94 100, 93 93, 90 100, 85d yield (%), ee (%)a 82, >99b 85, >99b 93, >99b 99, 94c 80, >99b 87, >99b 97, 85c
entry 1 2 3 4 5 6 7
b
R Ph o-ClPh o-BrPh p-MeOPh 2-naphtyl 1-naphtyl t-Bu
X 5-OMe 3,5-diCl 3,5-diCl 3,5-diCl 5-OMe 5-OMe 3,5-diBr
conv. (%), ee (%)a 30, 97 22, 92 15, 88 15, 84 20, 90 25, 91 39, 88
a Determined
by HPLC in comparison to authentic racemic materials. c Purified by silica gel chromatography. Purified by recrystallization. d Reaction performed in 1,1,1-trichloroethane with n-BuOH as additive. Krueger, C. A.; Kuntz, K. W.; Dzierba, C. D.; Wirschun, W. G.; Gleason, J. D.; Snapper, L. M. and Hoveyda, A. H. J. Am Chem. Soc. 1999, 121, 4284.
56
Snapper and Hoveyda's Ti-Tripeptide Schiff Base Catalyst for Strecker Synthesis: Catalytic Cycle
N Ph
P
N O Ti L L O
H N O Ph Ti NP O L2 NH
NH
P = CHPh2 NC Ph NHP RCN (R=TMS or H) N O Ti NP Ph
57
NH O L2
R NC
Snapper and Hoveyda's Ti-Tripeptide Schiff Base Catalyst for Strecker Synthesis: Application to ,-Unsaturated Imines
cat (10 mol%), Ti(Oi-Pr)4 (10 mol%), TMSCN (2 eq) i-PrOH (1,5 eq)a Ph toluene, 24 h R CN N H Ph Ph
Ph R N
entry 1 X: Schiff base of optimum ligand. 2 3 4
R Ph o-OMePh p-NMe2Ph o-NO2Ph
X 1-naphtyl 1-naphtyl 3,5-diBr 3,5-diBr
conv., ee (%)b,c >98, 84 94, 78 >98, 76 >98, 90
yieldd, ee (%) 80, 97 61, 97 93, 76 87, 97
a Entries 1-2 at 4 C, i-PrOH added over 20 h, entries b Determined by 1H NMR of crude reaction mixture. c d
3-4 at -20 C, i-PrOH added over 10 h.
Determined by chiral HPLC analysis in comparison with authentic materials. Purified by recrystallization. < 2% of 1,4-addition. Corresponding saturated imines undergo addition with lower yields and ee (15-25% yield, 24% ee for R = Ph)
Porter, J. A.; Wirschun, W. G.; Kuntz, K. W.; Snapper, L. M.; Hoveyda, A. H. J. Am. Chem. Soc. 2000, 122, 2657.
58
Snapper and Hoveyda's Ti-Tripeptide Schiff Base Catalyst for Strecker Synthesis: Application to ,-Unsaturated Imines
Ph R1 R2 entry 1 2 3
a b
cat (15 mol%), Ti(Oi-Pr)4 (15 mol%), TMSCN (2 eq) n-BuOH (1,5 eq)a Ph toluene, -20 C, 24 h R1 R2
CN N H
Ph Ph
N
R1 Me Me H
R2 H Me Me
X 3,5-diBr 3,5-diCl 1-naphtyl
conv., ee (%)b,c >98, 85 >98, 94 >98, 95
yieldd, ee (%) 84, 85 86, 94 80, 95
Added over 10 h. Determined by 1H NMR of crude reaction mixture. c Determined by chiral HPLC analysis in comparison with authentic materials.
d
Purified by silica gel chromatography.
59
Snapper and Hoveyda's Ti-Tripept...