Asymmetric Allylic Alkylation Reactions

L * R X R' L NucPd Cat. R R' Nuc

!-allyl-1 "

Helmchen Chem. Commun., 2007, 675691 *Trost Acc. Chem. Res. 2006, 39, 747 Trost Chem Rev 2003, 103, 2921 (Applications in Total Synthesis) Trost JOC 2004, 69, 5813 Trost in Catalytic Asymmetric Synthesis, 2nd Edition, Ojima, Ed.; ch 8E, p 593 Pfaltz and Lautens Comp. Asym. Cat. Vol II, Ch 24 Trost Acc. Chem. Res. 1996, 29, 355 Trost Chem Rev. 1996, 96, 395 Hayashi in Catalytic Asymmetric Synthesis, Ojima, Ed.; ch 7.1, p 325 Reiser ACIEE 1993, 32, 547 Trost Pure & App. Chem. 1992, 64, 315 Williams Tetrahedron: Asymmetry 1992, 3, 1089 Pfaltz Acc. Chem. Res. 1993, 26, 339

Asymmetric Allylic Akylation Reactions

Many different types of asymmetric allylic alkylation reactions have been reported. We will limit our discussion to the four most common ones:

!-allyl-2 "

1) Creation of a new stereogenic center on nucleophile:

Most common:

X R1 L

O R2 R3

O R1

O R2 R3
*

Pd Cat. L
"

O R1 R3

O R2

!Enantiodifferentiation occurs during nucleophilic attack at !-allyl. 2) Differentiation of ends of meso !-allyl:
NucNuc-

R R X L
*

R Nuc
Enantiomers

R Pd L

Nuc !Enantiodifferentiation occurs by selective nucleophilic attack at one end of symmetrical !-allyl. Both steric and electronic effects can be important.

Hayashi in Catalytic Asymmetric Synthesis, Ojima, Ed.; Ch 7.1, p 325 Trost Pure & App. Chem. 1992, 64, 315, Williams Tetrahedron: Asymmetry 1992, 3, 1089

Asymmetric Allylic Akylation Reactions

3) Unsymmetrical !-allyl: R
(R) Nuc-

!-allyl-3 "

R
+

or

R X

R
(S) "

Pd L L

Nuc

Nuc

R
+

Pd L L
*

Nuc

Nuc

!Enantiodifferentiation depends on two factors: kNuc(R)/kNuc(S) and the rates of these processes relative to the rate of interconversion of R and S. 4) Substitution of diastereotopic leaving groups:
*
*

L Pd

L Pd X X X

L X L Pd
*

X !Enantiodifferentiation occurs in ionization step. Most useful if X also contains nucleophile.

Hayashi in Catalytic Asymmetric Synthesis, Ojima, Ed.; Ch 7.1, p 325 Trost JACS 1992, 114, 9327, Trost Pure & App. Chem. 1992, 64, 315, Williams Tetrahedron: Asymmetry 1992, 3, 1089

Asymmetric Alkylation-Type 1
O O Me O O Me [(+)DIOP]PdCl2 cat NaOPh, 1) NaH / THF 2) ClPd("3-allyl) / L* OAc Postulate: R* R N Na O O Me OPh O O Me 81 % ee O O Me 7 % ee

!-allyl-4 "

unfavorable
P Pd P directs attack to one end of !-allyl
H Me Fe N Me PPh2 PPh2 OH

O Me Me

O Me

O Me

Ratio of attack from these orientations determines ee. These correspond to attack from attack opposite enantiofaces.

disfavored, larger group eclipses !-allyl

Hayashi in Catalytic Asymmetric Synthesis , Ojima, Ed.; Ch 7.1, p 325

O OR

O OR up to 86% ee
cat= O NH HN O 1/2 PdCl 2

1 mol% cat OAc Base

PPh2 Ph2P

O OR

0.8 mol% cat Base OC(O)OMe

O OR H 96% de 99% ee
Trost JACS 1997, 119, 7879

Model for Trost Ligand/Pd Systems!

R, R-Ligand!
O NH HN XO

!-allyl-5 "

P Pd

Flap Pd

In general, want LG to leave from and Nuc to attack from under ap! to minimize interaction w/wall!

H H
R

Wall

H H

Rationalization for stereochemical outcome with S,S-Ligand:!

Pd
O

Pd vs bad interaction
O O

Pd vs

3 possible orientations from under ap:! See Lloyd-Jones: JACS 2009, 131, 9945!

Trost ACR 2006, 39, 747!

Asymmetric Tsuji !-Allylation

O O O R Pd2dba3 (5 mol %) L (12.5 mol % THF, 25 oC via: O L O R PdL O -CO2 L Pd R O OTMS R O O Pd2dba3 (2.5 mol %) Ligand (6.25 mol %) THF, 25 oC OTMS Me n O Me n = 1; 94%, 86% ee n = 2; 96%, 79% ee n
see also: Trost 2005, 127, 2844!

!-allyl-6 "

O R O Ph2P L L Pd O R 96%, 88% ee O Me Me Me O Me N t-Bu

O LPd O R L Pd O

Pd R

94%, 92% ee

or

O R

red-elim

product O Me Me OTMS Me O O 79%, 91% ee O Me 99%, 81% ee O O (using dimethallyl carbonate)

O R

R = Me; 95%, 87% ee R = Et; 96%, 92% ee

OTMS Me

Stoltz JACS 2004 126, 15044

Total Synthesis of (+)-Dichroanone

Me O O Me Me O 2.5% Pd2dba3 6.25% (S)-t-BuPhox THF, 23 C, 30 min 83% 91% ee Me

!-allyl-7 "

O Me Me

O N t-Bu (S)-t-Bu-PHOX Me PPh2

O Me

OH Me Me O

Me (+)-Dichroanone

Stoltz JACS 2006, 128, 7738

Asymmetric Alkylation-Type 2
[ClPd(!3-allyl)]2 L2*, cat KOAc CH2(CO2Me)2, BSA, CH2Cl2, 23 C Me N L2* = N N

!-allyl-8 "

Ph H OAc

Ph

Ph MeO2C

Ph CO2Me

O tBuMe2Si

O SiMe2tBu

Pfaltz proposes:
X N R Ph

Me N Pd N R Ph X RPh H Pd Ph H R

steric interactions lead to lengthening of C-Pd -- this end is selectively attacked

Pfaltz Acc. Chem. Res. 1993, 26, 339 Williams Tetrahedron: Asymmetry 1992 3, 1089 Hayashi in Catalytic Asymmetric Synthesis, Ojima, Ed.; Ch 7.1, p 325

Asymmetric Alkylation-Type 2
O Ph2P N Ph2P N R'O 1 % [ClPd(!3-allyl)]2 / L2* cat R' MeO2C R' CO2Me R' R % ee O Pri O N PPh2

!-allyl-9 "

R R = Me, Bu, iPr, Ph, tBu R' OAc R'

Ph Ph 99 Me tBu 71 nPr tBu 69 iPr tBu 96

O Ph2P N Pd 2.10

t-Bu

2.24 Electronic Effect: Ph2Ph moiety is more "-accepting that the C=N moiety, causing lengthening of Pd-C bond which is trans to it (trans effect). This causes a greater positive charge density on this carbon and directs nucleophilic attack to it.
Pfaltz ACIEE 1993, 32, 566 and personal communication,Helmchen TL 1993 34, 1769, 1994, 35, 1523, Williams TL 1993 34, 3149, Synlett 1996, 705

Asymmetric Alkylation - Type 2

E 2.5 % n OAc E 0 C, CH2Cl2 THAB = hex4N+BrPdCl 2 E E 2 L= Ph2P O NHHN O PPh2 E E E 99 86 /L E Yield % 81

!-allyl-10 "

ee % 98

96

93

Yield % n OAc '' O NK O 1. NH2NH2 EtOH, ! 2. aq. HCl, ! H3N Cl 87

ee % 94

95 H3N Cl 84 H3N Cl

97

98

Suggests nature of the ion pair very important

Trost JACS 1994, 116, 4089

Asymmetric Alkylation-Type 3
Me OAc Me PhCH2NH2 [Pd2(dba)3CHCl3 /L2*] HNBn 0 C, THF 84 % ee OAc Me (R) PdL2* Me PdL2* + Me 97 : 3 Me H PdL * 2 H H L2*Pd H N(H)Bn L2*= Fe

OH H Me N Me PPh2 PPh2

!-allyl-11 "

OH

Me

Interconversion of (R) and (S) via !"#"! rearrangement is fast relative to nucleophilic attack.

Me (S)

Me Me Me P I Me Note: I and II are diastereomeric. H Me H # P Pd P Me ! H Me P Pd P Me Me P Pd H Me P P Pd # H H rotation Me

Me

II H Hayashi, Ito TL 1990 31, 1743, Hayashi in Catalytic Asymmetric Synthesis, Ojima, Ed.; Ch 7.1, p 325

Me Me Me P I Me H Me H " P Pd P Me H ! Note: I and II are diastereomeric and are of differing energy and reactivity. H Me P Pd P Me II Me P Pd H Me P P Pd " H H rotation Me

!-allyl-12 "

Me

Attack of diastereomeric !-allyls leads to enantiomeric products

Me Me P I H Me Me P II Me P Pd Me P P Pd Me H Me N(H)Bn H P Pd H Me P Pd H N(H)Bn Me H Me N(H)Bn

Me

H2NBn

Me

(R)

H2NBn

Me

(S)
N(H)Bn

Asymmetric !-Allyl Additions With Iridium Catalysts

R OCO2Me
+ R1R2NH

!-allyl-13 "

1 mol% [(COD)IrCl]2
2 mol% ligand

NR1R2 R
Ph N O N Ph

75%, 97% ee
Ph Bn n-Pr

76%, 97% ee

PNB Ph

NH

80%, 94% ee
Ph

91%, 96% ee

N Ph

n-Hexyl

88%, 96% ee
Ph

NEt2

92%, 97% ee

83%, 97% ee

66%, 95% ee

MO R OCO2Me

+ Li+ > Na+ > R3N

Me Ph Me O Ph

1 mol% [(COD)IrCl]2

OAr R
O OMe O Me O n-Pr

2 mol% L

Hartwig JACS,
R OAr 2002, 124, 15164,

2003, 125, 3426

L Ir P N Ph

O O Me Ph

O O

P N Me Ph Ph

O Ph

A Feringa Ligand

87% 95% ee

88% 97% ee

65% 94% ee

86% 90% ee

Hartwig has subsequently demonstrated that the true catalytic species has a cyclometallated structure, related to the complex shown. Use of this as a precatalyst gives higher activity and broader scope. Hartwig JACS 2003, 125, 14272

Intramolecular version: Helmchen CC 2004, 896!

[Ir(COD)Cl]2 R X L* HNu, base THF, RT R NHBn Ph 61%, 97% e.e.

For amine add n!

Me

Nu *

MeO2C Ph

CO2Me

O P N O

Me Me Me

87%, 90% e.e.

related ligand: Alexakis Org Lett 2004, 6, 3529!

Helmchen CC 2004, 116

Modified ligand gives best results. Alexakis OL 2005, 7, 1621

Ir-Catalyzed Enantioselective Allylation of Aromatic Amines

N(H)Ar R1

!-allyl-14 "

1% [Ir(cod)Cl]2 2% Ligand R1 OCO2Me H2NAr 10-50% DABCO, THF 2-16 h, rt R1

(major)

N(H)Ar

(minor)

Br HN Ph 66%, 94% ee

Me HN Ph Me

Me N Ph 90%, 95% ee Ph 89%, 96% ee Ph O P O Me Me Ph Ligand N

82%, 96% ee

DABCO needed to form iridacycle Hartwig ACIE 2004, 43, 4797

!-allyl-15 "

Asym Alkylation Type 3-Vinyl Glycinol Synthesis

L racemic O very cheap 2.5 mol% (5 mol% Pd) CH2Cl2 cat Na2CO3 99% yield 98% ee Pd L O O N H O NH H NH H OH L Pd L O I High ee indicates that I fast L Pd L II II equilibration very fast Trost ACIEE 1996, 35, 99 Trost JACS 2000, 122, 5968 H3N H O (S,S)-ethambutol CO2(R)-vigabatrin OH 68% ee in THF O NH HN O PdCl OH 2 O N O 75 + O N O OH 1

O NH O more acidic than simple amine or amide; better Hbonder -directs regiochemistry

Ph2P PPh2

Preparation of an Intermediate in the Total Synthesis of Terpestacin

O OH Me Me O (racemic) 1% Pd2dba3CHCl3, 2.6% Ligand 50% Bu4NCl CH2Cl2, TIPSOTf, 2,6-lutidine 95%, 88-96% ee O O Me OTIPS Me

!-allyl-16 "

Me O O ! HO Me Me OTIPS HO Me Me Terpestacin OH HO Me

Trost JACS 2007, 129, 4540

Asymmetric Alkylation-Type 4-1

O O O Ts(H)N O O N Ts *L2Pd Ts N O O + *L2Pd O PdL2* N(H)Ts L2*Pd(0) O O N(H)Ts O Ionization determines enantioselectivity O N(H)Ts CO2 + TsNH2 L2*= O Ph2P Ph Ph O

!-allyl-17 "

NH HN

PPh2

:N(H)Ts
O O

RO B As the ionization occurs, the Pd (with all of its ligands) rotates so that it can form a less severe !3-"-allyl. When this occurs, part of the interaction ligand is placed over the substrate. Depending on which direction the rotation occurs, a differing degree of unfavorable B steric interaction will result. The process occurs via the lowest energy path, which determines the direction of rotation. Clockwise Rotation

S Pd

B OR S Counterclockwise Rotation

more severe interaction

S Pd S

OR B

RO S B

B S Pd

Trost JACS 1992, 114, 9327 Added base significantly improves the process: Trost JOC 1998, 63, 1339

Asymmetric Alkylation-Type-4-2
CO2Me BzO OBz CO2Me BzO 3 / Pd2(dba)3CHCl3 CO2Me CO2Me

!-allyl-18 "

93 % ee

Intermolecular intermolecular!
PhCH2N(H)CH3 2 / Pd2(dba)3CHCl3 Bn

Me N OBz 95 % ee

Trost JACS 1992, 114, 9327

BzO Pd O OBz

BzO Pd O Nuc
Trost ACS 2006, 39, 747!

OCONHTs steps

HO

H N

OH OH Trost Chem. Eur. J. 1999, 5, 3279

OCONHTs

99% ee

O O

NTs (-)-Swainsonine

Applications in Total Synthesis

G= OTBDMS
OPPh2

!-allyl-19 "

OTBDMS OCO2allyl + N(H)Ts Br

OPPh2

G Ts N Br

G= CN 2% Pd(OAc)2 MePPh2, Ag2CO3 DMSO, 90 C 87% Heck

Pd2dba3CHCl3 (5.6% Pd) !-allyl

75%, 84% ee

G= CN NBOC G= N(H)BOC 10% Pd(OAc)2 40% BQ, MnO2 HOAc Wacker

N Ts H

N Ts H

N I

Me

10% Pd(OAc)2 BuN+ClK2CO3/ DMF Jeffrey-Heck

N H H

Me

H N (-)-Tubifoline

Me

Mori Org Lett 2001, 3, 1913

!-allyl-20 "

Applications in Total Synthesis

Me TESO OTES O Me O Me Me TMSO O O Ot-Bu 80 % Sorensen JACS 2002, 124, 4552 OMe Pd2(dba)3 (0.1 equiv) THF, 40 C, 12 h Me TESO Me O OTES Me OTMS Me O O (+) FR182877 t-Bu

Me MeO2CO Me Pd(PPh3)4, dppe THF MeO2C O O OTBS TBS H MeO2C O

OMPM

Me H H

O H

MPMO

H O TBSO 84 % OTBS O O OH

H (+)-macquarimicin A Tadano JACS 2003, 125, 14722

Total Synthesis of (+)- and (-)-Nigellamine A2

N Me O Me O Me LiN(TMS)2 EtO2C CO2Et Pd2dba3 (1.25%) L, quant, 95% ee O N Me H Me t-Bu (S)-t-Bu-PHOX O PPh2 Me O O H Me

!-allyl-21 "

Me

Me

O O Ph N O O

EtO2C

CO2Et (+)- and (-)-Nigellamine A2

Me

Ready JACS, 2006, 128, 7428

Application in Total Synthesis and Carbohydrate Synthesis

Highly recommended: Trost JOC 2004, 69, 5813 for a perspective and additional examples OH O N H + O AcO O [{(allyl)PdCl} ] (0.5 %), O Trost Ligand2(1.5 %) Et3N, DMF N H O N H O O O Me OH O TMC-69-6H Me

!-allyl-22 "

Me

65 %, 96 % ee

Frstner ACIEE 2003, 42, 5361 ROH O 0.5 % Pd2(dba)3CHCl3 2.5 % PPh3 OH O RO O OTBS NaBH4 CH3OH/CH2Cl2 - 78 C RO O OH OsO4/NMO HO O OTBS OH

BocO

O OTBS

CH2Cl2 or THF

t-BuOH/ H2O RO OTBS

O'Doherty JACS 2003, 125, 12406, JACS 2004, 126, 12406, 3428 OMe allylacetate, (!3-C3H5PdCl)2 / L Me O L=
O

OMe

OH

DME, Cs2CO3, -15 C

PPh2 Ph2P HN N H O

Me O 90%, 91% ee Me N Me Me Metazocine

Trost JACS 2003, 125, 8744