Trost’s Palladium Catalysed Asymmetric Allylic Alkylation (Pd-AAA)

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Trost’s Palladium Catalysed Asymmetric Allylic Alkylation (Pd-AAA) 1 Literature Meeting Charette’s group Miguel St-Onge October 9 th , 2007

description

Trost’s Palladium Catalysed Asymmetric Allylic Alkylation (Pd-AAA). Literature Meeting Charette’s group Miguel St-Onge October 9 th , 2007. Presentation. Trost and Palladium p - allyl complexes Stereochemistry of oxidative addition and nucleophilic attack Counter anion effects - PowerPoint PPT Presentation

Transcript of Trost’s Palladium Catalysed Asymmetric Allylic Alkylation (Pd-AAA)

Page 1: Trost’s Palladium Catalysed Asymmetric  Allylic Alkylation (Pd-AAA)

Trost’s Palladium Catalysed Asymmetric

Allylic Alkylation(Pd-AAA)

1

Literature MeetingCharette’s group

Miguel St-OngeOctober 9th, 2007

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Presentation

1. Trost and Palladium2. -allyl complexes

i. Stereochemistry of oxidative addition and nucleophilic attack

ii. Counter anion effectsiii.Syn vs anti complexesiv. Nucleophilic approach on allyl terminus

3. Ligands and cartoon model4. Classes of enantiodiscrimination processes5. Types of nucleophiles and their application

to total synthesis6. Exceptions to the model7. AAA with other metals8. Total synthesis of Tipranavir9. Conclusion

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Pr. Barry M. Trost

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Born in 1941 in Philadelphia Received B.A. From University of Pennsylvania (1962) Received Ph.D. at MIT under H.O. House’s supervision (1965) Professor of chemistry at University of Wisconsin (1969)

Vilas research professor of chemistry (1982) Professor of chemistry at Standford University (1987)

Takami professor of humanities and sciences (1990) 803 publications (2006) 38 honors and awards 14 Patents

Barry Trost web page at www.stanford.edu/group/bmtrost

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Palladium

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•Discovered in 1803 by William Hyde Wollaston •Isolated from (NH4)2PtCl6 •Name comes from Greek goddess of wisdom, Pallas or Palladion•Atomic number 46•[Kr] 4d10

•Pd0 = 18e square planar complexes•Pd(II) = 14e square planar complexes

PdPPh3Ph3P

Ph3P PPh3Pd

Cl

Cl NCMe

NCMe2+

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-Allyl Palladium Complex and C-C Bond Formation

5

LGM M

or M

Nu

A

B

AB

M

M

Nu

NuNu

LG = OAc, Cl

A = soft NuB = Hard Nu

Trost, B. M.*; Weber, L. J.Am.Chem.Soc. 1975, 97, 1611-1612.

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Trost’s Study

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PdCl2,NaCl, CuCl2, NaOAc, HOAc, 60°C, 75 min, 55%

PdCl2

PdCl2

A

B

C

D

PdCl2

PdCl2

PdCl2

DIPHOS, THF, r.t, 16hr, 69%

O O M+

H

CO2Me

CO2MeMeO2C

CO2MeH

OR

D

Trost, B.M; Weber, L. J. Am. Chem. Soc. 1975, 97, 1611-1612

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Study conclusion

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LiI, NaCN, DMF,120°C, 10 hr, 80%

H

CO2Me

CO2Me H

CO2Me

1) OsO4, ether, pyridine,r.t., 15 hr

2) TsOH, benzene,reflux, 0.5 hr, 64%

(2 steps)O

O

OHMe

H

O

O

OAcMe

HO

O

OAcH

MeOR

Conclusions: -Stereospecificity of allylic alkylation has potentially important consequences in the application of the method for the creation of stereochemistry in acyclic and macrocyclic systems.- Alkylation occurs on the face of the -allyl unit opposite to that of the palladium and use of soft nucleophiles are required for successful alkylation

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Stereochemistry of Oxidative Addition

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Ph

OAc1) PdCl2(dppe), PPh3, DIBAL-H Et2O, r.t., 12h2) NaBF4

Ph

PdPh2P PPh2

BF4

(S)-(E)-3-acetoxy-1-phenyl-1-butene(+)-(1R,2S,3S)

20D +57o (c = 0.8 in CHCl3)

Ph

PdPh2P PPh2

BF4

(-)-(1S,2R,3R)

Ph

PdCl Cl

(1S,2R,3R)

dppe, NaBF4CHCl2

D20 = -105o (c = 1.1, CHCl3)

Hayashi, T.*; Hagihara, T.; Konishi, M.; Kumada, M. J. Am. Chem. Soc. 1983, 105, 7768-7770.

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Stoichiometric vs Catalytic

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Ph

PdPh2P PPh2

BF4NaCH(CO2Me)2, THF

Ph

CH(CO2Me)2

Ph

CH(CO2Me)2

76%, 38% ee

47% ee

6%

+

Ph

OAc NaCH(CO2Me)2, THF(+)-(1R,2S,3S) (1 mol%)

Ph

CH(CO2Me)2

Ph

CH(CO2Me)2

90%, 58% ee 7%

+

58% ee

Conclusions:- Oxidative addition of palladium proceed with inversion of configuration and addition on -allyl palladium proceed also with inversion of configuration. - Net retention of configuration also occurs in enantiomeric catalytic system

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Catalytic Cycle

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PdL L Ph

X

Pd LL

PhPd

L L

Nu

PdLL

Nu X

Nu

Complexation

Oxidative addition(ionization)Nucleophilic addition

Decomplexation

Ph

PhPh

X

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Counter Anion Effects

11Amatore, C.; Jutand, A.; M’Barki, M. A.; Meyer, G.; Mottier, L. Eur. J. Inorg. Chem. 2001, 873.Cantat, T.; Génin, É.; Giroud, C.; Meyer, G.; Jutand, A.* J. Org. Chem. 2003, 687, 365-376.

PhPd

L L

+2L, + MY-2MCl

PdCl2

Ph

Pd

Cl Cl

Pd

Ph

Ph

X

Y = BF4, PF6, TfO, TsO

Y

Ph

PdCl

L L

Ph

PdCl

L L

2L Cl

Ph

OAc

Ph

Cl + Pd0L4

+ 2L+ Cl-OAc

Pd0(dba)2+

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Syn Complex vs Anti Complex ( equilibration)

12Trost, B.M.; Machacek, M.R.; Aponik, A. Acc. Chem. Res. 2006, 39, 747-760.

Rsyn

H

HH

R Pd

110o

Syn complex

Rsyn

H

HH

R

Pd

L

LX

+

+X-X

+X

-X

Rsyn

H

H

H

R

Pd X

+

Pd

+

Rsyn

H

HH

R

Syn complex

H

H

H

Ranti

R

Pd X

+

Rsyn

HH

H

R

Pd

L LX

+

H

H

H

Ranti

R

Pd

+

+X

-X

L LL L

LL LL

+X

-X

Anti complexUnfavorable A1,3

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Nucleophile Approach

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• Nucleophile addition is considered as a SN2-like displacement• Attack must be anti to the Pd leaving group (180o)• High impact for ligand working model analysis

R

R

H

H

H

Pd

Nu

Exo approach

R

R

H

H

H

Pd

Nu

endo approach

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Allyl Terminus

Less substituted terminus More substituted terminus

Trost, B.M.; Machacek, M.R.; Aponik, A. Acc. Chem. Res. 2006, 39, 747-760.

PdLL

RR

PdLL

R

PdLL

Nu

Nu

Ligand Sterics

PdLL

RR

PdLL

R

PdLL

R

PdLL

Nu R

PdLL

Nu

Ligand Electronics

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Redesign Catalytic Cycle

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PdL L

Ph

X

PdLL

PhPd

L L

Nu

PdLL

Nu X

Nu

Complexation

Oxidative addition(ionization)Nucleophilic addition

Decomplexation

Ph

PhPh

X

Ph

PdCl

L L

Ph

PdCl

L L

Ph

Nu

PdL L

or

Ph

Nuor

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Successful Ligands

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N

CN

NR R

H

Pfaltz

R= CO2Me, CH2OSiMe2t-Bu,CMe2OH

PPh2

P(Cy)2

FeCp

Togni, Spindler

Ph2PO

i-PrSt-Bu

Evans

PPh2PPh2

S

Faller

SPh N

NPh

Ph

Morimoto

Tognie, A.; Breutel., C.; Schnyder, A.; Spindler, F.; Landert, H.; Tijani, A J. Am. Chem. Soc. 1994, 116, 4062-4066.Pfaltz, A Acc. Chem. Res. 1993, 26, 339-345.Evans, D.A.; Campos, K.R.; Tedros, J.S.; Michael, F.E.; Gagné, M.R. J. Am. Chem. Soc. 2000, 122, 7905-7920.Faller, J.W.; Wilt, J.C. Organometallics, 2005, 24, 5076-5083.Morimoto, T.; Tachibana, K.; Achiwa, K. Synlett, 1997, 783-785.

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Trost’s Classic Ligands

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HNNHO

Ph2P

O

PPh2

(R,R)-Standard

HNNHO

Ph2P

O

PPh2

(R,R)-Naphthyl

Ph Ph

HNNHO

Ph2P

O

PPh2

(R,R)-Stillbene

NHHN OO

PPh2

Ph2P

(R,R)-Anthracenyl

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Pd

Nu Nu

Cartoon Model

18Trost, B.M.; Toste, F.D. J. Am. Chem. Soc., 1999, 121, 4545-4554.Lloyd-Jones G.C. Et. Al. Pure Appl. Chem., 2004, 76, 589-601.

HNNHO

P

O

PPd

H

H

Pd complex with (R,R)-Standard Ligand

Flap

WallR

PdH

HR

HNNHO

P

O

PPd

Flap

Wall-LG -LG

Page 19: Trost’s Palladium Catalysed Asymmetric  Allylic Alkylation (Pd-AAA)

Classes of Enantiodiscriminating Processes

Ionization of the leaving group• Class A- Desymmetrization of

meso diester• Class B- Desymmetrization of

prochiral leaving group on the same carbon

• Class C- Unsymmetrical -allyl Pd complexes (achiral)

Addition of the nucleophile • Class D- Meso-like -allyl

Pd complex• Class E- Unsymmetrical -

allyl Pd complexes (chiral)

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Rsyn

HH

H

R

Pd

Syn complex

Pd

+

Rsyn

H

HH

R

Syn complexLL

LL

+

PhPd

L L

Nu

PdLL

Ph

Ph

Nu

PdL L

orVs Nu

Page 20: Trost’s Palladium Catalysed Asymmetric  Allylic Alkylation (Pd-AAA)

Class A- Desymmetrization of meso Diester

20

OBz

SO2PhO2NNa

+O BzBz

(R,R)-Standard (4 mol%)(-allylPdCl)2 (1 mol%)

10% n-Bu4NBrCH2Cl2/H2O, 91%, 93% ee

O BzNu

Pd

OBn

Matched exo ionization

Nu

Matched exo addition

OBzPd

OCONHTs

OCONHTs(R,R)-Standard (8 mol%)

Pd2(dba)3. CHCl3

Et3N, THF 85%, > 99% ee

Pd

O

NTsO

ONTs

O

*No Et3N: 92%, 85% eeTrost, B.M.; Dudash, J., Jr.; Dirat, O. Chem-Eur. J. 2002, I81, 259-268.Trost, B.M.; Patterson, D.E., J. Org. Chem., 1998, 63, 1339-1341.

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Class B- Desymetrisation of Prochiral Leaving Group on the Same Carbon

21

PdH

R

RR`

HOAcOAc

R`

OAc

H

SYN, ANTI

PdH

RR`

H

OAc

SYN, SYN

+

+

RR`

OAc

SO2Ph

SO2Ph

Conditions:(R,R)-Standard (4 mol%)(-allylPdCl)2 (1 mol%)

10% n-Bu4NBrCH2Cl2/H2O,

73-91%, 85-93% ee

Trost, B.M.; Lee, C.B. J. Am. Chem. Soc. 1998, 120, 6818-6819.

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Class B- Desymmetrization of Prochiral Leaving Group on the Same Carbon

Ph

HOAcOAc Ph

CO2Me

CO2Me

Na+

(R,R)-Standard (7.5 mol%)(-allylPdCl)2 (2.5 mol%)

THF, r.t. Ph

OAc

E EPh

0% n-Bu4NBr : 75%, 95% ee1 eq n-Bu4NBr : 28%, 51% ee

HOAcOAc Ph

CO2Me

CO2Me

Na+

(R,R)-Standard (7.5 mol%)(-allylPdCl)2 (2.5 mol%)

THF, r.t. TBSO

OAc

E EPhTBSO

1.2 equiv. of Nu : 58%, 80% ee 4 equiv. of Nu : 98%, 90% ee

Trost, B.M.; Lee, C.B. J. Am. Chem. Soc. 1998, 120, 6818-6819.

Page 23: Trost’s Palladium Catalysed Asymmetric  Allylic Alkylation (Pd-AAA)

Class C- Unsymmetrical -Allyl Pd Complexes (Achiral)

23

O

TMS

NHTs

NO2(R,R)-Standard (6 mol%)(-allylPdCl)2 (2 mol%)

DBU, DCM, r.t. NTs

HPd

+

Matched ionization Mismatched addition

90%, 91% ee

TMS

TsN

Trost, B.M.; Machacek, M.R. Angew. Chem., Int. Ed. 2002, 41, 4693-4697.

Page 24: Trost’s Palladium Catalysed Asymmetric  Allylic Alkylation (Pd-AAA)

Class C- Unsymmetrical -Allyl Pd Complexes (Achiral)

24Trost, B.M.; Machacek, M.R. Angew. Chem., Int. Ed. 2002, 41, 4693-4697.

O

TMS NO2(R,R)-Standard (6 mol%)(Pd2dba3CHCl3 (2 mol%)

Et3N, DCM, 0oC O

HPd

+

Matched ionization

Mismatched addition

n= 1: 84%, 76%een= 2: 80%, 94%ee

TMS

OH

HO ( )n n( )

Pd

+

H

HO

TMS

Matched addition

Page 25: Trost’s Palladium Catalysed Asymmetric  Allylic Alkylation (Pd-AAA)

Class D- Meso-like -Allyl Pd Complex

25Trost, B.M.; Dudash, J., Jr.; Hembre, E.J. Chem.-Eur. J. 2001, 16, 1619-1629.

OTroc

OTroc

OTroc

OTroc

OTroc

OTroc

OTroc

OTroc

TrocOOTrocTrocO

OTroc

Pd

TrocOOTroc

TrocO

OTrocPd

Pd

TrocO OTrocOTroc

Mismatch ionization

Match ionization

Fast

Slow

Racemic

Conditions(R,R)-Standard (7.5 mol%)(-allylPdCl)2 (2.5 mol%)

20% THAB, NaOH 1M, DCM, r.t.

Page 26: Trost’s Palladium Catalysed Asymmetric  Allylic Alkylation (Pd-AAA)

Class D- Meso-like -Allyl Pd Complex

26

Pd

TrocO OTrocOTroc Match

OTroc

OTroc

OTroc

OCOPh

PhCOO

PhOCOOTrocTrocO

OTroc

PdMatch

Pd

PhOCO OTrocOTroc

PhCOO

Match

OCOPh

OTroc

OTroc

OCOPh

90%, >99% ee

Match

Trost, B.M.; Dudash, J., Jr.; Hembre, E.J. Chem.-Eur. J. 2001, 16, 1619-1629.

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Class E- Unsymmetrical -Allyl Pd Complexes (Chiral Acyclic Substrate)

27Trost, B.M.; Bunt, R.C.; Lemoine, R.C.; Calkins, T.L. J. Am. Chem. Soc. 2000, 122, 5968-5976.

RO

PdR

OH

PdR

OH

NO

O

NO

O

at 1oC

Mismatch Match

OHRN

O

O

Match

Conditions(R,R)-Naphthyl (1.2 mol%)(-allylPdCl)2 (0.4 mol%)

5% Na2CO3

R=H, 94%, 98%eeR=Me, 72%, 87%ee

Page 28: Trost’s Palladium Catalysed Asymmetric  Allylic Alkylation (Pd-AAA)

Class E- Unsymmetrical -Allyl Pd Complexes (Chiral Cyclic Substrate)

28

Conditions(R,R)-Standard (7.5 mol%)Pd2dba3CHCl3 (2.5 mol%)30% nBuN4Cl, DCM, r.t.

OO OBOC

OO OBOC

OOEtO

MeO OH

O

O

PdO

O

PdO

MM

MO

OEtO

MeO O

O

O O

89%, >95%ee

50%

50%

Trost, B.M.; Toste, F.D. J. Am. Chem. Soc. 2003, 125, 3090-3100.

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Lactone Isomerization

29Trost, B.M.; Toste, F.D. J. Am. Chem. Soc. 2003, 125, 3090-3100.

O

PdO

O

PdO

Pd

OO OBOCOO OBOC

OO

OOL2Pd

PdL2

OOPd

+ +

+

PdL2

Page 30: Trost’s Palladium Catalysed Asymmetric  Allylic Alkylation (Pd-AAA)

Chirality at the Nucleophile

30Trost, B.M.; Radinov, R.; Grenzer, H.M. J. Am. Chem. Soc. 1997, 119, 7879-7880.Trost, B.M.; Schroeder, G.M.; Kristensen, J Angew. Chem., Int. Ed. 2002, 41, 3492-3495.

Pd

OO

O

Pd

OOO

Pd

O OO

OAc(R,R)-Standard (1.2 mol%)( allylPdCl)2 (0.5 mol%)

Tol., r.t.86%, 86%ee

O O

O

O O

O +

Other nucleophile:O

N

O O

OO

90%, 93%ee99%, 88%ee 82%, 84%ee 94%, 82%ee

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Carbon Nucleophiles in Total Synthesis

31

BzO

OBz

P N

OMe

OO

1) Ligand (8 mol%),(()-allylPdCl)2 (2 mol%),

THF, r.t., 2) LDA, Nu

THF, -60oC, 8hO

O

Br

HN O

MeO2C

O

O

Br

HN

OCO2Me

OBz

83%, 99% ee

5 stepsN

O

O

H H H

(+)--Lycorane41%, >99 %ee

Chapsal, B.D.; Ojima, I. Org. Lett., 2006, 8, 1395-1398.

Malonate type:

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Carbon Nucleophiles in Total Synthesis

32

SO2PhO2N +

(R,R)-Standard (0.25 mol%)(-allylPdCl)2 (1 mol%)

THF/H2O, NaHCO3BzO

OBz

BzO

SO2Ph

NO2

NOSO2Ph

O

87%, > 99% ee

13 stepsOH

OH

NH2

HO

HO

(+)-valienamine2% yield

Sulfone Type:

O O

Ph

O

Ph

(R,R)-StandardPd2dba3

.CHCl3CH3NO2, CH2Cl2, BSA

O

PhNO2

75%, 99% ee

SiO N

Si

Trost, B. M.; Chupak, L. S.; Lubbers J. Am. Chem. Soc. 1998, 120, 1732-1740.Trost, B. M.; Surivet, J.-P. Angew. Chem., Int. Ed. 2000, 39, 3122-3124.

Nitro type:

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Oxygen Nucleophiles in Total Synthesis

33

Primary alcohols:

O

C9H19

(S,S)-Standard (3 mol%)Pd2dba3

.CHCl3 (1 mol%)BEt3 (1 mol%), PMBOH

CH2Cl2, r.t., 24h

HOC9H19

OPMB

74%, 99% ee

7 Steps HOC9H19

OMe

O

(-)-malyngolide12.5% overall yield

antibiotic

Trost, B. M.; Weiping, T.; Schulte, J. L. Org. Lett. 2000, 2, 4013-4015.Trost, B. M.; Kondo, Y. Tet. Let. 1991, 32, 1613.

OCO2CH3

CO2CH3 (R,R)-Standard (3.75 mol%)(-allylPdCl)2 (1.25 mol%)

CH3CH2COONa(C6H13)4NBr (1 mol%)H2O/CH2Cl2, r.t., 2.5h OCOEt

CO2CH3

95%, 98% ee

OO

O

OPh

H

H

O

phyllanthocinAnti tumor agent

Carboxylates:

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Oxygen Nucleophiles in Total Synthesis

34

Phenols

OO

OH

O

(S,S)-Anthracenyl (7.5 mol%)Pd2dba3

.CHCl3 (2.5 mol%)THF, r.t.

+ OCO2Me

OO

O

O

92%, 98% ee

OO

O

O

R2

R1(-)-calanolide A, R1 : H, R2 : OH

(-)-calanolide B, R1 : OH, R2 : H

4 Steps

6 Steps

anti-HIV compound

Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 1998, 120, 9074-9075.Trost, B. M., Tang, W. J. Am. Chem. Soc., 2002, 124, 14542-14543.

OCO2CH3

MeO

Br

CHO

72%, 88% ee

11 Steps

MeN

OR

OH

(-)-codeine, R = CH3

(-)-morphine, R = H

Page 35: Trost’s Palladium Catalysed Asymmetric  Allylic Alkylation (Pd-AAA)

Nitrogen Nucleophiles

35Trost, B. M.; Krische, M. J.; Radinov, R.; Zanoni, G. J. Am. Chem. Soc. 1996, 118, 6297-6298.You, S. L.; Zhu, X. Z.; Luo, Y. M.; Hou, X. L.; Dai, L. X. J. Am. Chem. Soc. 2001, 123, 7471-7472.

MeO

NH OAc (R,R)-Standard (1 mol%)(-allylPdCl)2 (3 mol%)THF, Et3N, -45oC, 2.5h

MeO

N

97%, 91% ee

R

OAc Ligand (4 mol%) (-allylPdCl)2 (2 mol%)

BnNH2, CH2Cl2Fe

P N O

PhEt2N

R

NHBn

R = ArO

OH94%, 98% ee, 97/3 (Br./Li.)

• Mono versus bisalkylation of primary amines• Regioselectivity on Pd -allyl system• Speed of nucleophile versus equilibration

Amines

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Nitrogen Nucleophiles in Total Synthesis

36

Azides

O

O

OCO2Me

OCO2Me

(S,S)-Standard (0.75 mol%)(-allylPdCl)2 (0.25 mol%)

TMSN3, CH2Cl2, r.t.O

O

OCO2Me

N3

82%, 95% ee

O

O NH

OH

H

OHHO OH

OH

O

(+)-pancratistatin11% overall yield from diol

9 Steps

OCOPh

OCOPh

(S,S)-Standard (0.75 mol%)(-allylPdCl)2 (0.25 mol%)

TMSN3, THF, 0oC

OCOPh

N3

88%, 95% ee

N

Cl

(-)-epibatidine

7 Steps

Trost, B. M.; Pulley, S.R. J. Am. Chem. Soc 1995, 117, 10143-10144.Trost, B. M.; Cook, G. R. Tet. Lett., 1996, 37, 7485-7488.

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Nitrogen Nucleophiles in Total Synthesis

37

SulfonamideCO2Me

OCO2t-BuNH

TsLigand (7.5 mol%)

Pd2dba3.CHCl3 (2.5 mol%)

CH2Cl2, 0oC

TsN

CO2Me88%, 90% ee

TsN

4 Steps, 60%

(-)-anatoxin-A

HNNHO

N

O

PPh2

O

N H

H

H

HO

N

O

(-)-Strychnine

N

N

H

(+)-tubifoline

Trost, B. M.,; Oslob, J. D.; J. Am. Chem. Soc. 1999, 121, 3057-3064.Mori, M.; Nakanishi, M.; Kajishima, D.; Sato, Y. Org. Lett. 2001, 3, 1913-1916.

Page 38: Trost’s Palladium Catalysed Asymmetric  Allylic Alkylation (Pd-AAA)

Nitrogen Nucleophiles in Total Synthesis

38

Imides

Trost, B. M.,; Patterson, D. E.; Chem. Eur. J. 1999, 5, 3279Buschmann, N.; Rueckert, A.; Blechert, S. J. Org. Chem. 2002, 67, 4325-4329.

H

H

O NTs

O

H

H

TsHNOCO

OCONHTs (S,S)-Standard (7.5 mol%)Pd2dba3

.CHCl3 (2.5 mol%)DMSO, THF

80%, 99% ee

N

OHH OH

OH

(-)-swainsonine15 steps, 15% overall yield

TsHNOCO

TsHNOCO

(S,S)-Standard (7.5 mol%)Pd2dba3

.CHCl3 (2.5 mol%)Et3N, CH2Cl2

ONTs

O

95%, 97% ee

7 Steps

Page 39: Trost’s Palladium Catalysed Asymmetric  Allylic Alkylation (Pd-AAA)

Nitrogen Nucleophiles in Total Synthesis

39Trost, B. M.; Shi, Z. J. Am. Chem. Soc. 1996, 118, 3037-3038.Trost, B. M.; Madsen, R.; Guile, S. D.; Tet. Lett., 1997, 38, 1707-1710.

OCOPhPhOCO(S,S)-Stilbene (6 mol%)Pd2dba3

.CHCl3 (2 mol%)THF, r.t.

(R,R)-Stilbene (6 mol%)Pd2dba3

.CHCl3 (2 mol%)THF, r.t.+

N

N NH

N

Cl

OCOPh

N

N N

N

Cl

PhOCO

N

NN

N

Cl

OCOPh

N

N N

N

NH2

O O

ent-adenoside acetonide

85%, 93% ee

7 Steps

76%, 94% ee

3 Steps

N

NN

N

NH2

HO OH

HO

(-)-neplanocin

Page 40: Trost’s Palladium Catalysed Asymmetric  Allylic Alkylation (Pd-AAA)

Sulfur Nucleophiles Pd -AAA

40

R2

R1

OAc

OAc

R1 = H, alkylR2 = aryl, alkyl, ester

(R,R)-Standard (7.5 mol%)(-allylPdCl)2 (2.5 mol%)

CH2Cl2/H2O, THABNaSO2Ph

R2

R1

SO2Ph

OAc

79-94%, 85-99% ee

OCOPh

PhOCO

(R,R)-Standard (3.7 mol%)Pd2dba3

.CHCl3 (1.4 mol%)THF/H2O, NaSO2Ph, r.t.

SO2Ph

PhOCO

85%, single enantiomer

Trost, B. M.; Organ, M. G.; O’Doherty, G. A. J. Am. Chem. Soc. 1995, 117, 9662-9670.Trost, B. M.; Crawley, M. L.; Lee, C. B. J. Am. Chem. Soc. 2000, 122,6120-6121.

Page 41: Trost’s Palladium Catalysed Asymmetric  Allylic Alkylation (Pd-AAA)

Exceptions

41

OHMeO Br

CHO

TrocOCO2CH3

+

(S,S)-Stilbene (3 mol%),(()-allylPdCl)2 (1 mol%),

Et3N, CH2Cl2, r.t.72%, 88% ee

OCO2CH3

MeO

Br

CHO

Trost, B. M.; Toste, D. F. J. Am. Chem. Soc. 2000, 122, 11262-11263.Trost, B.M.; Machacek, M.R.; Aponick, A. Acc. Chem. Res. 2006, 39, 747-760.

TrocO

(S,S)-Stilbene (3 mol%),(()-allylPdCl)2 (1 mol%),

Et3N, CH2Cl2, r.t.

OCO2CH3

Br

CHO

Pd

+ +

Nu

Pd

OtrocCN

(R,R)-Standard (7.5 mol%),(()-allylPdCl)2 (2.5 mol%),

CH2Cl2, r.t.O

CN

OMe

NCNu

+

Page 42: Trost’s Palladium Catalysed Asymmetric  Allylic Alkylation (Pd-AAA)

Exceptions

42Trost, B.M.; Machacek, M.R.; Aponick, A. Acc. Chem. Rev. 2006, 39, 747-760.

OCO2CH3

Br

CHO

Rsyn

H

HH

R Pd

110o

Syn complex

R

R

H

H

H

Pd

Nu

Exo approach

Pd

+

CO2CH3Nu-

Pd

+

Rsyn

H

HH

Pd<110o

Syn complex

MeO

O

O

MeO

Pd

+

O

OMe

180oC

Nu (exo)

Page 43: Trost’s Palladium Catalysed Asymmetric  Allylic Alkylation (Pd-AAA)

Exceptions

43

OTBS

MeO

OTroc

+

TBSO

MeOPd

)(

Match ionization

+

Pd

Syn isomerization

R

+

Pd

Anti isomerization

RH

Slow

Fast

+

Pd

Anti isomerization

R

H

OTBS

MeO

OTBS

MeO OPMPOPMP

Match attack Match attack

100% conv., 19:1

A

B

C

D

(R,R)-Stilbene (9 mol%),(Pd2dba3CHCl3 (3 mol%),

n-Bu4NCl (30 mol%)PMP, CH2Cl2, r.t.

Trost, B.M.; Gunzner, J.L.; Dirat, O.; Rhee, Y. H. J. Am. Chem. Soc. 2002, 124, 10396-10415.

Page 44: Trost’s Palladium Catalysed Asymmetric  Allylic Alkylation (Pd-AAA)

AAA with Other Metals: Tungsten

44Lloyd-Jones, G.C.; Pfaltz, A. Angew.Chem., Int. Ed., 1995, 34, 462.Co, T.T.; Paek, S.W.; Shim, S.C.; Cho, C.S.; Kim, T.-J.; Choi, D.W.; Kang, S.O.; Jeong, J.H Organometallics, 2002, 22, 1475-1482.

Ar

OPO

EtOEtO

NaH(CO2CH3)2, THF, r.t.Ligand (10 mol%)

P

O

NPhPh

WCOOC

CO

NAr

CO2MeMeO2C 89%yield96:4 Br : l88% ee

R OAc

R = Ph Pr

DimethylmalonateLigand (15 mol%)THF or Dioxane

80oC, 24h

R NuR

Nu+

0%, 0%13%,23%

0%, 0%0%, 0%

PPh2

N

H

O

W(CO)4

FeCp

PPh2

N

H

O

W(CO)2(-C3H5)(I)FeCp

C3H5I

Page 45: Trost’s Palladium Catalysed Asymmetric  Allylic Alkylation (Pd-AAA)

AAA with Other Metals: Iridium

45

Ar OCO2Me + R1R2NH[(COD)IrCl]2 (1 mol%)

Ligand (2 mol%)THF, r.t., 2

O

OP N

Ph

Ph

Ar Ar NHR1R2

Ar NHR12

if R2 = H

+ +

1 2

3

Results: 58-92% yield

83/13/4 to 99/0/1>90 ee

Ohmura, T.; Hartwig J.F. J. Am. Chem. Soc. 2002, 124, 15164-15165.Kiener, C.A.; Shu, C.; Incarvito, C.; Hatrwig, J.F. J. Am. Chem. Soc. 2003, 125, 14272-14273.

O

O P

N

Ph Ph

IrCl

Page 46: Trost’s Palladium Catalysed Asymmetric  Allylic Alkylation (Pd-AAA)

Novel Iridium Utilisation

• Preparation of -Substituted Allylboronates by Chemoselective Iridium-Catalyzed Asymmetric Allylic Alkylation of 1-Propenylboronates- Peng, F.; Hall*, D. G. Tet. Lett. 2007, 18, 3305-3309

• Salt-Free Iridium-Catalyzed Asymmetric Allylic Aminations with N,N-Diacylamines and ortho-Nosylamide as Ammonia Equivalents- Weihofen, R.; Tverskoy, O.; Helmchen, G.; Angew. Chem., Int. Ed. 2006, 33, 5546-5549

• Very Efficient Phosphoramidite Ligand for Asymmetric Iridium-Catalyzed Allylic Alkylation- Alexakis*, A.; Polet, D.; Org. Lett. 2004, 20, 3529-3532

• Regio- and Enantioselective Iridium-Catalyzed Allylic Alkylation with In Situ Activated P,C-Chelate Complexes - Lipowsky, G.; Miller, N.; Helmchen, G. Angew. Chem., Int. Ed. 2004, 43, 4595 –4597

46

Page 47: Trost’s Palladium Catalysed Asymmetric  Allylic Alkylation (Pd-AAA)

AAA with Other Metals: Molybdenum

47

NO

O

Ph

RAr X

Ligand (15 mol%)C7H8Mo(CO)3 (10 mol%)

LiHMDSTHF, 65oC

HN

Me3Si SiMe3HNNH

O

N

O

N

+N

O

O

Ph

R

Ar

X = OCO2CH3

76 - 92% y.85 - 99% ee

96:4 - >98:2 dr

H

Ar

ON

Ph

R

OH

Ar

O

N

Ph

R

ONO

O

Ph

R

ArN

O

O

Ph

R

Ar

Favored Disfavored

Trost, B.M.; Dogra, K. J. Am. Chem. Soc. 2002, 124, 7256-7257.

Page 48: Trost’s Palladium Catalysed Asymmetric  Allylic Alkylation (Pd-AAA)

Molybdenum AAA Transition State

48

A

B

NNHO

N

O

MoOCOC

OC CO

Na

MeO OMe

ONa O

+ 2CO

MeO2C CO2Me

Ar OCO2Me

NaOCO2Me + 2CO

Krska, S. W.; Hughes, D. L.; Reamer, R. A.; Mathre, D. J.; Sun, Y.; Trost, B. M. J. Am. Chem. Soc. 2002, 124 (43), 12656-12657.

HNNHO

N

OMo(CO)4

NH

O

N

O

N

MoOC

Co

Ph

+ Ar X

AB

Page 49: Trost’s Palladium Catalysed Asymmetric  Allylic Alkylation (Pd-AAA)

Synthesis of Tipranavir (Aptivus)

49

OCl

1) EtMgBr, THF, 0oC2) NaOH 1M, Et2O, r.t.

86% over 2 steps

O (S,S)-Standard (3 mol%)Pd2dba3CHCl3 (1 mol%)

1 mol% Et3B, PMBOH (1 eq.).

OH

OPMB

Pd

*

OB

OPMB

PHI, 10mol% Pd(OAc)2,40 mol% P(o-Tol)3

Tol., Et3N, reflux, 92% 69%, 98% ee

OH

OPMB

Ph

OH

OPMB

Ph

5 mol% Pd/CH2 1 atm

MeOH, pyr.r.t., 99%

1) DMP, CH2Cl2, r.t.2) Ph3P=CH2, THF, reflux,

94% (two steps)OPMB

Ph

1) Cathecolborane(Ph3P)3RhCl, THF, 25oCNaOH (3N), H2O2 (30%)

2) DMP, CH2Cl2, r.t.88% (two steps

CHO

OPMB

Ph

Trost, B.M.; Andersen, N.G. J. Am. Chem. Soc. 2002, 124, 14320-14321.

Page 50: Trost’s Palladium Catalysed Asymmetric  Allylic Alkylation (Pd-AAA)

Synthesis of Tipranavir (Aptivus)

50

NO2

HO Boc2O, CH2CL2Et3N, DMAP (cat.)

r.t., 98%

NO2

BocO Mo(CO)3(C7H8) (10 mol%)Ligand (15 mol%)

dimethyl sodiomalonateTHF, reflux, 94%, 96% ee NO2

MeO2C

MeO2C

DMSO/H2ONaCl, 150oC, 100%

NO2

MeO2C

HNNHO

N

O

N

CHO

OPMB

Ph NO2

MeO2C+

1) NaHMDS, THF, -78oC2) DMP, CH2Cl2, r.t.

89% (two steps)

NO2

MeO2C

O

PMBO

Ph

1) CAN, CH3CN/H2O, 88%2) NaOH, MeOH,

4oC, 77%

NO2

O

OH

OPh

1) 5-CF3-2-pyridinesulfonylCl2) CH2Cl2, pyridine, DMSO,

-25oC, 92%HN

O

OH

OPh

SO2-p-CF3Ph

Trost, B.M.; Andersen, N.G. J. Am. Chem. Soc. 2002, 124, 14320-14321.

15 steps, 25%yield

Page 51: Trost’s Palladium Catalysed Asymmetric  Allylic Alkylation (Pd-AAA)

Conclusion

• High yields and enantioselectivities are obtain• 5 mechanisms for enantiodiscrimination• Diversity of bond type (C-C, C-O, C-N, C-S)• Chirality can be set at substrates, nucleophiles or both• AAA react with sp3 instead of sp2 centers• Transforms achiral, prochiral and more importantly

chiral racemic substrates into enantiopure compounds (through DYKAT)

• Cartoon model developped to predict final stereochemistry (almost no exceptions)

• Versatile method using mild conditions• Usefull central strategy for total synthesis• Scope have been expanded to other metals

51