TBDPS and Br-TBDPS Protecting groups as Efficient Aryl Group Donors in Pd-Catalyzed Arylation of Phenols and

Anilines

Huang, C.; Gevorgyan, V. J. Am. Chem. Soc. 2009, 131, 10844

Daniel Tzvi Cohen Short Literature

Feb. 23, 2010

Asymmetric Total Synthesis of (—)-Plicatic Acid via a Highly Enantioselective and Diastereoselective Nucleophilic

Epoxidation of Acyclic Trisubstituted Olefins

Sun, B.F.; Hong, R.; Kang, Y.B.; Deng, L. J. Am. Chem. Soc. 2009, 131, 10384

OH

OH

OHCOOH

OH

OH

MeO

HO

MeO

(—)-Plicatic Acid

(—)-Plicatic Acid Background

1. Gradner, J.A.F.; Barton, G.M.; Maclean, H. Can. J. Chem., 1959, 37, 1703

!Isolated from western red cedar (Thuja plicata) by MacLean1 in 1959

! The relative and absolute configurations were determined by X-ray crystallography and ORD

! Densely functionalized motif with contiguous quaternary-quaternary-tertiary stereocenters

! First total synthesis reported

OH

OH

OHCOOH

OH

OH

MeO

HO

MeO

(—)-Plicatic Acid

1

2

7

7'

88'

Retro-synthesis of (—)-Plicatic Acid

OH

OH

OHCOOH

OH

OH

MeO

HO

MeO

(—)-Plicatic Acid

1

2

7

7'

88'

OH

OH

OHCOOEt

OBn

OBn

MeO

BnO

MeO

OHCOOEt

OBn

OBn

MeO

BnO

MeO O

= Ar

OBnMeO

O

COOEt

Ar O

OBnMeO

O

COOEt

Ar

Asymmetric Nucleophilic Epoxidation of Various

Acrylate derivatives

1) Sun, B.F.; Hong, R.; Kang, Y.B.; Deng, L. J. Am. Chem. Soc. 2009, 131, 10384

2) Aoki, M.; Seebach, D. HelV. Chim. Acta 2001, 84, 187

R1 OR2

O O

R3

+ O

O Me

MeHOO

Ph

Ph

HO

Ph Ph

TADOOH

LiOH (0.1 eq.),THF

-40-0°C1.5-4 days

R1 OR2

O O

R3

O*

*

R1 = Aryl, ester

R2 = Ethyl, allyl

R3 = Aryl, alkyl

yield = 60-99%ee = 84- 96%

Stepwise Synthesis of (—)-Plicatic Acid

HO

MeO

1) NaH, BnBr, quant.

2) a) NMO, OsO4 (cat.) b) NaIO4, quant.

BnO

MeO

OSnCl2 (cat.)

N2CHCOOEt, 92%

BnO

MeO

O

CO2Et

+

BnO

BnO

OMe

CHO

Piperidine,PhCOOH

E/Z = 5:3recycled 80% of E

BnO

MeO

O

CO2Et

BnO

BnO

OMe

(S,S)-TADOOH

LiOH (cat.)83%, 98% ee

BnO

MeO

O

CO2Et

BnO

BnO

OMe

O

Mechanism to accesses !-keto-ester

Holmquist, C. R., Roskamp, E. J., JOC 1989, 54, 3258

N2OEt

O

R H

OLA

+R

O

LA

HOEt

O

N

N

Formal [1,2]

-N2

R

O

OEt

O

LA = BF3, ZnCl2, ZnBr2, AlCl3, SnCl4, GeCl2, SnCl2-2 H2O

Continued Synthesis of (—)-Plicatic AcidBnO

MeO

O

CO2Et

BnO

BnO

OMe

OTfOH (0.04 eq.), 0°C to rt.

70% cis 17% trans

MeO

BnO

MeO

OBn

O

CO2EtOH

OBnAr =Friedel-Crafts

MeO

BnO

Ar

O

CO2EtO

Si(Me)2CH2Br

ClSi(Me)2CH2Br, Imidazole75% (94% brsm)

SmI2, NiI2 (0.1 eq),

0°C, 58%

MeO

BnO

Ar

CO2EtOH

OH

Si(Me)2OH

Barbier reaction

Barbier Reaction Mechanism

SETR X M+ R X M(I)+

SETR M X

R2

R1

O

R MX

R2

R1

O

R MX

Concerted pathway

‡

R1 R2

R

OMX

Generation of Organometallic reagent

Radical (stepwise) pathway

O

R1

R2+

R MX

SET O

R1

R2

R MX

OMX

R1 R2

R

Final Steps in the Synthesis of (—)-Plicatic Acid

MeO

BnO

Ar

CO2EtOH

OH

Si(Me)2OH H2O2, NaHCO3

87% (90% brsm)

MeO

BnO

Ar

CO2EtOH

OH

OH

Fleming-Tamao-Kumada oxidation

n-PrSNa, DMF

97%

MeO

BnO CO2NaOH

OH

OH

OBn

OBn

MeO

H2, Pd/C, MeOH

then, Dowex-5072%

MeO

HO CO2HOH

OH

OH

OH

OH

MeO

Summary and Conclusions for the Synthesis of

(—)-Plicatic Acid

! First reported Total synthesis of (—)-Plicatic Acid

! Development of an enantioenriched epoxidation methodology using TADOOH

! Minimal use of protecting groups

! 12 steps ( 20 mg, 14% overall percent yield)

! Extensive spectroscopic and chromatographic analysis showed that the synthetic and

natural (—)-plicatic acid were indistinguishable

TBDPS and Br-TBDPS Protecting groups as

Efficient Aryl Group Donors in Pd-Catalyzed

Arylation of Phenols and Anilines

Huang, C.; Gevorgyan, V. J. Am. Chem. Soc. 2009, 131, 10844

Aryl-Aryl bonds

R1

R2

+

R2

R1

! Traditional methods of coupling are an arylhalide (or equivalent) and an arylmetal

! Recently C—H arylation methods have emerged, but there are limits

! Intermolecular reactions suffer from low reactivity and/or regioselectivity

!Directing groups or activating groups are sometimes hard to remove

Huang, C.; Gevorgyan, V. J. Am. Chem. Soc. 2009, 131, 10844

Chiral Biphenol-Based Monodentate PhosphoramiditeChiral Biphenol-Based Monodentate Phosphoramidite

LigandsLigands

Alexander, J. B., La, D. S., Cefalo,D. R., Hoveyda, A. Shrock, R. R.; J. Am. Chem. Soc. 1998, 120, 4041

OH

Me

Me

Me

Me

H2SO4, 80°C, 6 hrs

OH

Me

Me

Me

MeMe

quant.

K2Cr2O7

H2SO4, HOAc, 60°C

30-40%

OH

OH

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

OH

OH

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

R

O

O

R

R1

Me

Me

R1

P N

R2

R2

(R) or (S)

R

O

O

R

R1

Me

Me

R1

P N

R2

R2

Reported Here:

! Intramolecular aryl-aryl coupling with easily removable silicon tethers

!TBDPS used as an aryl donor for o-bromophenols via Pd-catalyzed intramolecular arylation

! Br-TBDPS used as an aryl donor for simple phenols and anilines

Rn

O Sit-Bu

Br

Ph

[Pd]

baseRn

O Sit-Bu

Ph

Rn

X Sit-Bu

Ph

[Pd]

base Rn

X Sit-Bu

Ph

X= O, NPh

Br

Silicon Motif1) Ease of deprotection (F- source)

Rn

X Sit-Bu

Ph

TBAF/THF

70°C Rn

X

X = OH or NHPh

91-100%

2) Easy access to deuteriated biaryls

Rn

O Sit-Bu

Ph

CsF, DMF, D2O

80°C, 46 hr Rn

OH

84%

D

3) Easy access to biphenols

O Sit-Bu

Ph

NaH, t-BuOOH, NMP

TBAF

OH

FF

HO95%

TBDPS used as an aryl donor for o-bromophenols

Rn

O Sit-Bu

Br

Ph

Rn

O Sit-Bu

Ph

Pd(OAc), 5 mol %, PCy3-BF4, 10 mol%,

PivOH, Cs2CO3,3Å MS, p-xylene, 140°C

O Sit-Bu

Ph

R

R= H, MeO,Cl, F

73-96%

O Sit-Bu

Ph

O Sit-Bu

Ph

O2N

F

51% 49%

O Sit-Bu

Ph

X

1) X=Y= tBu 30%

2) X= CHO, Y= MeO 52%

Y O Sit-Bu

Ph

83%

O Sit-Bu

Ph

100%

O Sit-Bu

Ph

F

59%

F

Br-TBDPS Used as an Aryl Donor

R

X Sit-Bu

Ph

R

X Sit-Bu

Ph

X= O, NPh

Br

Pd(OAc), 5 mol %, PCy3-BF4, 10 mol%,

PivOH, Cs2CO3,3Å MS, p-xylene, 140°C

O Sit-Bu

Ph

97% (10:1)

O Sit-Bu

Ph

100%

PhN Sit-Bu

Ph

77%

TBSO

O Sit-Bu

PhO Si

t-BuPh

98% (2.9:1)98% (2.9:1)

O Sit-Bu

Ph

99%

Summary & Conclusions

! Two intramolecular methods of Pd-catalyzed arylations of phenols and anilines

! TBDPS protecting groups can be used aryl donors for o-bromophenols

! Br-TBDPS can serve as a simple aryl group donor for simple phenols and anilines

! Incorporation of deterium on biaryls

!Preparation of o-biphenols by desilylation and oxidation