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