Decarboxylation of allylic β - Harvard...
Transcript of Decarboxylation of allylic β - Harvard...
M.C. White, Chem 253 ππππ-Allyl chemistry -224- Week of November 8, 2004
Decarboxylation of allylic β-ketoestersIndicate the mechanism of the following transformation:
O
O OPd2dba3 2.5 mol%PPh3 10-20 mol%
THF, rt
O
Pd0Ln O
O O
PdIILn
O
O
O
PdIILn
O
O
Pd0Ln
O
Tsuji Acc. Chem. Res. 1987 (20) 140.
CO2
M.C. White, Chem 253 ππππ-Allyl chemistry -225- Week of November 8, 2004
Allylic carbonatesPh O
O
OMe
Pd2dba3 2.5 mol%PPh3 10-20 mol%
THF, rt
note: no external base is needed
Ph
LnPdII
O
OMe
O
CO2
Ph
LnPdII
OMe
+
O
CO2Me
PPh3 Ph
LnPdII
PPh3
OMe
H
Ph
CO2Me
O90%
O
H
CO2MeMe
O
MeO2CMe
Chemoselectivity: allylic carbonates are more reactive towards Pd mediated oxidative addition than allylic acetates.
AcOOCO2Me
+
O
CO2Me
H
Pd2dba3 2.5 mol%PPh3 10-20 mol%
THF, rt
AcO
O
CO2Me
77%
no product corresponding to attack at the allylic acetate was observed.
Olefin geometry: anti/syn isomerization of the π-allyl intermediate occurs at a faster rate than nucleophilic attack.
OCO2Meneryl acetate (Z)
+
O
CO2MePd2dba3 2.5 mol%PPh3 10-20 mol%
THF, rt
O
CO2Me54%, (52:48 E/Z)
Tsuji TL 1982 (23) 4809.review: Tsuji Acc. Chem. Res. 1987 (20) 140.
M.C. White Chem 253 ππππ-Allyl chemistry -226- Week of November 8, 2004
Difunctional allylic alkylating agents
R
OCO2CH3
OCO2CH3
Pd2dba3/dppe 5 mol%
THF, 50oC
CO2Me
CO2MeNa (CH3CN)2W(CO)4 25 mol%
bpy 25 mol%, THF, 50-80oC
R
CO2MeCO2Me
R
CO2MeCO2Me
R
OCO2CH3 CO2Me
CO2Me
R OCO2CH3
MeO2C CO2Me
A
B
R
OCO2CH3 CO2Me
CO2Me
A
R
CO2Me
CO2Me
PdIILn
R
CO2MeCO2Me
R OCO2CH3
MeO2C CO2Me
B
R
MeO2C CO2Me
PdIILn
R
CO2MeCO2Me
Rationalize the formation of different products. In each case indicate the intermediates.
Trost JACS 1987 (109) 2176.
M.C. White, Chem 253 ππππ-Allyl chemistry -227- Week of November 8, 2004
π-Trimethylenemethane cyclizations
CO2CH3
SiMe3
OAc
(Ph3P)4PdDPPE
THF
+
CO2CH3
51 % yield
SiMe3
OAc
PPh2
Pd(0)
Ph2P
SiMe3
PPh2
PdPh2P
OAc
PPh2
PdPh2P
C6H11
O
OCH3
PPh2
PdPh2P
O
OCH3
C6H11
C6H11
CO2CH3
PPh2
PdPh2P
C6H11 CO2CH3
+ PPh2
PdPh2P
palladium π-trimethylenemethanecomplex
The geometry of (E)-olefins is retained in the products, suggesting that the mechanism is concerted ([3+2]) OR that the mechanism is stepwise but collapse of the intermediate enolate is faster than σ-bond rotation. (Z)-olefins give mixtures of syn and anti products; this argues that the mechanism for π-trimethylenemethane cyclizations is in fact stepwise.
Trost ACIEE 1986 (25) 1.
Silicon-carbonbond weakenedby the proximalpositive charge
M.C. White, Chem 253 ππππ-Allyl chemistry -228- Week of November 8, 2004
CyclizationsCarbon and oxygen spirocycles:
OAc
CO2Et
CO2Et
CO2EtCO2Et
OAc
O
CO2Me
O
CO2Me
O
CO2Me
Ln(OAc)PdII
Pd(PPh3)4 7 mol%
NaH, THF , 65oC
66%
note that attack at the least sterically hinderedposition results in abridgehead olefin:
Pd(PPh3)4 7 mol%
NaH, THF , 65oC
>99%Godleski JOC 1982 (47) 383.
O
OTESTESO
TMSO O
Ot-Bu
O
O
OMe
O
OTMS
O
O-tBu
TESOOTES
19-membered ring formation
Pd2dba3 10 mol%
THF, 40oC, 12h
80% O
O O
H
H
CH3
CH3H
H
OH
H3C
HO
CH3
H
H
H
H
(+)-FR182877
Macrocyclizations occur readily. Regioselectivity favors substitution at the least sterically hindered carbon, particularly when bulky nucleophiles are used.
Sorenson JACS 2002 (124) 4552.
cis-fused decalin systems:
AcO O
CO2R
Pd2dba3/PPh3 cat
NaH, THF, 65oC
CO2RRO2CH
H
EE
O
E
>98% ciscomplements the Robinson annulation approach which generally leads totrans-fused rings.
AcO
O
CO2R
CO2RRO2C
= E
Pd2dba3/PPh3 cat
NaH, THF, 65oCO
E
EEH
H
75%, >98% cis
Backvall TL 1989 (30) 617.review on cyclizations: Trost ACIEE 1989 (28) 1173.
M.C. White, Chem 253 ππππ-Allyl chemistry -229- Week of November 8, 2004
Asymmetric functionalization via deracemization
RR
X
*LnPd0
enantiotopic ends of ameso π-allyl intermediate. a RR
Nu
bRR
Nu
Deracemization
RPd*Ln
R
Nua
b
RPd*Ln
syn/anti
R
Nua
note that syn/anti isomerization results in an errosion in ee's.
Solutions:
N
O
t-Bu
Ph2P
Pd
The stronger π-acceptor properties of phosphines vs.imines results in differential trans-effects between thetwo coordinating functionalities. The strong P-Pd bond translates into a long (weaker) Pd-C bond trans to it.This is thought to increase the ionic nature of the bondresulting in more carbonium character at thecorresponding carbon and preferential attack by thenucleophile at that site.
R R
OAc
R R
MeO2C CO2Me
[ClPd(η3-allyl)]2 1 mol%
2 (2.5 mol%), DMF, 65oC
CO2Me
CO2MeNa
2
alkyl substituted 1,3 allyl's give high ee's:
R = Me, 50% yield, 97% ee i-Pr, 96% yield, 88% ee Ph, 99% yield, 99% ee
Pfaltz's electronic disymmetry. Pfaltz ACIEE 1993 (32) 566.
Challenge: creating an effective asymmetric environment outside the coordination sphere of the metal opposite to the chiral ligand.
Hayashi's nucleophile directing tether: Hayashi TL 1986 (27) 191.
FePPh2
PPh2
Pd
NO
Nu
H
The hydroxyl group on theligand tether is thought tointeract attractively with theincoming nucleophile viaH-bonding and direct ittowards attack at one end of the π-allyl group.
Ar Ar
OAc
O
H
1
[ClPd(η3-allyl)]2 0.5mol%
1 (1 mol%), THF
CO2Me
CO2MeNa
Ar Ar
MeO2C CO2Me
Ar = Ph, 97% yield, 90% ee 1-Np, 40% yield, 92% ee
The 1,3-diphenylallyl systemfavors the syn,syn isomer.Syn-anti isomerizations often lead to erosions in ee's foracyclic substrates.
M.C. White, Chem 253 ππππ-Allyl chemistry -230- Week of November 8, 2004
Asymmetric functionalization via deracemizationChallenge: creating an effective asymmetric enviroment outside the coordination sphere of the metal opposite to the chiral ligand.Solutions:
NH HN
OO
PPh2Ph2P
chiral backbone
linkerlinker
P P
Pd
The primary chirality of the stereogeniccenters of the backbone gets translated via thelinker units into a secondary chirality at thephosphines that are closest to the Pd-allyl unit.The conformational bias for edge-facestacking of the phosphine phenyl groupsenforces chiral "propellers" that reach outtowards the allyl unit and sterically block thetrajectory of nucleophilic attack from one side. The steric bulk of the diphenylphosphine unitsis also thought to retard the rate of syn/antiisomerization.
Cat+ Nu-
open quadrant
3
Trost Acc. Chem. Res. 1996 (29) 355.
Trost JACS 1994 (116) 4089.
Cyclic systems:Because the rxn is performed in nonpolar media, the Nu existsas an ion pair. Trost has found that the molecular recognitionevent depends more on the nature of the cation than of the anion that ultimately attcks the π-allyl unit. The larger the cation, thehigher the ee.
OAc
CO2Me
CO2MeCat[ClPd(η3-allyl)]2 2.5mol%
3 (7.5 mol%), THFCO2Me
CO2Me
+Cat %Yield % ee
Na+
N(CH3)4+
N(n-C6H13)4+
N(n-C6H13)4+
in CH2Cl2
K+
Cs+
Cs+ in CH2Cl2
77%
88%
92%
81%
90%
76%
98%
38%
41%
68%
98%
51%
76%
>99%
All the ammonium cations were added as chloride salts.
CH2Cl2 results in aneven tighter ion pair.
CO2Me
CO2Me
86% yield96% ee
CO2Me
CO2Me
99% yield93% ee
N
O
O
87% yield94% ee
largermetal ion
bulkierammonium
ion
Results under optimal ammonium salt conditions:
M.C. White, Chem 253 ππππ-Allyl chemistry -231- Week of November 8, 2004
Asymmetric functionalization: regio-and stereoselective amination
Me OCO2R
+
Ph NH2
FePPh2
PPh2
N OH
OH6 mol%
Pd2(dba)3 1.5 mol%, THF, 0oC
Me
HN Ph
MeHN Ph
+
87% yield97: 3 (branched: linear)
84% ee
(91:9, E/Z) note: result indicates thatsyn/anti isomerization is slowrelative to nucleophilic attack.
MePd*Ln
MePd*LnH
H
MeH*LnPd
H
Me
Ln*Pd
Me
OCO2Me
+
50%
Me
OCO2Me
50%
conditionsas above
Me
HN Ph
82%
Me
HN Ph
18%
π-σ-π isomerization is fastrelative to nucleophilic attack
Hayashi TL 1990 (31) 1746.
achiral substrate
racemic substrate
R X
or
R
X
*LnPd0
RPd*Ln
π−σ−π (aka η3-η1-η3)isomerization
R
Nu
R
Nu
diastereomeric
Nu
Nu
+ R Nu
Both a regio- and stereoselectivity challenge
R
Ln*Pd
M.C. White/M.W. Kanan Chem 253 ππππ-Allyl chemistry -232- Week of November 8, 2004
Dynamic kinetic asymmetric transformation of 5-Acyloxy-2-(5H)-furanone
Trost JACS 1999 (121) 3543.
OOEtO
O
H3CO OH
IOBocO
OO
OEtO
O
H3CO O
I
OH
O
NH
NH PPh2
PPh2
O
O
+ 1.2 eq.
racemic
2.5 % Pd2dba3, 7.5% 1
30% Bu4NCl, CH2Cl2
1
Pd
OBocOO
Pd0P
P
OO
OOPd
P P
OO
Pd
PP
Cl
PP
OOEtO
O
H3CO O-
I
OOEtO
O
H3CO O
I
OH
O
Pd0P
P
+
+
+ Cl-
- Cl-
+
The addition of Cl- ion is thought to accelerate the equilibration between the two -allyldiastereomers by promoting formation of an η1
intermediate. Since the kinetic discriminationbetween the two reactive diastereomers is high,increasing their rate of equilibration increases theoverall selectivity of the reaction.
racemic
OBocOO
OO
Pd
*
*
*
P P
*
via
OO
Pd
P P
*
via
OOEtO
O
H3CO O
I
OH
O
OOEtO
O
H3CO O
O
H
H
O O
O
H3CO O
O
O
The ee of the product could not be directly determined, however the ee of the product of the subsequent Heck cyclization was > 95%.
reductive Heck
> 95% ee Aflatoxin B
H+
M.C. White/M.W. Kanan Chem 253 ππππ-Allyl chemistry -233- Week of November 8, 2004
Intramolecular asymmetric allylic alkylation in the synthesis of [2.2.2] bicycles
Trost OL 2002 4 3427-3430.
N
HO
CO2Et
OCO2CH3
Pd0P
P
N
CO2EtO
H
N
HO
CO2Et
PdP P
PdP
P
N
OCO2Et
H
Pd0P
P
N
CO2EtH
PdP
P
*+
*
+
OAdecarboxylation
*
*+
*
O
N
CO2Et
Pd
PP
*
O
N
CO2Et
Pd
P
P
*
O
The ligand framework provides moderate diastereocontrol withexcellent enantiocontrol for the major diastereomer in thiscyclization, which can proceed through any of four transition states.
-OMe
CO2
4 possible transition states for cyclization
MeOH
pseudo-enantiomeric
2
N
OCO2Et
H
3
N
HO
CO2Et
OCO2CH3
N
OCO2Et
H
N
OCO2Et
H
+
Pd2dba3 2 mol %
2 3
84 % yield; 2 : 3 = 4.6 : 1; ee 2 = 99%
CH2Cl2, rt
5 mol %Pd0
P
P*
1
Pd0P
P* = HNNH
PPh2 Ph2P
O O
M.C. White, Chem 253 ππππ-Allyl chemistry -234- Week of November 8, 2004
Asymmetric functionalization: regio-and stereoselective alkylation
Ph OAc
CO2Me
CO2MeNa
[Ir(COD)Cl]2 4 mol%, THF
P(C6H4-p-CF3)2
O
N
i-Pr4 mol%
Ph
MeO2C CO2Me
Ph+
CO2Me
CO2Me
99% yield 95:5 (branched:linear)
91% ee
Stereochemical model:
Ph3P
IrIIIPh3P
CO
Cl
NH2 OTf
crystallographically characterized IrIII π-allyl complex
IrI
Ar2P S
ClO
N
i-Pr
Ph OAc
IrIII
Ar2P
ON
i-PrPh
Cl
S
OAc
Ph
MeO2C CO2Me
Nu
The benzylic carbon preferentially orients trans tothe diarylphosphine. Rationale: sterics and/orbetter stablization of the carbonium ion characterresulting from the trans influence of PAr2. The Ph substituent is also oriented trans to the oxazolinei-Pr substituent. Rationale: sterics.
Helmchen TL 1997 (38) 8025.
Chen OM 1997 (16) 1159.
M.C. White, Chem 253 ππππ-Allyl chemistry -235- Week of November 8, 2004
Asymmetric functionalization: regio-and stereoselective alkylation/amination
O
OP N
[Ir(COD)Cl]2 2 mol%, THF
4 mol%
MeO2C
MeO2CNa
OAc
Ph1
Ph
OAc
2
Ph
CO2MeMeO2C
from 1: 54% yield 95:5 (branched: linear) 43% eefrom 2: 92% yield 98:2 (branched:linear) 69% ee
Alkylated of (R)-2 (>99 % ee) gives product of 75% ee. Helmchen Chem. Comm. 1999 741.
Hartwig explores amine nucleophiles: Hartwig JACS 2002 (124) ASAP.
Ph OCO2Me
O
OP N
[Ir(COD)Cl]2 1 mol%, THF, 50oC
2 mol%
Ph
Ph NH2
HN Ph
89% yield 98:2 (branched:linear)
94% ee
(R)
limitations: use of the liganddiastereomer (Ra,RC,RC)-3 gives the opposite enantiomer in diminishedyield (66%) and ee (75%).
Ph
Ph(Ra,RC,RC)-3
Hartwig notes that thebranched allylic carbonate gives aminated productswith low ee's.
Ph
N
91% yield 97:3 (branched:linear)
96% ee
Ph
N
92% yield 99:1 (branched:linear)
97% ee
O
* *Ph
HNhex
88% yield 98:2 (branched:linear)
96% ee
O
HN Ph
58% yield 96:2:2 (branched:linear:bisalkylated)
97% ee
HN Ph
* *
58% yield 96:2:2 (branched:linear:bisalkylated)
97% ee
Precedent for using phosphoramidite ligands to effect asymmetric Ir mediated allylic substitutions:
M.C. White, Chem 253 ππππ-Allyl chemistry -236- Week of November 8, 2004
NH HN
OO
N N
15 mol%
(EtCN)3Mo(CO)3 10 mol%THF, reflux
Ph OCO2CH3
CO2CH3
CO2CH3
Na
Ph
MeO2C CO2Me
+
Ph
CO2Me
CO2Me
from 1:88% yield 32:1 (branched: linear) 99% eefrom 2:70% yield 13:1 (branched: linear) 92% ee
1
Ph
OCO2CH3
2
If the reaction were proceeding via initial preferential formation of one of the two possible diastereomeric π-allylmolybdenumcomplexes, starting with racemic 2 would result in racemicproduct or the products of a kinetic resolution (max. 50% yieldof enantioenriched alkylated product). Since racemic substrategives nearly equivalent levels of ee to those observed for 1, themain pathway is thought to proceed via dynamic π−σ−πisomerization of the initially formed π-allylmolybdenumcomplexes with preferential nucleophilic attack on one of the 2diastereomeric complexes.
Molybdenum-catalyzed asymmetric alkylations
Synthesis of quaternary amino acids
Trost JACS 2002 (124) 7256.
+CH3OH
K2CO3
solvolysis of the crudeazlactone in methanol yields the protected quaternaryamino acids in high yields
Ph OCO2t-Bu
N
O
O
Ph
Me
NH HN
OO
N N
15 mol%
(EtCN)3Mo(CO)3 10 mol%LiHMDS
THF, reflux
N
O
O
Ph
Me
Ph
83% yield of branched product96:4 dr99% ee
Ph
Me
Ph(O)CHN CO2CH3
pro-chiralazlactone
pro-chiralallyl carbonate
M.C. White, Chem 253 ππππ-Allyl chemistry -237- Week of November 8, 2004
Asymmetric functionalization: prochiral nucleophileAsymmetric alkylation
The geometric requirements of the chiralpocket created by the diphenylphosphinepropellers can also effect selectivenucleophilic attack of an allyl unit by one face of a prochiral nucleophile. Whenprochiral allyl units are used, excellentdiastereoselectivities can also beachieved.
NH HN
OO
PPh2Ph2P
chiral backbone
linkerlinker
P P
Pd open quadrant
3
X
Y Z vs. ZX
Y
O O
OR+ OAc
[ClPd(η3-allyl)]2 0.5mol%
3 (1.2 mol%), tol, rt
TMG (N,N,N',N'-tetramethylguanidine)Upon deprotonation, the base usedresults in the cationic partner to the enolate formed. Na bases gavelower ee's.
O O
OR
NH
NN
HO
CO2R
86% yield86% ee
O O
OR +
OCO2Me
[ClPd(η3-allyl)]2 0.5mol%
3 (1.2 mol%), tol, rt
TMG (N,N,N',N'-tetramethylguanidine)
O
CO2CH2Ph
71% yield97% ee88% de
Trost JACS. 1997 (33) 7879.
M.C. White, Chem 253 ππππ-Allyl chemistry -238- Week of November 8, 2004
Asymmetric functionalization: desymmetrization
NH HN
OO
PPh2Ph2P
chiral backbone
linkerlinker
P P
Pd open quadrant
3
OR OR
ab
Path a depicts ionization of the pro-R leaving group. A "clockwise" twist of the catalyst leading to ionizationpositions the open quadrant of the ligand over the faceof the cyclopentyl allyl, thus minimizing stericallyunfavorable interaction. Inversely, ionization via pathb leads to severe steric interactions between thesubstrate and the phenyl group of thediphenylphosphine.
Desymmetrization of meso-biscarbamates.
Pd0P P
*
O O OO
TsHNNHTs
Pd0P P
*
OO
NHTsPdII
P
P
*TsNHCO2
-
O O
TsHNPd
P
P
*TsNHCO2
-
O O OO
TsHNNHTs
O
TsN
O
R
S
O
TsN OS
R
a
attack via sterically unfavored path b
92% yield85% ee
b
path a
path b
Pd0P P
*
When base is added (NEt3), the ee increases to99%. One rationale given by Trost to account for this dramatic increase in ee is that deprotonationof the carbamate increases the rate ofintramolecular attack relative to intermolecularattack by the displaced carbamate anion.
Trost JACS 1992 (114) 9327.Trost JOC 1998 (63) 1339.
M.C. White, Chem 253 ππππ-Allyl chemistry -239- Week of November 8, 2004
Asymmetric functionalization: desymmetrization
OO
O
Ph
O
Ph
CO2Me
CO2MeNa
NH HN
Ph Ph
OO
PPh2Ph2PO
O
Ph
CO2Me
CO2MeO
O
Ph
MeO2C
MeO2C
NH HN
OO
PPh2Ph2P+
6 mol%
Pd2(dba)3 2 mol%
68% yield92% ee
Pd2(dba)3 2 mol%
6 mol%
80% yield93% ee
Desymmetrization via intermolecular nucleophilic attack:
Trost JACS 1992 (114) 9327.
"From furan to nucleosides" an example of intermolecular nucleophilic attack. Trost JACS 1996 (118) 3037.
OOC(O)PhPh(O)CO
NH HN
Ph Ph
OO
PPh2 Ph2P
N
NN
NH
ClNH HN
Ph Ph
OO
PPh2 Ph2PO
NPh(O)CO
N
N
N
Cl
OOC(O)PhN
N
N
N
Cl
Pd2(dba)3 2 mol%NEt3
6 mol%+6 mol%
Pd2(dba)3 2 mol%NEt3
OOC(O)PhN
N
N
N
H2N
OH OH
L-adenosine
93% ee 93% ee
ONPh(O)CO
N
N
N
H2N
OH OH
D-adenosine
M.C. White/Q. Chen Chem 253 ππππ-Allyl chemistry -240- Week of November 8, 2004
N
Ts
CO2Me
N
H
Me O
CO2Me
O
OMeO
NH
Ts
NH HNO O
NPPh2
racemic
2.5% Pd2dba3•CHCl3, 7.5% L*
CH2Cl2, 0 °C
L* = 88% ee90% yield
(-)-Anatoxin-aaka "very fast death factor"
Total synthesis of (-)-Anatoxin-a via desymmetrization
N
Ts
CO2Me
CO2Me
O
OMeO
NH
Ts
CO2MeN
H
Ts
PdL*
O
MeO
O
CO2
CO2MeNH
Ts
PdL*
H3CO
CO2MeNTs
PdL*
CH3OH
PdL*
trans substituted cyclooctene did not give any cyclization product.
After initially observing slow reaction rates andlow ee's with the standard bis phosphine ligands,the authors reasoned that the "chiral space" created by these standard ligands was too restrictive forthe steric demands of the cyclooctenyl substrate.Alternatively, application of the less stericallydemanding P,N-bidentate chiral ligand shownresulted in dramatic rate enhancements and goodee for the cyclization reaction.
Trost JACS 1999 (121) 3057.
M.C. White Chem 253 ππππ-Allyl chemistry -241- Week of November 8, 2004
QuestionProvide a mechanism for the following transformation.
O O
Ph
O O
H
H
mixture of stereoisomers
Ph
SiMe3AcO
+
(Ph3P)4Pd
toluene, ∆∆∆∆