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Trost’s Palladium Catalysed Asymmetric
Allylic Alkylation(Pd-AAA)
1
Literature MeetingCharette’s group
Miguel St-OngeOctober 9th, 2007
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
2
Pr. Barry M. Trost
3
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
Palladium
4
•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
NCMe
2+
-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.
Trost’s Study
6
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
Study conclusion
7
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
Stereochemistry of Oxidative Addition
8
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, NaBF4
CHCl2
D20 = -105o (c = 1.1, CHCl3)
Hayashi, T.*; Hagihara, T.; Konishi, M.; Kumada, M. J. Am. Chem. Soc. 1983, 105, 7768-7770.
Stoichiometric vs Catalytic
9
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
Catalytic Cycle
10
PdL LPh
X
Pd LL
PhPd
L L
Nu
PdLL
Nu X
Nu
Complexation
Oxidative addition(ionization)
Nucleophilic addition
Decomplexation
Ph
PhPh
X
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.
Ph
PdL L
+2L, + MY-2MCl
PdCl2
Ph
Pd
Cl Cl
Pd
Ph
Ph
X
Y = BF4, PF6, TfO, TsO
Y
Ph
Pd
Cl
L L
Ph
Pd
Cl
L L
2L Cl
Ph
OAc
Ph
Cl + Pd0L4
+ 2L+ Cl-OAc
Pd0(dba)2+
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
H
H
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
H
H
H
R
Pd
L L
X
+
H
H
H
Ranti
R
Pd
+
+X
-X
L LL L
LL L
L
+X
-X
Anti complex
Unfavorable A1,3
Nucleophile Approach
13
• 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
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
Pd
LL
Nu
Nu
Ligand Sterics
PdLL
RR
PdLL
R
PdLL
R
PdLL
Nu R
PdLL
Nu
Ligand Electronics
Redesign Catalytic Cycle
15
PdL L
Ph
X
PdLL
PhPd
L L
Nu
PdLL
Nu X
Nu
Complexation
Oxidative addition(ionization)
Nucleophilic addition
Decomplexation
Ph
PhPh
X
Ph
Pd
Cl
L L
Ph
Pd
Cl
L L
Ph
Nu
PdL L
or
Ph
Nuor
Successful Ligands
16
N
CN
N
R RH
Pfaltz
R= CO2Me, CH2OSiMe2t-Bu,CMe2OH
PPh2
P(Cy)2
FeCp
Togni, Spindler
Ph2PO
i-PrS
t-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.
Trost’s Classic Ligands
17
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
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
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)
19
Rsyn
H
H
H
R
Pd
Syn complex
Pd
+
Rsyn
H
HH
R
Syn complexL
L
LL
+
PhPd
L L
Nu
PdLL
Ph
Ph
Nu
PdL L
orVs Nu
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.
Class B- Desymetrisation of Prochiral Leaving Group on the Same Carbon
21
PdH
R
R
R`
HOAcOAc
R`
OAc
H
SYN, ANTI
PdH
RR`
H
OAc
SYN, SYN
+
+
R
R`
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.
22
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.
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.
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
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.
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.
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
O
H
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
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
M
OOEtO
MeO O
O
O O
89%, >95%ee
50%
50%
Trost, B.M.; Toste, F.D. J. Am. Chem. Soc. 2003, 125, 3090-3100.
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
OO
Pd+ +
+
PdL2
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 O
O
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
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
O
CO2Me
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:
Carbon Nucleophiles in Total Synthesis
32
SO2PhO2N +
(R,R)-Standard (0.25 mol%)(-allylPdCl)2 (1 mol%)
THF/H2O, NaHCO3BzO
OBz
BzO
SO2Ph
NO2
NO
SO2Ph
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:
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
HO
C9H19
OPMB
74%, 99% ee
7 Steps HO
C9H19
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:
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.
O
CO2CH3
MeO
Br
CHO
72%, 88% ee
11 Steps
MeN
OR
OH
(-)-codeine, R = CH3
(-)-morphine, R = H
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
OAcLigand (4 mol%)
(-allylPdCl)2 (2 mol%)BnNH2, CH2Cl2
Fe
PN
O
Ph
Et2N
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
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
OH
HO OH
OH
O
(+)-pancratistatin
11% 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.
Nitrogen Nucleophiles in Total Synthesis
37
Sulfonamide
CO2Me
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.
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
O
NTsO
95%, 97% ee
7 Steps
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
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.
Exceptions
41
OH
MeO Br
CHO
TrocO
CO2CH3
+
(S,S)-Stilbene (3 mol%),(()-allylPdCl)2 (1 mol%),
Et3N, CH2Cl2, r.t.72%, 88% ee
O
CO2CH3
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.
O
CO2CH3Br
CHO
Pd
+ +
Nu
Pd
Otroc
CN
(R,R)-Standard (7.5 mol%),(()-allylPdCl)2 (2.5 mol%),
CH2Cl2, r.t.O
CN
OMe
NCNu
+
Exceptions
42Trost, B.M.; Machacek, M.R.; Aponick, A. Acc. Chem. Rev. 2006, 39, 747-760.
O
CO2CH3Br
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)
Exceptions
43
OTBS
MeO
OTroc
+
TBSO
MeOPd
)(
Match ionization
+
Pd
Syn isomerization
R
+
Pd
Anti isomerization
R
H
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.
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
OP
OEtO
EtONaH(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
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
ArAr NHR1R2
Ar NHR1
2
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
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
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
O
N
Ph
R
O
H
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.
Molybdenum AAA Transition State
48
A
B
NNHO
N
O
MoOC
OCOC 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
Synthesis of Tipranavir (Aptivus)
49
O
Cl
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.
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
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
