1 organocatalysis: chiral amines in asymmetric synthesis natalie nguyen march 4, 2003
Post on 18-Jan-2016
221 Views
Preview:
TRANSCRIPT
1
Organocatalysis:Chiral Amines in Asymmetric
Synthesis
Natalie NguyenMarch 4, 2003
2
N
N
R
HOH
N
N
HO
HR
NH
CO2H
N
N
R2
R1
NN
R
R
-Lactone and -Lactam formation
Acylation of Alcohols and Amines
Kinetic Resolution
Baylis-Hillman Reaction
CO2H
NH2
Aldol ReactionMannich ReactionMichael Additions
NH
NR1
R2
O
Ph
Friedel-Crafts Alkylation Indole Alkylation
Diels-Alder Cycloadditon
France, S.; Guerin, D.J.; Miller, S.J.; Lectka, T. Chem. Rev. 2003, 2985
Chiral Organocatalysts in Asymmetric Synthesis
R = OMe (Quinidine)R = H (Cinchonine)
R = OMe (Quinine)R = H (Cinchonidine)
3
Chiral Amines in Asymmetric Synthesis
NH
CO2H
NH
NR1
R2
O
Ph
HCl
Proline Catalyzed: Aldol Reaction Mannich Reaction
Imidazolidinone Catalyzed: Diels – Alder Cycloaddition
Total Synthesis of (+)-Hapalindole Q
4
Proline: Enzyme Mimic
Inexpensive Available in both enantiomeric forms
“Chemzyme”: Mode of action very similar to enzymes
NH
CO2HNH
CO2H
(S)-proline (R)-proline
NOH
O
H
NCO2
R
NCO2H
R
NH
CO2H
BifunctionalAcid and Base
Hydrogen-bond donorand acceptor
Iminium Enamine
5
Proline in Asymmetric Synthesis
The proline catalyzed Robinson annulation was one of the earliest examples of an enantioselective reaction
Yamada, 1969
Yamada, S.; Otani, G. Tetrahedron Lett. 1969, 4237
Ph
Me
CHO+
Ph
Me
N
COR
O
CHOMe
Ph
O
AcOH, H2O
O
PhMe
49% ee
NH
48%
MeOH:C6H6 (1:9)
preformed enamine
O
N
6
Proline in Asymmetric Synthesis
Hajos and Parrish, 1974
O
O
ONH
CO2H3 mol%
DMF, rt, 72 h52%
O
OOH
74% ee
p-TsOH
C6H6
O
O
Enantioselective Step
Hajos, Z.G.; Parrish, D.R. J. Org. Chem. 1974, 39, 1615Danishefsky, S. et al. J. Am. Chem. Soc. 1996, 118, 2843
O
(S)-proline
O
O
OH
OHO
OBnH
O
OAcHO
AcO
Baccatin III
O
O
Synthesis of Taxol (Danishefsky, 1996)
7
Intramolecular Aldol Reaction: Solvents and Catalyst
O
O
ONH
CO2H3 mol%
DMF, rt, 20 h100%
O
OOH
93% ee
Hajos, Z.G.; Parrish, D.R. J. Org. Chem. 1974, 39, 1615Eder, U.; Sauer, G.; Wiechert, R. Angew. Chem., Int. Ed. Engl. 1976, 9, 412
Intramolecular aldol cyclization works best in aprotic polar solvents Protic solvents lower the enantioselectivity drastically
Catalyst Screening
Pyrrolidine ring, secondary nitrogen and carboxylic acid are important to catalysis
CO2H
NH2 NCO2H
NH
CO2Me
NH
CO2H NH
CO2H
8
Intramolecular Aldol Reaction: Mechanism
O
O
ONH
CO2H
O
O
N
CO2
O
O
N
CO2HO
NOH
CO2
O
OOH
+O
O
N
OH
CO2H -H2O
H2O
Enantioselective Step
Brown, K.L.; Damm, L.; Dunitz, J.D.; Eschenmoser, A.; Hobi, R.; Kratky, C. Helv. Chim. Acta. 1978, 61, 3108
O
OOH
si-face attackO O
Me
N
re si
CO2H
re-face attackO
OOH (R)
(S)
(S)
(R)
9
Intramolecular Aldol Reaction: Proposed Transition State
Attack occurs on the face opposite the carboxylic acid
Transition state is controlled and stablized by N-H-----O hydrogen bonding
Transition state is controlled and stablized by O-H-----O hydrogen bonding
Agami, 1984-1986 Houk, 2001-2003
N
HO
O
OO
Me
Agami, C.; Meynier, F.; Puchot, C.; Guilhem, J.; Pascard, C. Tetrahedron 1984, 40, 1031Bahmanyar, S; Houk, K.N. J. Am. Chem. Soc. 2001, 123, 12911
NO
O
OHH
H
Me
O
10
Intramolecular Aldol Reaction: Proposed Transition State
Attack occurs on the face opposite the carboxylic acid
Transition state is controlled and stablized by N-H-----O hydrogen bonding
Transition state is controlled and stablized by O-H-----O hydrogen bonding
Favorable electrostatic interactions +NCH-----O - (2.4 Å)
Agami, 1984-1986 Houk, 2001-2003
Agami, C.; Meynier, F.; Puchot, C.; Guilhem, J.; Pascard, C. Tetrahedron 1984, 40, 1031Bahmanyar, S; Houk, K.N. J. Am. Chem. Soc. 2001, 123, 12911
N
HO
O
OO
Me
NO
O
OHH
H
Me
O
11
Intramolecular Aldol Reaction: Proposed Transition State
Reaction is second order in proline A negative non-linear effect was
observed Two prolines are involved
Reaction is first order in proline A linear effect was observed One proline involved
Agami, 1984-1986 Houk, 2001-2003List, 2003
Agami, C.; Puchot, C.; Sevestre, H. Tetrahedron Lett. 1986, 27, 1501Hoang, L.; Bahmanyar, S.; Houk, K.N.; List, B. J. Am. Chem. Soc. 2003, 125, 16
N
O
O
OO
Me
H
NCO2
NO
O
OHH
H
Me
O
12
Intramolecular Aldol Reaction: Proposed Transition State
Me
O
O
N
O
O HHH
Bahmanyar, S.; Houk, K.N. J. Am. Chem. Soc. 2001, 123, 12911
si-face attack re-face attack
NO
O
OHH
H
Me
O
The hydrogen bonding allows the iminium double bond to be almost planer
Favorable electrostatic interactions +NCH-----O - (2.4 Å)
The hydrogen bonding forces the iminium double bond out of planarity
Small electrostatic interaction +NCH-----O - (3.4 Å)
Transition state is 3.4 kcal/mol higher in energy
13
Intermolecular Aldol Reaction
Evans’ Oxazolidinone Chiral auxillary
O
ClMe
HN O
O
Ph
BuLiO
NMe
O
O
Ph
1. Bu2BOTfEt3N
2. PhCHO
O
BO
N
O
OPh
Me
Bu
BuH
Ph
O
N O
O
Me
OH
Ph
Ph
LiOH, H2O2O
OH
Me
OH
Ph
syn-aldol
First Proline Catalyzed Direct Aldol Reaction (List, 2000)
OH
O
NO2
30 mol% (S)-proline
DMSO, 68%
OHO
NO2
76% ee
+
List, B.; Lerner, R.A.; Barbas III, C.F. J. Am. Chem. Soc. 2000, 122, 2395
14
Intermolecular Aldol Reaction: Mechanism
List, B. Tetrahedron, 2002, 58, 5573Bahmanyar, S.; Houk, K.N. J. Am. Chem. Soc. 2001, 123, 11273
OH
N
H
ArO
O
Previously proposed Zimmerman-Traxler transition state is unlikely because N-H bonding does not occur
O
NH
CO2H+ NCO2
NCO2H
O
H
H
N
O
O
OH
H
Ar
HN
O2COH
O OH
NO2
NO2NO2
15
Intermolecular Aldol Reaction: Amino Acid Catalysts
Catalyst Yield ee
68% 76%
(L)-His, (L)-Val
(L)-Tyr, (L)-Phe<10% -
55% 40%
<10% -
NH
CO2H
NH
CO2H
NH
CO2H
NH
CONH2
NH
CO2H
S
NH
CO2H
S
NH
CO2H
Catalyst Yield ee
<10% -
67% 73%
66% 86%
<10% -
List, B.; Lerner, R.A.; Barbas III, C.F. J. Am. Chem. Soc. 2000, 122, 2395 Sakthivel, K.; Notz, W.; Bui, T.; Barbas III, C.F. J. Am. Chem. Soc. 2001, 123, 5260
O+ H
O
NO2
20 mol% catalyst
rt, DMSO
OHO
NO2
16
Intermolecular Aldol Reaction: Amino Acid Catalysts
Catalyst Yield ee
68% 76%
(L)-His, (L)-Val
(L)-Tyr, (L)-Phe<10% -
55% 40%
<10% -
NH
CO2H
NH
CO2H
NH
CO2H
NH
CONH2
NH
CO2H
S
NH
CO2H
S
NH
CO2H
Catalyst Yield ee
<10% -
67% 73%
66% 86%
<10% -
O+ H
O
NO2
20 mol% catalyst
rt, DMSO
OHO
NO2
List, B.; Lerner, R.A.; Barbas III, C.F. J. Am. Chem. Soc. 2000, 122, 2395 Sakthivel, K.; Notz, W.; Bui, T.; Barbas III, C.F. J. Am. Chem. Soc. 2001, 123, 5260
17
Intermolecular Aldol Reaction: Substrate Scope
Reaction works best with large excess of ketone
Reaction is general to: aromatic aldehydes -substituted aldehydes
-Unsubstituted aldehydes: Aldol condensation product
was the major product
O OH
Product Yield ee
1
2
68%
60%
76%
86%
1 85% 99%
1 34% 72%
1
2
0%
0%
-
OHO
NO2
NH
CO2H S
NH
CO2H
1 2
O OH
O+
R2H
O 20 mol% catalyst
rt, DMSO:ketone (4:1)
OHO
R2
R1 R1
O OH
NO2
List, B.; Lerner, R.A.; Barbas III, C.F. J. Am. Chem. Soc. 2000, 122, 2395 Sakthivel, K.; Notz, W.; Bui, T.; Barbas III, C.F. J. Am. Chem. Soc. 2001, 123, 5260
18
Intermolecular Aldol Reaction: Anti-Aldol Products
Thiaproline (2): Not as general as
proline
Product Yield anti/syn ee
1
2
60%
45%
20:1
20:1
99%
95%
1 85% 1:1 (anti) 85%
(syn) 76%
1 68% 20:1 97%
O OH
O
Ph
OH
OH
O OH
Notz, W.; List, B. J. Am. Chem. Soc. 2000, 122, 7386Sakthivel, K.; Notz, W.; Bui, T.; Barbas III, C.F. J. Am. Chem. Soc. 2001, 123, 5260List, B.; Pojarliev, P.; Castello, C. Org. Lett. 2001, 3, 573
R1
O
R2
+O
H R3
20 mol% catalyst
rt, DMSO:ketone (4:1) R1 R3
O
R2
OH
NH
CO2H S
NH
CO2H
1 2
19
Cross Aldol Reaction
H
O
R1 +O
H R2
10 mol% (S)-proline
DMF, 4 oC
O
H
OH
R1
R2
Product Yield anti/syn ee
88% 3:1 97%
81% 3:1 95%
80% 24:1 95%
82% 24:1 99%
O
H
OH
O
H
OH
O
H
OH
O
H
OH
Bu
Northrup, A.B.; MacMillan, D.W.C. J. Am. Chem. Soc. 2002, 124, 6798
Transition State
HH
NO
O
OHH
R2
R1
H
20
Mannich Reaction
The rate of the Mannich reaction must be faster than the rate of aldol reaction
O+
CHO
NO2
+
H2N
OMe 35 mol% (S)-proline
DMSO, 50%
O HN
OMe
NO294% ee
+
O OH
NO2
minor aldol product
List, B. J. Am. Chem. Soc. 2000, 122, 9336List, B.; Pojarliev, P.; Biller, W.T.; Martin, H.J. J. Am. Chem. Soc. 2002, 124, 827
First Proline Catalyzed Direct Mannich Reaction (List, 2000)
R
O OH kAldol
N
H
O
R2
Keq = 1
R1-NH2
-H2OH
N
R2
R1 kMannich
R2
O HNR1
CO2H N CO2H
21
O
HR3+ N CO2H
R2
R3R1
NN
O
O
HR2
MeO
H
R1
HR1
NO
O
OHH
R3
R2
H
R1 R3
O
R2
HNPMP
R1 R3
O
R2
OH
Mannich
AldolH2N
OMe
syn anti
List, B.; Pojarliev, P.; Biller, W.T.; Martin, H.J. J. Am. Chem. Soc. 2002, 124, 827
Mannich Reaction: Transition State
(E)-enamine (E)-enamine
22List, B.; Pojarliev, P.; Biller, W.T.; Martin, H.J. J. Am. Chem. Soc. 2002, 124, 827List, B.; Pojarliev, P.; Biller, W.T.; Martin, H.J. J. Am. Chem. Soc. 2002, 124, 827
O
HR3+ N CO2H
R2
R3R1
NN
O
O
HR2
MeO
H
R1
HR1
NO
O
OHH
R3
R2
H
R1 R3
O
R2
HNPMP
R1 R3
O
R2
OH
Mannich
AldolH2N
OMe
syn anti
List, B.; Pojarliev, P.; Biller, W.T.; Martin, H.J. J. Am. Chem. Soc. 2002, 124, 827
Mannich Reaction: Transition State
(E)-enamine (E)-enamine
(E)-imine
23List, B.; Pojarliev, P.; Biller, W.T.; Martin, H.J. J. Am. Chem. Soc. 2002, 124, 827List, B.; Pojarliev, P.; Biller, W.T.; Martin, H.J. J. Am. Chem. Soc. 2002, 124, 827
O
HR3+ N CO2H
R2
R3R1
NN
O
O
HR2
MeO
H
R1
HR1
NO
O
OHH
R3
R2
H
R1 R3
O
R2
HNPMP
R1 R3
O
R2
OH
Mannich
AldolH2N
OMe
syn anti
List, B.; Pojarliev, P.; Biller, W.T.; Martin, H.J. J. Am. Chem. Soc. 2002, 124, 827
Mannich Reaction: Transition State
(E)-enamine (E)-enamine
(E)-imine
Nonbondinginteractions
24
Mannich Reaction: Amino Acid Catalysts
Catalyst Yield ee
90% 93%
56% 76%
22% 15%
60% 16%
NH
CO2H
S
NH
CO2H
NH
CO2H
OH
NH
CO2H
HO
List, B.; Pojarliev, P.; Biller, W.T.; Martin, H.J. J. Am. Chem. Soc. 2002, 124, 827
O+
O
H+
H2N
OMe35 mol% catalyst
Acetone HNO
OMe
25
Mannich Reaction: Amino Acid Catalysts
List, B.; Pojarliev, P.; Biller, W.T.; Martin, H.J. J. Am. Chem. Soc. 2002, 124, 827
Catalyst Yield ee
90% 93%
56% 76%
22% 15%
60% 16%
NH
CO2H
S
NH
CO2H
NH
CO2H
OH
NH
CO2H
HO
O+
O
H+
H2N
OMe35 mol% catalyst
Acetone HNO
OMe
26
Mannich Reaction: Variation in Aldehydes
Aldehyde Yield ee
50% 94%
90% 93%
35% 96%
56% 70%
O
H
O
H
List, B.; Pojarliev, P.; Biller, W.T.; Martin, H.J. J. Am. Chem. Soc. 2002, 124, 827
O+
O
RH+
H2N
OMe35 mol% (S)-proline
Acetone
R
O HN
OMe
O
H
R
NN
O
O
H
MeO
H
Transition StateO
H
NO2
27
Mannich Reaction: Variation in Ketones
Product Yield ee
96%
2.5:1
99%
94%
93% 98%
O HN
Ar
PMP
O HN
Ar
PMP
O HN
Ar
PMP
OMe
List, B.; Pojarliev, P.; Biller, W.T.; Martin, H.J. J. Am. Chem. Soc. 2002, 124, 827
O
R+
OHC
NO2
+
H2N
OMe 35 mol% (S)-proline
DMSO
O HN
OMe
NO2R
ArR1
NN
O
O
HR2
MeO
H
Transition State
28
Aldol and Mannich Reaction
Direct Aldol Deprotonation or silylation is not required
Direct Mannich Imine electrophile can be generated in situ
Proline proved to the optimal catalyst Nontoxic Inexpensive Both enantiomers available Can be used in wet solvents and open to air Can be removed from reaction mixture by aqueous workup
NH
CO2H
(S)-proline
29
Organocatalyzed Diels-Alder Cycloaddition
Asymmetric Diels-Alder Reaction by Chiral Bases (Kagan, 1989)
O
N
O
R
H
H
N
O
O
Riant, O.; Kagan, H.B.; Tetrahedron, 1989, 30, 7403
O
N
N
HO
HMeOQuinidine, 50 mol%
CHCl3, -50 oC97%N
O
O
HO
N
O
O
61% ee
Transition State
30
Diels-Alder Cycloaddition
Exo vs Endo
O OO
O
Enantioselectivity in Diels Alder Reaction
exo endo
O
OO
+O
31
Diels-Alder Cycloaddition : Lewis Acids and Iminiums
Lewis Acids and Iminiums lowers the energy of the LUMO
O
dienophile
HOMO
LUMO
HOMO
LUMO
LUMO
HOMO
diene
Energy
Z
activateddienophile
32
Organocatalytic Diels-Alder Cycloaddition
MacMillan’s Catalyst Design: Lowers the energy of LUMO of the dienophile Kinetically labile ligand for catalytic turnover Chiral molecule would induce stereoselectivity
Ahrendt, K.A.; Borths, C.J.; MacMillan, D.W.C. J. Am. Chem. Soc. 2000, 122, 4243
NH
R1 R2 O
NR2R1
N
R2
R1
O
33
Diels-Alder Cycloaddition: Catalyst Screening
Catalyst Yield endo:exo exo ee
81% 1:2.7 48%
92% 1:2.6 57%
82% 1:3.6 74%
99% 1:1.3 93%
NH
CO2Me
NH
CO2MeMeO2C
Bn NH
Bn
MeO2C CO2Me
NH
NO
Ph
Ahrendt, K.A.; Borths, C.J.; MacMillan, D.W.C. J. Am. Chem. Soc. 2000, 122, 4243
Ph O +10 mol% catalyst
MeOH-H2O
23 oC OHC
Ph
endo
+
Ph
CHO
exo
HCl
34
Diels-Alder Cycloaddition: Catalyst Screening
Catalyst Yield endo:exo exo ee
81% 1:2.7 48%
92% 1:2.6 57%
82% 1:3.6 74%
99% 1:1.3 93%
NH
CO2Me
NH
CO2MeMeO2C
Bn NH
Bn
MeO2C CO2Me
NH
NO
Ph
Ahrendt, K.A.; Borths, C.J.; MacMillan, D.W.C. J. Am. Chem. Soc. 2000, 122, 4243
Ph O +10 mol% catalyst
MeOH-H2O
23 oC OHC
Ph
endo
+
Ph
CHO
exo
HCl
35
Diels-Alder Cycloaddition: Variation in Dienophiles
O
Ph O
O
R Yield endo:exo exo ee endo ee
75% 1:1 86% 90%
81% 1:1 84% 93%
99% 1:1.3 93% 93%
20% 1:7 - -
Ahrendt, K.A.; Borths, C.J.; MacMillan, D.W.C. J. Am. Chem. Soc. 2000, 122, 4243
O
Et
R O +5 mol%
MeOH-H2O
23 oC
NH
NO
Ph
HCl
OHC
R
endo
+
R
CHO
exo
36
Diels-Alder Cycloaddition: Variation in Dienes
Diene Yield endo:exo endo ee
82% 14:1 94%
90% - 83%
75% 5:1 90%
72% 11:1 85%
Ph
Me
Me
OAc
Ahrendt, K.A.; Borths, C.J.; MacMillan, D.W.C. J. Am. Chem. Soc. 2000, 122, 4243
O +X
20 mol%
MeOH-H2O
23 oC
NH
NO
Ph
HCl
endo
H
CHO
X
37
Diels-Alder Cycloaddition: Transition State
Ahrendt, K.A.; Borths, C.J.; MacMillan, D.W.C. J. Am. Chem. Soc. 2000, 122, 4243
Formation of (E)-imine to avoid nonbonding interactions between the geminal methyls Benzyl group shields the top face leaving the si-face exposed
O
NH
NO
Ph
+ N
NO
Ph
NN
O
N
N
Ph
O
CHO
N
N
Ph
O
endo
exo
CHO
+
+
NN
O
38
Diels-Alder Cycloaddition: Transition State
Ahrendt, K.A.; Borths, C.J.; MacMillan, D.W.C. J. Am. Chem. Soc. 2000, 122, 4243
Formation of (E)-imine to avoid nonbonding interactions between the geminal methyls Benzyl group shields the top face leaving the si-face exposed
O
NH
NO
Ph
+ N
NO
Ph
NN
O
N
N
Ph
O
CHO
N
N
Ph
O
endo
exo
CHO
+
+
NN
O
39
Diels-Alder Cycloaddition: Transition State
Ahrendt, K.A.; Borths, C.J.; MacMillan, D.W.C. J. Am. Chem. Soc. 2000, 122, 4243
Formation of (E)-imine to avoid nonbonding interactions between the geminal methyls Benzyl group shields the top face leaving the si-face exposed
O
NH
NO
Ph
+ N
NO
Ph
NN
O
N
N
Ph
O
CHO
N
N
Ph
O
endo
exo
CHO
+
+
NN
O
40
Diels-Alder Cycloaddition: Catalyst Screening
Catalyst Yield endo:exo ee
20% 7:1 -
89% 25:1 90%NH
NO
Ph
O
NH
NO
Ph
Northrup, A.B.; MacMillan, D.W.C. J. Am. Chem. Soc. 2000, 122, 4243
O
Et+
NH
NR2
R3
O
R1
20 mol%, H2O, 0 oC
HClO4
Ph
endo
OEt
41
Diels-Alder Cycloaddition: Variation in Dienophiles
Dienophile Yield endo:exo ee
89% 24:1 90%
78% 6:1 90%
24% 8:1 0
O
O
Northrup, A.B.; MacMillan, D.W.C. J. Am. Chem. Soc. 2000, 122, 4243
O
R1
O
R2+
20 mol%, MeOH-H2O
23 oC
NH
NO
Ph
O
HClO4
R1
endoOR2
NN
O
OR2
R1
Transition State
42
Diels-Alder Cycloaddition: Variation in Dienes
Diene Yield endo:exo endo ee
88% 200:1 94%
91% 100:1 89%
92% 200:1 83%
90% 200:1 90%
Ph
Me
Me
OMe
NHCBz
Northrup, A.B.; MacMillan, D.W.C. J. Am. Chem. Soc. 2000, 122, 4243
NN
O
OEt
R2
R1
Transition State
O
Et+
R2R1
20 mol%, MeOH-H2O
23 oC
NH
NO
Ph
O
HClO4
R2
COEt
R1
43
Diels-Alder Cycloadditon: Conclusions
Organocatalyzed Diels-Alder Cycloadditions Highly enantioselective Applicable to a variety of substrates
Chiral Amines Nontoxic Can be used in wet solvents and open to air Can be removed from reaction mixture by aqueous workup
NH
NO
Ph
O
HClO4
NH
NO
Ph HCl
44
The Total Synthesis of (+)-Hapalindole Q by an Organomediated Diels-Alder Reaction
Isolated from the terrestrial blue-green algae Hapalosiphon fontinalis
Cyanobacterium indigenous to the Marshall Islands
Isolated in 1984 by Moore and co-workers
Exhibits antimycotic activity through its ability to directly inhibit RNA polymerase
Has been synthesized by 5 groups
Aaron C. Kinsman and Michael KerrJ. Am. Chem. Soc. 2003, 125, 14120
NH
HNCS
(+)-Hapalindole Q
NH
R1
R2
H
C, D, E, F
NH
R1
R2
H
H
A, B, J, M, O
Hapalindoles
R1 = NC, NCSR2 = H, Cl, OH
45
(+)-Hapalindole Q: Retrosynthesis
(+)- Hapalindole Q
SCN
NHCHO
NTs
Diels-Alder
NN
O
TsN
NH
NO
PhHCl
NTs
CHO
+
46
(+)- Hapalindole Q: Synthesis
SCN
NH
NTs
CHO
+HO OH
O O
py, reflux, 2 h86%
NH 20 mol%
NTs
CO2H
EtOH, cat H2SO4reflux
Dean-Stark, 24 h97% N
Ts
CO2Et
-10 to 0 oC, 2 h, >95%
DIBAL- H, CH2Cl2
NTs
OH
Dess-Martin periodinaneCH2Cl2
0 oC, 1 h, 72%NTs
CHO
47
(+)- Hapalindole Q: Synthesis
SCN
NH
NTs
CHO
+
NH
HNO
Ph
rt, DMF/MeOH (1:1)5% H2O, 35%
NN
O
TsN
70% de93% ee endo
CHO
NTs
TsN
CHO
92% ee exo
85:15
HCl
NN
O
TsN
48
(+)- Hapalindole Q: Synthesis
CHO
NTs
TsN
CHO NaClO2, NaH2PO4 (aq)
2-methyl-2-butene
NTs
OHOTsN
O
OH1. Et3N, PhMe
2. MeOH, sealed tube150 oC, 17 h, 79%
NHCO2Me
NTs
TsN
NHCO2Me
85:15
85:15
85:15
POO
ON3
SCN
NH
49
(+)- Hapalindole Q: Synthesis
NHCO2Me
NTs
TsN
NHCO2Me
5 mol % K2OsO2(OH)415 mol % DABCO, MeSO2NH2
K2CO3, K3Fe(CN)6, THF, H2Ort, 2 d, 75%
NHCO2Me
NTsHO
HO
NHCO2Me
NTs
OHOH
85:15
+Unreacted exo
isomer
NaIO4/SiO2, CH2Cl2
2 h, >95%
O
MeO2CHN
O
NTs
3:1
endo exo
SCN
NH
50
(+)- Hapalindole Q: Synthesis
KOt-Bu, Ph3PCH3I
PhMe, 60 oC, 2 h
81%
MeO2CHN
O
NTs
KOt-Bu, Ph3PCH3I
PhMe, 60 oC, 2 h
67%
MeO2CHN
NTs
TBAF, THF
reflux, 12 h
H2N
NH0 oC, 20 h,
29% two steps
CH2Cl2
S
NN
NN
O
MeO2CHN
O
NTs
NH
HNCS
(+)-Hapalindole Q
51
(+)- Hapalindole Q: Conclusion
The first total synthesis utilizing an organomediated Diels-Alder reaction It was the most structurally complex molecule used with MacMillan’s
catalyst (+)-Hapalindole Q was synthesized in 12 steps in 1.7% overall yield
NH
HNCS
(+)-Hapalindole Q
52
Conclusions
The First Proline Catalyzed Direct Aldol reaction Direct Mannich reaction
Organocatalyzed Diels-Alder Cycloadditions Highly enantioselective Applicable to a variety of substrates Key step in the synthesis of (+)-Hapalindole Q
NH
CO2H
(S)-proline
NH
NO
Ph
O
HClO4
NH
NO
Ph HCl
53
Acknowledgements
Dr. Alex Fallis
The Fallis Group
Megan ApSimon
Dr. Christophe Benard
Matt Clay
Aaron Dumas
Dr. Nancy Lamb
Dr. Sara Palmier
Jeremy Praetorius
Thiva Thurugam
Kelly VanCrey
54
55
Diels-Alder Reaction: Synthesis of Catalyst
NH2
O
OMeMe-NH2
EtOH NH2
O
NHMe
O O
HNN
p-TSA
59%
Ahrendt, K.A.; Borths, C.J.; MacMillan, D.W.C. J. Amer. Chem. Soc. 2000, 122, 4243
NH2
O
NHMeSm(SO3CF3)3, THF
OCHO
O
HNN
O
46%
top related