Post on 01-Apr-2015
A Dash of proline to induce chirality
Christian Perreault
Literature MeetingFebruary 6th, 2006
Synthesis of (-)-Littoralisone
Enantioselective Organocatalytic α-Oxidation of aldehydes
OOO
OHOH
OHO
H
O
O
H
H
H
OH
O
H
David W. C. MacMillan et Al. J. Am. Chem. Soc. 2005, 127, 3696.
1,4 Selective Michaël addition induced by proline
Aldol reaction catalyzed by proline
• Nine-membered lactone in an heptacyclic framework
• Glycosidic unity : (β)-D-Glucose
• Elaborated optically active cyclobutane
• 14 stereocenters within a 24 carbon framework
(-)-Littoralisone
OOO
OHOH
OHO
H
O
O
H
H
H
OH
O
H
Challenge of the synthesis
Verbena littoralis
(1) Castro, O., Umana, E. Int. J. Crude Drug Res. 1990, 28, 175 (2) Ohizumi, Y.,et al J. Org. Chem. 2001, 66, 2165.
OHOO
OHOH
OHO
H
O
O
H
H OOO
OHOH
OHO
H
O
O
H
H
H
OH
O
H
(-)-Brasoside 1 (-)-Littoralisone 2
Origins
• Verbena littoralis grows in Costa Rica
• It is a shrub widely used in folk medecine as an effective antidiarrhetic.
• It has also been claimed as a remedy for typhoid fever, for relieving inflammations from insects bites and for cancer.
• First isolation and structure elucidation of Littoralisone in 2001
• This heptacyclic iridolactone glucoside shown activity on PC12D nerve cells.
(-)-Littoralisone retrosynthesis
Intramolecular organocatalysed 1,4-addition
Two steps approach carbohydrate synthesis
OOO
OHOH
OHO
H
O
O
H
H
H
OH
O
H
O
H
HOAc
OO
OH
OTMSO
O
BnO
OO
TMSO
OBn
OBnOBn
O
BnO
OOO
OBnOBn
OBnO
H
O
O
H
H
O
BnO
OOBn
O
OBn
(-)- citronellol
[2+2]
+
(-)-Littoralisone synthesis
OH
O
OMes
ONHPh
OMes
O
OMes
OMes
OH
CO2Me
(-)- citronellol
MesCl, DMAP,pyridine
CH2Cl223°C99%
O3, PPh3
CH2Cl2, MeOHpyridine-78°C96%
i) D-proline, PhN=ODMSO, 23°C
ii) (EtO)2P(O)CH2CO2MeDBU, LiCl, MeCN
-15°C
iii) MeOH, NH4Cl56%
One isomer
1 2
3 4
Enantioselective α-Oxidation of Aldehyde
Stork, G.; Terrell, R.; Szmuszkovicz, J. J. Am. Chem. Soc. 1954, 76, 2029.
Stork, G.; Brizzolara, A.; Landesman, H.; Szmuszkovicz, J.; Terrell, R. J. Am. Chem. Soc. 1963, 85, 207.
R’= Alkyl-X, BzCl, Acrylonitrile
Stork identified the usefullness of a condensed secondary amine on a carbonyl, for α-alkylation on the molecule
Enantioselective α-Oxidation of Aldehyde
(1) Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1973, 38, 3239.(2) Eder, U.; Sauer, G.; Wiechert, R. Angew. Chem. Int. Ed. Engl. 1971, 10, 476.
(1) (2)
Enantioselective α-aminoxylation of Aldehyde
(1) List, B.; Lerner, R. A.; Barbas, C. F. J. Am. Chem. Soc. 2002, 122, 2395. (2) List, B.; Pojarliev, P.; Biller, W. T.; Martin, H. J. J. Am. Chem. Soc. 2002, 124, 827.(3) Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 6798.(4) Bahmanyar, S.; Houk, K. N. J. Am. Chem. Soc. 2001, 123, 11273. (Proposed transition state)(5) List, B.; Lerner, R. A.; Barbas, C. F. J. Am. Chem. Soc. 2000, 122, 2395 (Proposed transition state)
(1)
(3)
(2)
(4-5)
Enantioselective α-amination of Aldehyde (1)
(1) List, B.; J. Am. Chem. Soc. 2002, 124, 5657. (2) Udodong, U. E.; Fraser-Reid, B. J. Org. Chem. 1989, 54, 2103.
First direct catalytic asymmetric α-amination of aldehyde Good yield an ee Product is a useful precursor for 2-oxazolidinones and other α-amino and α-hydrazino acid derivatives
scheme 1
scheme 2(2)
Enantioselective α-aminoxylation of Aldehyde
Zhong, G. Angew. Chem. Int. Ed. 2003, 42, 4247. (June)MacMillan, D. W. C. et al. J. Am. Chem. Soc. 2003, 125, 10808. (July)Hayashi, Y.; Junichiro, Y.; Kazuhiro, H.; Shoji, M. Tetrahedron Lett. 2003, 44, 8293 (August)
Broad scope of compatible functionnality (scheme 1)
Alternative for Aminohydroxylation and Dihydroxylation of terminal alkene (scheme 3)
scheme 1 scheme 2
scheme 3
Enantioselective α-aminoxylation of aldehyde + olefination in situ (1)
(1) Zhong, G.; Yongping, Y. Org. Lett. 2004, 6, 1638. (2) Momiyama, N,; Yamamoto, H. J. Am. Chem. Soc. 2003, 125, 6038
Eliminate problems of purification Acceptable yield (for 2 steps) and good ee’s Good method to create an allylic alcohol
O
OMes
ONHPh
OMes
OH
CO2Me
i) D-proline, PhN=ODMSO, 23°C
ii) (EtO)2P(O)CH2CO2MeDBU, LiCl, MeCN
-15°C
iii) MeOH, NH4Cl56%
One isomer
3 4
scheme 1 (1)
scheme 2 (2)
Donna Blackmond’s et al observation
(1) Mathew, S. P.; Iwamura, H.; Blackmond, D. G. Angew. Chem. Int. Ed. 2004, 43, 3317.(2) Nielsen, L. P. C. N.; Stevenson, C. P.; Blackmond, D. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 1360.(3) Singh, U. K.; Strieter, E. R.; Blackmond, D. G.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 14104
Rate is a lot faster (10min.) compared to other proline catalyzed reaction ex: Aldol reaction between acetone and isobutyraldehyde required 48h at 30mol%
(1)
(2-3)
Rate of the reaction accelerate over time process Experiment suggest an autocatalytic or autoinductive reactions!
Experiment suggest that the reaction is mediated by a proline-product adduct
Donna Blackmond’s et al observation
(1) Mathew, S. P.; Iwamura, H.; Blackmond, D. G. Angew. Chem. Int. Ed. 2004, 43, 3317.
Enantiomeric excess was higher than that expected for a linear relationship Clue to establish a model for the evolution of homochirality through precursor of low optical activity (Rate acceleration + ee’s improvement in time)
(1)
Finding the active specie (1)
(1) Mathew, S. P.; Iwamura, H.; Blackmond, D. G. Angew. Chem. Int. Ed. 2004, 43, 3317.(2) Puchot, C.; Samuel, O.; Dunach, E.; Zhao, S.; Agami, C.; Kagan, H. B. J. Am. Chem. Soc. 1986, 108, 2353(first explanation for non-linear product enantioselectivity)
This scheme showes a general mechanism for a product-induced reaction in which both rate and selectivity improve over time for the case in which one enantiomer is present in excess concentration relative to the other.
First proposition for the improved catalyst: α-effect and bronsted acid
(1)
(1) Iwamura, H.; Mathew, S. P.; Blackmond, D. G. J. Am. Chem. Soc. 2004, 126, 11770.
Rate enhancement is independent of the enantiomer of 3 and the proline utilized No erosion of ee and final configuration dictated by the proline stereochemistry
Utilization of specie 6 improves efficiency (reaction rate) of other proline catalyzed transformations such as aldol and aminoxylation reaction.
Finding the active specie
This reaction presents same nonlinear effect than for the aminoxylation
(1) Iwamura, H.; Mathew, S. P.; Blackmond, D. G. J. Am. Chem. Soc. 2004, 126, 11770.
(1)Finding the active specie
(1) Iwamura, H.; Wells, D. H.; Mathew, S. P.; Klussmann, M.; Armstrong, A.; Blackmond, D. G. J. Am. Chem. Soc. 2004, 126, 16312.
Reaction 2b
a) 10mol% of 5bb) 10mol% of 5cc) 20mol% of 4L
a) and b) presents the same kinetics properties: active specie cannot be 5b or 5c but help the formation of the super catalyst
a) and b) as well as c), show an acceleration proportionnal to the product concentration: acceleration is not due to a solvatation of proline in time
Finding the active specie (1)
three-point hydrogen bonding help to increased the active specie concentration into the cycle In aldol reaction, the two-point hydrogen bonding inhibited the formation of a more active species Transition state (in this proposition) is similar to the first proposed by List and Houk
(1) Blackmond, D. G. et al J. Am. Chem. Soc. 2004, 126, 16312.
Blackmond theory
DFT calculation using B3LYP/6-31G
H
O
O
H
OO
NH
H
O
OH
O
OH
(-)-Littoralisone synthesis
OH
O
OMes
ONHPh
OMes
O
OMes
OMes
OH
CO2Me
(-)- citronellol
MesCl, DMAP,pyridine
CH2Cl223°C99%
O3, PPh3
CH2Cl2, MeOHpyridine-78°C96%
i) D-proline, PhN=ODMSO, 23°C
ii) (EtO)2P(O)CH2CO2MeDBU, LiCl, MeCN
-15°C
iii) MeOH, NH4Cl56%
One isomer
1 2
3 4
(-)-Littoralisone synthesis
OMes
OTBDPS
CO2Me
O
OTBDPS
O
TBDPSClimidazole
DMAP, DMF23°C97%
1) DIBAL, Et2O-78°C96%
2) DMP, CH2Cl223°C
5 6OMes
OH
CO2Me
4
H
H
O
OTBDPSO
O
H
HOAc
TBDPSO
i) L-Proline, DMSO40°C
7 8
ii) Ac2O, pyridineDMAP
0°C83% (2 étapes)
Anomeric effect
O
H
HOAc
OO
11
O
OAc
H
H
VS
2 anomeric effects
1 anomeric effectO
H
HOAc
OO
O
OAc
H
H
O
OTBDPS
O
T (°C)
PhNHMe
CHCl3
CHCl3
CHCl3
DMSO
DMSO
DMSO
O
H
HOH
TBDPSO
A
H
TBDPSO HO
O
B
A:B
30 mol% catalyst
6
entrie catalyst solvent time (h) Combined Yield (%)
1
2
3
4
5
6
+
L-proline 23 12 61 3:1
L-proline 23 48 54 1:19
23 48 87
conditions
1:19
L-proline 40 48 91 10:1
(±)-proline
D-proline
40
40
48
48
86
83
2:1
1:2
O
H
HOH
TBDPSO
A
Only AD-Proline
DMSO48h, 40oC
Organocatalyzed Michael addition
Kinetic control
O
OTBDPS
O
NR2
OTBDPS
O O
H
HOH
TBDPSO
A
H
TBDPSO HO
O
B
1) Enamine / Enone
6
proline +
O
OTBDPS
O
OH
OTBDPS
NR2 O
H
HOH
TBDPSO
A
H
TBDPSO HO
O
B
+
2) Enol/ Eniminium
6
proline
• 2 plausible reactive species
Organocatalyzed Michael addition
• 3 parameter to look at:
1) enol / enamine geometry: trans favored
Me
OR
X
NCO2H
Me
OR
X
OH
N
CO2H
Me
OR
Me
OR
XOH
X
Organocatalyzed Michael addition
2) enol / enamine reactive face
a) Allylic strain
b) Proline’s asymmetric induction / hydrogen bonding
In DMSO,Hydrogen bonding activation is questionable!
Me
OR
ON
CO2H
Me
OR
ON
CO2H
Favored
Me
OR
ON
Me
OR
ON
CO2H
Favored
OO
H
Me
OR
OMe
OR
OX
X
A1,3min
A1,3max
Organocatalyzed Michael addition
c) Relative orientation of nucleophile / electrophile
3) enone / eniminium reactive face
a) Allylic strain
Me
OR
XX Me
OR
X
X
Favored
Me
OR
XXMe
ORX
X
Favored
A1,3minA1,3max
Organocatalyzed Michael addition
b) Proline asymmetric induction
c) nucleophile / electrophile relative orientation
Me
OR
XX
Me
ORX
Favored
X
Me
OR
NX
HO2C
Me
OR
NX
HO2C
Favored
Organocatalyzed Michael addition
O
OTBDPS
O O
H
HOH
TBDPSO
A
H
TBDPSO HO
O
B6
+
10:1
O
OTBDPS
O O
H
HOH
TBDPSO
A
H
TBDPSO HO
O
B6
+
1:2
L-proline
DMSO
DMSO
D-proline
O
OTBDPS
O
NR2
OTBDPS
O O
H
HOH
TBDPSO
A
H
TBDPSO HO
O
B
1) Enamine / Enone
6
L-proline +
10:1
Organocatalyzed Michael addition
Me
OR
ON
CO2H
Me
OR
O
N
CO2H
Me
RO
ON
HO2C
Me
RO
N
HO2C
O
A1,3min
A1,3min
A1,3max
A1,3max
A1,3max A1,3min
A1,3minA1,3max
Majo
Mino
Majo
Mino
O
OTBDPS
O
NR2
OTBDPS
O O
H
HOH
TBDPSO
A
H
TBDPSO HO
O
B
1) Enamine / Enone
6
L-proline +
10:1
Organocatalyzed Michael addition
Me
OR
ON
Me
OR
O
N
Me
RO
ON
Me
RO
N
O
A1,3min
A1,3min
A1,3max
A1,3max
A1,3max A1,3min
A1,3minA1,3max
Mino
Majo
Mino
Majo
CO2H
HO2C
CO2H
HO2C
O
OTBDPS
O
NR2
OTBDPS
O O
H
HOH
TBDPSO
A
H
TBDPSO HO
O
B
1) Enamine / Enone
6
D-proline +
1:2
Organocatalyzed Michael addition
Me
OR
N
HO2C
OH
Me
OR
N CO2H
OH
Me
RO
NOH
Me
RO
OH
N
HO2C
CO2HA1,3min
A1,3min
A1,3min
A1,3minA1,3max
A1,3max
A1,3max
A1,3max
Majo
Mino
Majo
Mino
O
OTBDPS
O
OH
OTBDPS
NR2
O
H
HOH
TBDPSO
A
H
TBDPSO HO
O
B
+
2) Enol / Eniminium
6
L-proline
10:1
Organocatalyzed Michael addition
Me
OR
N
HO2C
OH
Me
OR
N CO2H
OH
Me
RO
NOHCO2H
Me
RO
OH
N
HO2C
A1,3min
A1,3min
A1,3min
A1,3minA1,3max
A1,3max
A1,3max
A1,3max
Mino
Majo
Mino
Majo
O
OTBDPS
O
OH
OTBDPS
NR2
O
H
HOH
TBDPSO
A
H
TBDPSO HO
O
B
+
2) Enol / Eniminium
6
D-proline
1:2
Organocatalyzed Michael addition
• The two combinations implying proline can be operative to explain stereochemistry observed
• Hydrogen bonding to explain diastereoselectivity is questionnable
• Others kinetic datas necessary to identified the reactive specie:
Which active specie you think it is involved? Any other ideas?
Me
OR
N
HO2C
OH
A1,3min
A1,3min
Enol / Eniminium
Me
OR
ON
CO2HA1,3min
A1,3min
Enamine / Enone
Organocatalyzed Michael addition
(-)-Littoralisone synthesis
POCl3
O
H
HOAc
TBDPSO CHO
O
H
HOAc
OO
O
H
HOAc
TBDPSO CO2H
DMF-20°C à 23°C
73%
NaClO2, NaH2PO4
t-BuOH, 2-methylbutène23°C93%
1) HF-pyridine,THF23°C
2) DCC, CH2Cl223°C82%
9
10
O
H
HOAc
TBDPSO
8
11
(-)-Littoralisone synthesis
α:β = 8:1
H
OBn
O
H
OBn
O
HOBn
O
OBn
OHD-proline
Dioxane4:1 dr
98% ee78%
12
BnO
O
O
OHDMP
BnO
O
O
OCH2Cl223°C95%
TMSCl, Et3N
CH3CN23°C82%
13 14
BnO
O
O
OTMS
HOBn
O
OBn
OH
OH
OO
OH
OBn
OBn
O
BnOMgBr2-OEtToluene-20°C
10:1 dr65%
12
1615
TMSO
OZ
HOY
O
OY
OH
OTMS
OZ
OH
OY
OH
OY
O
YO
OH
YO
OZ
OH
Acide de Lewis
H
O
OY
D-Proline
OY
HO2C H
O
OY
H
O
OYOY
OH
Glycosidic part done by a MacMillan methodology
Alan B. Northrup, David W. C. MacMillan, Sciences. 2004, 305, 1752.
1) Enantioselective organocatalyzed dimerisation of aldehydes
2) Mukaiyama aldol + Cyclisation
1) Enantioselective organocatalyzed dimerisation of aldehydes
• α-hydroxyaldehyde must readily participate as both a nucleophilic and electrophilic coupling partner
• product must be inert to enolization and or carbonyl addition
Alan B. Northrup, David W. C. MacMillan, Sciences. 2004, 305, 1752.David W. C. MacMillan et Al. J. Am. Chem. Soc. 2003, 125, 10808.Northrup, A. B.; Mangion, I. K.; Hettche, F.; MacMillan, D. W. C. Angew. Chem. Int. Ed. 2004, 43, 2152
Carbohydrate synthesis in two steps via 2 selective aldol reactions
H
OR
O
H
OR
O
O H N
O
O
RORO
HOR
O
OR
OH
OH O
RORO
D-proline
98% ee4:1
78%
2) Mukaiyama aldol + cyclisation catalysed by a lewis acid
Alan B. Northrup, David W. C. MacMillan, Sciences. 2004, 305, 1752.
Carbohydrate synthesis in two steps via 2 selective aldol reactions
TMSO
OZ
HOY
O
OY
OH
OTMS
OZ
OH
OY
OH
OY
O
YO
OH
YO
OZ
OH
Acide de Lewis
Carbohydrate synthesis in two steps via 2 selective aldol reactions
Alan B. Northrup, David W. C. MacMillan, Sciences. 2004, 305, 1752.
OO
OH
OBn
OBn
O
BnO OH
OO
TMSO
OBn
OBn
OBn
O
BnO
OO
OBn
OBn
OBn
O
BnO OH
OO
OBn
OBn
OBn
O
BnO
BnO
TMSCl, Et3NPd/Al2O3, HCO2NH4
MeOH23°C68%
BnBr, Ag2O
CH2Cl223°C
PhH80°C91%
16 17
18 19
(-)-Littoralisone synthesis
α:β = 8:1
α:β = 12:1 β only
(-)-Littoralisone synthesis
O
H
HOAc
OO
OO
TMSO
OBn
OBn
OBn
O
BnO
OO
OHOH
OOHO
H
O
O
H
H
H
OH
O
H
TMSOTf (0.3 equiv.)
OOO
OBnOBn
OBnO
H
O
O
H
H
O
OBn
+CH3CN-30°C74%
1) hu (350 nm)PhH23°C
2) 50 mol% Pd/C, H2EtOAc23°C
84% (2 steps)
(-)-Littoralisone
11 19 20
• Efficient and convergent synthesis
• 13 steps for the longest sequence
• 13% overall yield (average of 85% per step)
• 13 stereocenters installed, 14th from chiral pool
• 6 steps of protection / deprotection
Conclusion