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Boronic Acids and Esters in the Petasis-Borono Mannich Mult
icomponentReaction
Wu Hua
2010-9-25
Research:
• New chemistry of organotitanium compounds
• New chemistry of organoboron compounds
• New Synthetic Methods and Strategies
• Lipoxins and other Lipids
B.S., 1978, Aristotelian University of Thessaloniki, GreecePh.D., 1983, University of Pennsylvania
Mechanism of the Mannich Reaction :
HO
HN R
R
H
O
HH
N
H
RR + H+/ - H-
NR
R
HO
HH
H+
NR
R
O
HH
HH - H2O H
HN
R
RNR
R
H
H
O
R
H H
R'
-H+ O
R'
H
R
O
R'
H
R
NR
RH
H
O
R'R
R2N
Major advantage of this MCR:
b.Large variety of organoboronic acids are readily available.
a.Immense potential scaffold variability.
c.Most of these compounds are also air- and water-stable as well as low-toxic and environmentally friendly .
d.boronic acids also tolerate many functional groups, thereby allowing the facile synthesis of multifunctional molecules without the excessive use of protecting groups.
N. A. Petasis, I. Akritopoulou, Tetrahedron Lett. 1993, 34, 583.
This 3-CR (3-component reaction) can also been described as a boronic acid Mannich variant.
Reaction of vinyl boronic acids with the adducts of secondary amines andparaformaldehyde gives tertiary allylamines. This simple and practical method was used for the synthesis of geometrically pure naftifine, a potent antifungal agent.
NH
(a) (CHO)2dioxane, 90¡æ, 1h
(b)
BHO
HO
Ph
90¡æ, 30min
N Ph
NH
R3R2
H
O
R4
OH
NR3R2
R4HO
OH
NR3R2
R4H
O
HOB
OH
R1
NR3R2
R4H
OB
OHHO
R1
NR3R2
R4R1
OB
OHHO
NR3R2
R4
OH
R1
B(OH)3
+ -H2O
H2O+
General Mechanism:
O
OH H
O
OH
O
HR
OH
O
glycolaldehydeglyoxylic acidsalicylaldehyde
a. A complete study of three different aldehydes demonstrated the following order of reactivity: glycolaldehyde > glyoxylic acid > salicylaldehyde.
b. Regarding the nature of the boronic acids employed in the reaction, vinyl boronic acids are in general more reactive than their aryl counterparts.
A new, general, and practical method forthe synthesis of β,γ-unsaturated α-amino acids.
Nicos A. Petasis. J. Am. Chem. Soc. 1997, 119, 445-446
R3
R2B
OR
OR
NR5
HR6
R4 O
O OH
R3
R2
NR4
R5
R6
O
OHR1
Koolmeister, Scobie, M. Tetrahedron Lett. 2002, 43, 5965.
R2NH
R1
H
OOH
O
R3
B
O
OCH2Cl2, r.t.
R3
N
COOH
R2 R1
+
Jourdan, Piettre, S. R. Tetrahedron Lett. 2005, 46, 8027.
R2NH
R1
H
OOH
O
R3
B
O
O
R3
N
COOH
R2 R1
+
Analogously to the condensation with phenyl boronic acid derivatives, heteroaryl amino acids were also obtained in good yields from heteroaryl boronic acids.
More reactive than their aryl counterparts.
Petasis, N. A.; Goodman, A.; Zavialov, I. A. Tetrahedron 1997, 53, 16463.
S
COOH
NH
Ph
Ph
S
HN
COOH
OMe
O
COOH
NH
Ph
Ph
O
HN
Ph
Ph
COOH
92% 79% 81% 84%
(a) microwave irradiation, 120 C, 10 min, DCM; (b)TMS–diazomethane, THF, rt, 3 h.
(a) microwave irradiation, 120 C, 10 min, DCM
N. J. McLean. Tetrahedron Letters, 2004, 45, 993–995
Electron-poor (hetero-)anilines often gave unsatisfactory yields and conversions. However, Sanofi-Aventis chemists could show that even these problematic cases can be easily mastered under microwave conditions.
O
O
HOB
OH
OHArHN
R2
R1O
O
NR1
R2
Ar
a, b+ +
B
OH
OHArHN
R2
R1
a+ +
O
OH
N
ArR2
R1OH
N
OH
OO
H N
HOOCOH
H
N
HOOCOH
+B
OH
OHH
R = aryl
N
OH2
OOB
OHHO
R
N
OOB
OHHO
R
N
OOB
OHHO
R
N
RO
OBOHHO
N
RHO
O
Naskar, D.; Neogi, S.; Roy, A.; Mandal, A. B. Tetrahedron Lett. 2008, 49, 6762.
The presence of a substituent in the nitrogen atom of the indole ring was observed to be crucial to success of the reaction. In the absence of such a substituent, low yields of the corresponding product were obtained.
N. A. Petasis, Tetrahedron Letters, 42 (2001) 539–542
B
OH
OH
R1
R3
R2
R4NH
R5
OH
H
O
R6R1
R3
R2
NR5R4 OH
R6
+ +
N
OHOH
R4
R5
- H2O
R6
OB
OHOH
R3
R2
R1
N
R5
R4
H2O
- B(OH)3
Salicylaldehyde and Derivatives
O R
Ph NH
Ph H
O
OH
RO
H
N PhPh
RO
N PhPh
B(OH)2
H
O
N PhPh
(HO)2B
R
H
OH
N PhPh
R
BHO
OH
Wang, Q.; Finn, M. G. Org. Lett. 2000, 2, 4063.
Pedro M. P. Gois. Eur. J. Org. Chem. 2009, 1859–1863
Water as the solvent
Stas, S.; Tehrani, K. A. Tetrahedron 2007, 63, 8921.
NR2
ClCl
R3BF2
R3BF3K
BF3.OEt-KBF4
NR2
ClCl
BF F
R3
NR2
ClCl
F2B
R3
NaOH HNR2
ClClR3
Cl ClH
N
D D
RBF3KBF3.Et2O
N
ClCl
B
R
FF DD
N
ClCl
B
R
FF DD
Cl Cl
NB
D
D
FF
R
Cl Cl
NB
D
D
FF
R
Aqueous Workup
Cl Cl
HN D
DR
Stas, S.; Abbaspour Tehrani, K.; Laus, G. Tetrahedron 2008, 64, 3457.
Aza-cope rearragement
Petasis reaction has been tested for this proposal in three different approaches.
a. The first comprises the use of a stereogenic carbon in the amine that can induce some regioselectivity on the formation of the new carbon-nitrogen bond.
b. Enantiopure or enantioenriched boronic ester, resulting in the formation of an enantiomerically pure side product.
c. A more elegant process is the use of a chiral ligand that can complexwith the boronic ester.
Asymmetric Petasis-Borono Mannich Reaction
The first report in the asymmetric version of this reaction was made by Petasis, using an enantiomerically pure aminewith two different boronic acids.
Petasis, N. A.; Goodman, A.; Zavialov, I. A. Tetrahedron 1997, 53, 16463.
PhB
OH
OH
H2N
Ph
CH2Cl2, r.t.
Ph COOH
HN
Ph
H
O
OH
O H2NOH
Ph
CH2Cl2, r.t. Ph COOH
HN
Ph
OH
88% ( 66%de)
78% (>99%de)
Jiang, B.; Yang, C.-G.; Gu, X.-H. Tetrahedron Lett. 2001, 42, 2545.
N-tosyl-3-indolylboronic acid reacted with glyoxylic acid using chiral methylbenzylamine as the chiral auxiliary and the secondary amines were obtained exclusively as one diastereoisomer in reasonable yields
NR
B(OH)2
Ts
Ph
NH2
H COOH
O CH2Cl2r.t., 12h
NR
Ts
COOHHN
Ph
+ +
B
Oi-Pr
i-PrO
R1
O N
R2H
+
Ph
OH
OH
Ph15 mol%
Molecular SievesC6H5CH3, r.t.
R2
HN O
R1
Ph
O
OH
Ph
BO
up to 94% Yield >99% ee
Lou, S.; Moquist, P. N.; Schaus, S. E. J. Am. Chem. Soc. 2007, 129, 15398.
N
R1 R2
R4
R3
B(OH)2
PhOCOCl CatalystH2O,NaHCO3,DCM
N
R1 R2
COOPh
R4
R3
CF3
F3C NH
NH
S
N
HOCatalyst
Yamaoka, Y.; Miyabe, H.; Takemoto, Y. J. Am. Chem. Soc. 2007, 129, 6686.
The best enantioselectivities were reported by Takemoto and co-workers in the addition of boronic acids to N-acylated quinoline salts.
CF3
F3C N N
S
N
OB
HO
Ph
H HO
N OR
ElectrophileActivation
NucleophileActivation
Lou, S.; Schaus, S. E. J. Am. Chem. Soc. 2008, 130, 6922.
PhB
OEt
OEt
R1 NH
R2
H
O
COOEt
15mol% (S)-VAPOL
Molecular sieves Toluene
Ph COOEt
NR2R1
OH
Ph
Ph
OH
(S)-VAPOL
HO OH
O
Ph NH2
H3C(H2C)7+ Et2O, r.t.
HNPh
HO
HO
(CH2)7CH3
NH2HO
HO
(CH2)7CH3
FTY72028% overal yield
O OH
OH
OH OH
PhB(OH)2
allyl-amine
Et2Or.t., 16h
RN
PhH
HOHO
OR
HON
HO
HO
H OH
OH
OH
Uniflorine A
Application
FF
O OH
1. Oxalyl Chloride DMF, CH2Cl2
2.N
TMS
Ph H
FF
O N
H Ph
B
Oi-Pr
i-PrO
(S)-3,3'-Ph2-BINOL 15mol%
Molecular SievesC6H5CH3, r.t.
F F
OHN
Ph
F F
OHN
Ph NN
NN
75% Yield>91% ee Maraviroc
A new class of compounds for HIV therapy.
a. Typically Pt-3CR works satisfactorily with secondary or hindered primary amines, hydrazines and anilines in solvents such as DCM at room temperature. Alkenyl, electron-rich and electron-neutral (hetero-)aryl boronic acids can be employed.
c. As a result of this exquisite reactivity, the Petasis reaction (Scheme 1) has become an attractive method for the preparation of an assortment of compounds, amongwhich amino acids, heterocycles and alkylaminophenols are the most easily accessible.
Summary
b. The use of secondary amines is desirable when compared to primary ones, since the latter usually results in low yields because of the lower reactivity of the imine compared to the iminium formed from the former.
a. Regarding the asymmetric version, no suitable chiral catalyst has been developed for the general reaction.
b. One other aspect that seems to be prominent is the discovery of substitutes for each component of the reaction, particularly the discovery of new suitable aldehydes without the need of a hydroxyl group for the boron activation.
Problem
O
OH H
O
OH
O
HR
OH
O
glycolaldehydeglyoxylic acidsalicylaldehyde
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