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