Pentanidium catalyzed enantioselective phase transfer reactions 3

Generally, classic asymmetric C-N bond formation reactions include amination of ketones, aldehyde, esters and Mannich reactions of imines.1 3.1.1 Mannich reaction with nitrogen nucleophi

Chapter 3

Pentanidium Catalyzed Enantioselective Phase-Transfer

Amination Reaction

3.1 Introduction to asymmetric C-N bond formations

A recent report about the potential drug candidates indicates that 90% of these

molecules contain nitrogen and 54% are chiral.1 Furthermore, in this report, it is

shown that 19% of the reactions utilized carbon–heteroatom bond-forming reactions

This is the reason why new stereoselective carbon–heteroatom bond forming reactions

are very important Various C-N bond formation reactions were developed so that

diverse structures can be readily accessed Generally, classic asymmetric C-N bond

formation reactions include amination of ketones, aldehyde, esters and Mannich

reactions of imines.1

3.1.1 Mannich reaction with nitrogen nucleophiles

Asymmetric additions of carbon nucleophiles to imines have been a popular area of

study by many research groups.2 Catalytic asymmetric Mannich reactions have been

well investigated during the last two decades, including Brønsted base catalysis,

Brønsted acid catalysis, transition metal catalysis, enamine catalysis, phase-transfer

catalysis and thiourea catalysis. 3

As a new approach to catalytic imine addition chemistry, utilizing nitrogen

nucleophiles to imines to produce protected aminals, has rarely been investigated with

limited examples In 2005, Antilla’s group developed Brønsted acid catalyzed imine

amidation4, which was inspired by the addition of nitrogen nucleophile to enone

mediated by metals or Brønsted acid Previous works required doubly activated imine

which contains electron-withdrawing groups at the imine nitrogen and the carbon

This is the first report of general catalytic addition of amine to imine (Scheme 3.1)

Under Brønsted acid S-VAPOL conditions, sulfonamide attacks various Boc-protected

imines to afford excellent yields and ee, up to 99%

Scheme 3.1 Asymmetric imine amidation with TsNH2 catalyzed by 117 S-VAPOL

However, this reaction was limited to sulfonamide nucleophiles, with other amides

affording lower enantioselectivities Later in the same year, Antilla group5 broadened

the substrate scope by applying phthalimide as nucleophile for the addition of imide

to imines (Scheme 3.2)

Scheme 3.2 Asymmetric imine amidation with phthalimide catalyzed by 117

S-VAPOL

Although possibly considered metabolically unstable, cyclic aminals and acetals are

relatively common structural elements of diverse commercial pharmaceuticals

Realizing the ubiquitous occurrence of stereogenic cyclic aminals and similar

structures in drugs and other compounds of use and the lack of available

enantioselective routes toward their preparations, asymmetric synthesis of chiral

aminals shows great importance Protected aminals have been incorporated into many

peptide chains, which is so called retro-inverso mimic.6 These retro-inverso peptide

mimics was first popularized by Goodman, due to the applications as proteinase

inhibitors, neurotensins, somatostatins, glycosidase inhibitors, amino acid based

sweeteners.7 Previously, methodologies to synthesize aminal products have normally

been through Curtius or Hoffman-type rearrangements6 of protected amino acid

derivatives or by a benzotriazole-mediated approach by Katritzky.8

Figure 3.1 shows several gem-diamine containing pharmaceuticals, which include

Aquamox and Thiabutazide, two members of the benzo(thia)diazine class of cyclic

aminals used for the treatment of high blood pressure.9a Other examples include S,

O-acetal Cevimeline,9b O, O-acetal Pipoxolan,9c N, N-acetal Physostigmine,9d which

are all useful pharmaceuticals

Figure 3.1 Gem-diamine containing pharmaceuticals

List’s group10 also developed a direct synthesis of chiral aminals from aldehydes

using chiral phosphoric acid 123 as catalyst After screening various phosphoric acids

including VAPOL, high ee was obtained with 123 was as catalyst, affording up to 99%

ee (Scheme 3.3) Aliphatic aldehydes provide excellent results, while benzaldehyde

only gave moderate ee value Furthur more, the substrate sulfonamides could also

give corresponding cyclic products with excellent enantioselectivities This

methodology has also been applied to synthesize pharmaceutically relevant

compounds 124a-e as shown in Figure 3.2.10

Scheme 3.3 Synthesis of chiral aminals from aldehydes using 123 as catalyst

Figure 3.2 Pharmaceutically relevant compounds

3.1.2 Amination reaction with azodicarboxylate

Stereoselective C-N bonds formation reaction through the direct amination of

substrates is also an important synthetic strategy for organic synthesis One of the

most important amination methodologies is α-amination of carbonyl compounds

through the use of azodicarboxylates, which was developed by Evans via a chiral

catalyst, magnesium bis(sulfonamide) complex.11 Many classes of carbonyl

compounds, such as aldehyde, ketone, α-keto esters, oxindoles and α-cyano esters had

been used in amination reactions with azodicarboxylates A large amount of works

have appeared in this area, so several representative examples were chosen to be

presented here

Early in 2002, Jørgensen’s group had developed direct asymmetric α-amination of

aldehyde with L-proline, providing α-amino aldehyde 127, α-amino alcohols 128a

and α-amino acids 128b.12 Excellent yields and enantioselectivities were obtained

(Scheme 3.4)

Scheme 3.4 Enantioselective α-amination of aldehyde by L-proline

Recently, Lu’s group applied cinchona alkaloid derived primary amine 130 as catalyst

to furnish the asymmetric amination of α-branched aldehyde (Scheme 3.5).13 CSA

was required to form the chiral ion pair, which shows to be the real catalyst in the

catalytic cycle

Scheme 3.5 Enantioselective amination of α-branched aldehyde by 130

Also, cinchona alkaloid derived primary amine 134 could also be applied in the

asymmetric amination of aromatic ketones Chen’s group realized the transformation

by using 134 as catalyst, achieving excellent results (Scheme 3.6).14

Scheme 3.6 Enantioselective amination of aromatic ketone by 134

Our group have also developed C-N bonding formation by using fluorinated aromatic

ketones as nucleophiles.15 Chiral bicycic guanidine 138 was basic enough to abstract

the double activated H This methodology provides a facile route to the construction

of fluorinated quaternary stereogenic centers (Scheme 3.7)

Scheme 3.7 Enantioselective amination of fluorinated aromatic ketone catalyzed chiral bicycic guanidine 138

Lu’s group applied the similar strategy, using fluorinated compound as nucleophile, to

achieve highly enantioselective amination of fluorinated β-keto ester by novel chiral

guanidine 139 derived from cinchona alkaloids (Scheme 3.8).16 Fluorinated products

could be transformed to fluorinated Penicillin derivatives easily

Scheme 3.8 Enantioselective amination of fluorinated keto ester by chiral guanidine

139

In the area of guanidine catalysis, Terada’s group developed binaphthyl derived

axially chiral guanidine as catalyst for the highly enantioselective amination of 1, 3-

dicarbonyl compounds.17 Due to the high reactivity and efficience, catalyst loading

could lower down to 0.05 mol% (Scheme 3.9)

Scheme 3.9 Enantioselective amination of 1, 3-dicarbonyl compounds by axially chiral guanidine 144

Amination of 1, 3-dicarbonyl compounds could also be easily achieved by

phase-transfer catalysis Maruoka’s group reported a new binaphthyl-derived

quaternary phosphonium salt as chiral phase-transfer catalyst, which shows excellent

reactivity and enantioselectivity towards the asymmetric amination of β-keto eters.18

Scheme 3.10 Enantioselective amination of β-keto eters by phase-transfer catalyst

147

Shibasaki’s group realized the enantiofacial selectively amination of oxindoles by

using bimetallic and monometallic Schiff base catalysis.19 When Z is OH, two Ni

atoms would coordinate to the ligand, which leads to R enantiomer selectively While

Z is protected by methyl group, only one Ni atom could coordinate with the ligand,

which leads to S enatiomer selectively (Scheme 3.11)

Scheme 3.11 Enantiofacial selectivity switch in bimetallic vs monometallic Schiff

base catalysis

In the amination of α-substituted α-cyanoacetates reactions, Deng’s group also could

tune R and S enantiomer selectively by using quinine and quinidine catalyst 152

(Scheme 3.12).20 Products containing nitrogen-substituted quaternary stereocenters

are potential chiral building blocks, such as α, α-disubstituted α-amino acids

Scheme 3.12 Amination of α-substituted α-cyanoacetates by quinine and quinidine catalyst 152

Besides reaction Mannich reaction and amination, there many other reactions could

also generate C-N bond, such conjugate addition of azides, siloxyamine, for amination

in particular, not only azodicarboxylate, but nitrosobenene type compounds were

reported for hydroxylamination reaction

Despite the great success of amination reactions, few groups have investigated the

α-amination of glycinate Schiff bases, to obtain asymmetric gem-diaminal glycine

derivatives Such derivatives can be easily modified to obtain chiral α, α-diamino

carbonyl compounds, which provided an alternative synthetic route to the chiral

aminal subunits found in pharmaceutical drugs In 2009, Zhou et al utilized a

bifunctional AgOAc catalyst for the α-amination of glycinate Schiff bases to obtain

adducts with enantioselectivity up to 98% ee (Schem 3.13).21 However, to date, no

report has been described the use of asymmetric phase-transfer catalysis for the

synthesis of these optically active α-amino acid derivatives, by emulating the

approach of phase-transfer reactions

Scheme 3.13 Enantioselective α-amination of glycinate Schiff bases 1 with 154 Our pentanidium 80a shows excellent reactivity toward conjugate addition reaction of

glycinate Schiff bases So similarly, it might also show similar reactivity toward

α-amination reaction of glycinate Schiff bases Herein, we describe the

enantioselective α-amination of glycinate Schiff bases by pentanidium with good

yield and enantioselectivity

3.2 Pentanidum catalyzed asymmetric α-amination of glycinate Schiff

base

Similarly, α-amination of glycinate Schiff base proceeded via a nucleophilic conjugate

addition pathway 1 was first deprotonated by base to form an anionic enolate species,

which attacked the electrophilic N=N double bond in 126c A preliminary screening

for α-amination of glycinate Schiff base 1 was done using 126c under phase-transfer

conditions to determine whether asymmetric induction by pentanidium was present

Using NaOH(s) at room temperature and toluene as solvent, an enantioselectivity of

33% ee was obtained With this promising lead, further optimization was pursued, in

an attempt to further improve enantioselectivity using pentanidium as a chiral

phase-transfer catalyst

Scheme 3.14 Enantioselective α-amination of glycinate Schiff bases 1 by pentanidium 80a

3.2.1Optimization studies

Initial optimization studies were done at room temperature using weak bases in toluene, which included carbonates and fluoride salts Increasing the basicity of carbonates had a positive effect on the enantioselective outcome This was indicated

by an increase in ee from sodium (28% ee) to potassium (48% ee) and cesium (50%

ee) carbonate, which correlated with the increase in size of the metal ion on going

down the group (Table 3.1, entries 1-3) Stronger carbonates also improved in conversion rates, and higher yields could be obtained within shorter times The effect

of water on enantioselectivity was next studied by using saturated Cs2CO3 (aq) as

base Unfortunately, enantioselectivity decreased slightly to 43% ee, and the reaction

took twice as long to complete (entry 4) This was probably due to the hydration of carbonate anions by water molecules leading to a reduction in basicityand diminished

ability to deprotonate the acidic proton in 1 Other carbonates used such as Zn2CO3 and Ag2CO3 either gave poorer yields or ee values, and hence not suitable for use in

further optimization

A similar trend could be observed for fluoride salts, and enantioselectivity was

increased when the base was changed from KF (46% ee) to CsF (60% ee) (entries 7

and 8), this corresponded to an increase in the base strength due to the larger metal counter cation CsF was thus promising as a potential base for the α-amination reaction On the other hand, stronger bases such as sodium hydroxide increased

reaction rate, but led to side products due to hydrolysis of the labile ester group in 1

and gave a reduced ee value of 33% at room temperature The enhanced reaction rate

for hydroxides encouraged us to lower the temperature further to determine if

enantioselectivity could be improved

Table 3.1 Investigation on the effect of base on α-amination reaction

a Reactions conducted using 0.01 mmol of 1 and 126c in 0.5 mL toluene for indicated time b Solid base

used, unless otherwise stated c Yield of isolated product d Determined by chiral HPLC using Chiralpak

AD-H column

Since Cs2CO3 and CsF gave relatively high ee values (50% and 60%, entries 3,8

respectively) at room temperature with moderately fast reaction rates, further

optimization was conducted at a reduced temperature of 0oC Unfortunately, the

reaction proceeded extremely slowly for Cs2CO3 and an almost equivalent ee value of

51% (Table 3.2, entry 1) was obtained (as compared to room temperature)

Furthermore, the reaction did not proceed for CsF, and no product was observed after

2 days (entry 2) Thus, stronger bases were subsequently investigated at 0oC, and

reaction rate was greatly enhanced, with the exception of LiOH·H2O and Ca(OH)2,

which gave either poor ee values or no product at all (entries 3 and 11) When

temperature was reduced to 0oC for NaOH, enantioselectivity increased from 33% to

55% ee (entry 4) However, further reduction in temperature to -20oC reversed the

trend, and enantioselectivity dropped to 40% ee (entry 5) This could possibly be due

to a greater negative effect of the temperature reduction on the rate of the catalyzed

Table 3.2 Investigation on the effect of temperature on α-amination reaction

a Reactions conducted using 0.01 mmol of 1 and 126c in 0.5 mL toluene for indicated time b Solid base

used, unless otherwise stated c Yield of isolated product d Determined by chiral HPLC using Chiralpak

AD-H column