Pentanidium catalyzed enantioselective phase transfer reactions 1

Figure 1.3 Interaction between glycine Schiff base enolate and ammonium cation 1.2 Asymmetric Phase-Transfer Catalysts - Chiral Quaternary Ammonium Salt.. The asymmetric alkylation of

Chapter 1

Asymmetric Phase-Transfer Catalysis

Catalyst and Reactions

1.1 Introduction to Asymmetric Phase-Transfer Catalysis

Early in the mid to late 1960s, Starks together with Makosza and Brandstrom reported the catalytic activity of quaternary onium salts,1 which was the starting point of phase-transfer catalysis Since then, phase-transfer catalysis went through an exponential growth as a practical methodology for organic synthesis The advantages

of this method lie in their simple experimental procedures, mild reaction conditions, inexpensive and environmentally reagents and solvents, and the possibility of conducting large-scale preparations.2 Nowadays, it becomes one of the most important synthetic methods used in various fields of organic chemistry, and also in many industrial applications However, the development of asymmetric phase-transfer catalysis based on the use of structurally well-defined chiral, nonracemic catalysts had progressed rather slowly Invention and development of novel chiral phase-transfer catalysts (PTCs) for suitable reactions are the driving force in phase-transfer catalysis, including chirarity installation and chiral modification to tetraalkylonium ions (Q+) Ever since chiral phase-transfer catalysts derived from cinchona alkaloids were uncovered in 1980s, 3 asymmetric phase-transfer catalysis stepped into a new era In particular, during the last two decades, asymmetric phase-transfer catalysis has drawn great scientific interest, and recent efforts have resulted in notable achievements

1.1.1 General Mechanism of Asymmetric Phase-Transfer Catalysis

In 1971, Starks proposed the term “phase-transfer catalysis” to explain the acceleration of reaction rate in the reaction between two substances located in two

different immiscible phases in the presence of trtraalkylammonium or phosphonium salts.4 For example, the rate for the replacement reaction of 1-chlorooctane with aqueous sodium cyanide is accelerated by hexadecyltributylphosphonium bromide for thousands times Phosphonium salts can transfer the cyanide anion from aqueous phase to organic phase by forming a quaternary phosphonium cyanide complex which makes the cyanide anion more soluble in organic solvents and sufficiently nucleophilic Therefore, the reactivity of cyanide is tremendously enhanced in this process The high rate of displacement is mainly due to the three characteristic features of the pairing cation (Q+): organic soluble, high lipophilicity and the large ionic radius

Generally, in asymmetric phase-transfer catalysis, two representative mechanisms were proposed for phase-transfer catalyzed reactions First one is base catalyzed phase-transfer reactions Typically, under basic condition, active methylene or methine groups could be easily functionalized by phase-transfer catalysis Glycinate Schiff base 5 is selected as the example to illustrate how the mechanism works (Figure 1.1)

As shown in Figure 1.1, reaction proceeds from the interfacial deprotonation step

Substrate 1 was deprotonated at the interface by the base from aqueous phase to give

the corresponding metalenolate, which stays at the interface of the two layers Subsequently, phase-transfer catalyst and metalenolate would undergo ion-exchange process to generate lipophilic chiral onium enolate, which could diffuse rapidly into

Figure 1.1 General mechanisms for the asymmetric alkylation of glycine Schiff base

the organic phase Since enolate is in organic phase as homogeneous state, it would

react with the electrophile RX much faster to afford the optically active

monoalkylation product Meanwhile, enolate generated at the interface shows low

reactivity due to the less contact with electrophile This type of reactions only works

on two conditions: 1: ion-exchange step is sufficiently fast and chiral onium enolate is

highly reactive (thousands times faster than the reaction between enolate and RX) 2: phase-transfer catalyst Q+ should provide effective shielding of one of the two enantiotopic faces of the enolate anion The former minimizes the intervention of the direct alkylation of metal enolate to give racemic product, and the latter rigorously controls the absolute stereochemistry In general, reaction variables (base, solvent, temperature, substrate concentration, and stirring rate) can be tuned to optimize the reactions Another, relatively less-studied system is the nucleophilic addition of an organic or inorganic anion to prochiral electrophiles Chiral phase-transfer catalyst undergoes ion-exchange process with the anion, which is usually used as aqueous

solution of solid, to generate a chiral ion pair Then the anion would attack a prochiral electrophile to create a new chiral center The asymmetric epoxidation of chalcone using an aqueous solution of sodium hypochlorite is used as a typical example (Figure 1.2) Chiral onium hypochlorite (Q*+OCl-) is formed at the interface by ion-exchange, which would penetrate into the organic phase and react with the ennone.6 Differing from the previous example, chiral cation (Q+) should be designed to recognize enantiotopic face of the electrophilic reacting partner

Figure 1.2 General mechanism for the nucleophilic addition of anions to prochiral

(Figure 1.3).7 Three faces of this tetrahedron (F1.F2.F3) are efficiently blocked by steric groups, leaving one face (F4) sufficiently open to allow close contact between the enolate (of substrate) and the ammonium cation (of the catalyst) F1 was totally blocked by the ring system itself F2 was blocked by the allyl or benzyl group of the secondary hydroxyl group F3 was blocked by the substituent of the nitrogen The extended π conjugation of the enolate and the imine adopt a face to face π interaction with the quinoline, which blocks one face of the E-enolate of imine So the electrophile could only approach from the the other face to afford one enantiomer7

Figure 1.3 Interaction between glycine Schiff base enolate and ammonium cation

1.2 Asymmetric Phase-Transfer Catalysts - Chiral Quaternary

Ammonium Salt

1.2.1 Cinchona Alkaloid Based Phase-Transfer Catalysts

1.2.1.1 First generation

In 1989, five years after the pioneering work by the Merck research group,8a Cinchona alkaloid derived ammonium was successfully utilized as catalyst for the asymmetric synthesis of -amino acids by O’Donnell et al.,8b,c by using glycinate Schiff base 1 as

a key substrate (Scheme 1.1) The asymmetric alkylation of glycinate Schiff base 1

preceded smoothly under mild phase-transfer conditions, with N-(benzyl)-

cinchoninium chloride 3 as catalyst, giving the alkylation product (R)-5 in good yield

and moderate enantioselectivity (Scheme 1.1, eq 1) By simply switching to the

cinchonidine derived catalyst 4, the product could be obtained with a similar degree of

enantioselectivity, but with the opposite absolute configuration (S) (Scheme 1.1, eq 2)

Scheme 1.1 Asymmetric alkylation of glycinate Schiff base 1 with 3 or 4

1.2.1.2 Second generation

In the investigation of alkylation reaction of glycinate Schiff base 1, it was found that

the O-alkylated ammonium salts show significant improvement.9 Ammonium

bromide 6a-b (Figure 1.4), give 81% ee in the asymmetric phase-transfer catalyzed

alkylation reactions

Figure 1.4 O-alkylated N-(benzyl)-cinchoninium and cinchonidinium bromide

1.2.1.3 Third generation

Although asymmetric alkylation of the glycinate Schiff base 1 can be achieved by

using chiral phase-transfer catalysts derived from the relatively inexpensive, commercially available cinchona alkaloids, research in this area was rather slow, due

to the low reactivity and enantioselectivity However, a new class of cinchona alkaloid derived catalysts bearing an N-anthracenylmethyl group (third-generation catalysts) developed by two independent research groups have opened up a new era of

asymmetric phase-transfer catalysis In 1997, Lygo et al. developed the

N-anthracenylmethylammonium salts 7 and 8, 10 and applied them to the asymmetric

phase-transfer alkylation of 1 to synthesize -amino acids with much higher

enantioselectivity (Scheme 1.2) At the same time, Corey et al.11 prepared

O-allyl-nanthracenylmethyl cinchonidinium salt 11 By using solid cesium hydroxide

monohydrate (CsOH·H2O) at very low temperature, they achieved a high asymmetric

induction in the enantioselective alkylation of 1 (Scheme 1.3)

Scheme 1.2 Asymmetric alkylation of glycinate Schiff base 1 with N-anthracenyl

methyl ammonium salts 7 and 8

Scheme 1.3 Asymmetric alkylation of glycinate Schiff base 1 with 11

1.2.1.4 Bis- and tri- ammonium salts

During the development of the asymmetric sharpless dihydroxylation, it was found that ligand with two cinchona alkaloid unites attached to hetercyclic spacers led to a considerable increases in both the enantioselectivities and the scope of substrates This effect had been utilized successfully by Jew, Park, and co-workers for the design

of new chiral phase-transfer catalysts, with two and three cinchona alkaloid units, respectively.12 These catalysts substantially enhanced the enantioselectivities of the

alkylation of 1 and also expanded the range of alkyl halides During the search for the

ideal aromatic spacer, they found that catalyst 12 consisting of 2,7-bis(bromomethyl)

-naphthalene and two cinchona alkaloid units exhibited remarkable catalytic activity

and efficiency Thus, 1 mol% of 12 was sufficient for the asymmetric alkylation of 1

with various alkylating agents (Scheme 1.4).12

Scheme 1.4 Asymmetric alkylation of glycinate Schiff base 1 with 12

1.2.2 Binaphthyl Based Chiral Spiro Ammonium Salts

1.2.2.1 Bis-binaphthyl based ammonium salt

In 1999, Maruoka’s group13 deleloped the structurally rigid, chiral spiro-ammonium

salts 13 (Figure 1.5), which were derived from commercially available (S)-1,1’-bi-2-

naphthol, as new C 2-symmetric phase-transfer catalysts and successfully applied them

to the highly efficient, enantioselective alkylation of 1 under mild phase-transfer

conditions The key finding was a significant effect of an aromatic substituent at the 3, 3’-position of one binaphthyl subunit of the catalyst (Ar) on the enantiofacial

discrimination (S, S)- 13e proved to be the catalyst of choice for the preparation of a

variety of essentially enantiopure α-amino acids by this transformation In general, 1

mol% of 13e was sufficient for the smooth alkylation, and the catalyst loading could

be reduced to 0.2 mol% without loss of enantiomeric excess The use of aqueous cesium hydroxide (CsOH) as a basic phase at low reaction temperature was recommended for the reaction with simple alkyl halides such as ethyl iodide

Figure 1.5 Bis-binaphthyl based ammonium salts 13a-13e

1.2.2.2 Binaphthyl biphenyl substituted ammonium salt

Although the conformationally rigid, N-spiroammonium compounds with two chiral

binaphthyl subunits represent a characteristic feature of 13, they also impose

limitations on the catalyst design due to the requirement of using two different chiral

binaphthyl moieties Accordingly, they developed a new class of C 2-symmetric chiral

quaternary ammonium bromide 14 with an achiral, conformationally flexible biphenyl

subunit (Figure 1.6).14

Figure 1.6 Binaphthyl-biphenyl substituted ammonium salts 14

The phase-transfer asymmetric benzylation of 1 with (S)-14a, which has β-naphthyl

groups at the 3, 3’-positions of the flexible biphenyl moiety, proceeded smoothly at 0 o

C to afford the corresponding alkylation product (R)-10 in 85% yield with 87% ee

after 18 h The enantioselectivity was ascribed to the considerable difference in the catalytic activity between the rapidly equilibrated, diastereomeric homo- and

heterochiral catalysts: homochiral (S, S)-14a was primarily responsible for the efficient asymmetric phase-transfer catalysis to produce 10 with high enantiomeric excess, whereas heterochiral (R, S)-14a displays low reactivity and stereoselectivity

As a supportive evidence, (R, S)-13c, which has similar conformational structure with(R, S)-14a, only provides 11% ee

1.2.2.3 Binaphthyl bialkyl substituted ammonium salt

Later, they found that quaternary ammonium bromide (S)-15 with flexible

straight-chain alkyl groups instead of a rigid binaphthyl moiety functions as an unusually active chiral phase-transfer catalyst.15 Remarkably, the reaction of 1 with

benzyl bromide proceeded smoothly under mild phase-transfer conditions in the

presence of only 0.01mol% (S)-15 to afford the corresponding alkylation products

with excellent enantioselectivities (Scheme 1.5)

Scheme 1.5 Asymmetric alkylation of glycinate Schiff base 1 with 15

1.2.3 Other Types of Phase-Transfer Catalysts

1.2.3.1 C 2-symmetric chiral pentacyclic guanidine

Nagasawa and co-workers16 reported the asymmetric alkylation of 1 with the

C 2-symmetric chiral cyclic guanidines 16 The introduction of methyl substituents is

crucially important to achieve high enantioselectivity The chiral catalyst 16a results

in the alkylation of various alkyl halides in good yields and excellent ee (Scheme 1.6)

Scheme 1.6 Asymmetric alkylation of glycinate Schiff base 1 with 16

1.2.3.2 C 3-symmetric amine based ammonium salt

Takabe, Mase, and co-workers prepared the C 3-symmetric amine-based chiral

phase-transfer catalyst 17 and applied it to the asymmetric benzylation of 1 (Scheme

1.7). 17 The observed asymmetric induction was attributed both to electrostatic interaction of enolate and cation, and the hydrogen-bonding interaction between the

hydroxy groups of the catalyst and nitrogen atom of substrate 1

Scheme 1.7 Asymmetric alkylation of glycinate Schiff base 1 with 17

1.2.3.3 Two-center tartrate based bis-ammnounium salt

Shibasaki and co-workers applied the concept of two-center asymmetric catalysis to

invent tartrate-derived bis-(ammonium)salts 18, which resulted in the highly enantioselective alkylation of 1.18 During the investigation, a counter-ion effect was

observed: the enantioselectivity of the phase-transfer catalyzed allylation of 1 with

18b (BF4 salt) was slightly higher than with 18a (iodide salt)(Scheme 1.8)

Scheme 1.8 Asymmetric alkylation of glycinate Schiff base 1 with 18

1.2.3.4 Miscellaneous ammonium salt

Lygo et al constructed a library of 40 quaternary ammonium salts through the

reaction of commercially available chiral secondary amines with a series of conformationally flexible biphenyl units.19 Screening of the library against the

asymmetric benzylation of 1 under liquid-liquid phase-transfer conditions led to the identification of a highly effective catalyst 19 that exhibited impressive catalytic

activity and enantioselectivity (Scheme 1.9)

Scheme 1.9 Asymmetric alkylation of glycinate Schiff base 1 with 19

Sasai’s group designed a bis(spiroammonium) salt 20 as a chiral phase-transfer catalyst, and successfully applied it to the alkylation reaction of 1 with excellent yield

and enantioseletivity (Scheme 1.10) 20

Scheme 1.10 Asymmetric alkylation of glycinate Schiff base 1 with 20

Table 1 summarizes asymmetric alkylation of glycinate Schiff base 1 with various

phase-transfer catalysts with different reactions conditions Since this reaction is highly important in making amino acid The investigation with new phase transfer catalyst is still a hot topic in organic catalytic chemistry

Table 1 Phase-transfer catalyzed asymmetric alkylation of glycinate Schiff base 1