design of high-performance chiral phase-transfer catalysts

Review

Design of high-performance chiral phase-transfer catalystswith privileged structures

By Keiji MARUOKA*1,†

(Communicated by Ryoji NOYORI, M.J.A.)

Abstract: In the end of the 20th century, due to various advantages of organocatalysisincluding environmental friendliness, operational simplicity, mild reaction conditions, easy recoveryetc., had led to its recognition as a powerful strategy for the establishment of practical organicsynthetic methods. Over the two decades since then, tremendous effort has been devoted to thedesign of novel high-performance organocatalysts to realize unprecedented reactions includingasymmetric transformations. In this review, our recent results on the rational design of various typesof chiral phase-transfer catalysts with privileged structures, and their successful application to awide variety of asymmetric transformations are described.

Keywords: organocatalyst, privileged structure, phase-transfer catalyst, amino acid,asymmetric transformation

1. Introduction

In recent years, the design of new chiral catalystsand environmentally-benign asymmetric transforma-tions is becoming increasingly important for theconstruction of new and useful chiral molecules fromsimple organic compounds. In this context, organo-catalysis has recently emerged as a field of researchproviding practical technologies which are alterna-tive or complementary to the more traditional, bio-catalyzed and transition metal-catalyzed systems.The characteristic features of organocatalysis includeits operational simplicity, and the ready availability,easy recovery and reuse of organocatalysts, and lowtoxicity of the catalysts, which can make it a highlyattractive method for preparing complex and multi-functionalized organic molecules.1) Thus, this reviewdescribes the special type of organocatalytic chem-istry developed in the lab from 1998 onwards. Majorcontribution in this paper is in the field of asym-metric organocatalysis and the design of chiral, high-

performance organocatalysts with privileged struc-tures. The term of “privileged structure” is oftenused in medicinal chemistry as a useful concept forthe rational design of new lead drug candidates, andis defined as molecular frameworks which are capableof providing useful ligands for more than one typeof receptor or enzyme target by judicious structuralmodifications. For example, a benzodiazepine andsubstituted indole are identified as privileged struc-tures of cholecystokinin (CCK) antagonist, Asperli-cin (Scheme 1).2) A similar concept is also applicableto selective organic synthesis, particularly asymmet-ric catalysis, and indeed the preparation of privilegedchiral ligands and catalysts which is cruciallyimportant for this purpose.3) Hence, the essentialpoint of our strategy is to design high-performancechiral organocatalysts with appropriate privilegedstructures based on chiral binaphthyl core structures.This review focuses on the design of high-perform-ance chiral phase-transfer catalysts, for successfulapplication to various new asymmetric methodolo-gies in order to develop a new type of organocatalyticchemistry.4)

2. Design of chiral phase-transfer catalystswith binaphthyl core structures

It is known that about 90 of the top-500 (18%)best-selling drug products in the world utilizes ,-

*1 Graduate School of Science, Kyoto University, Kyoto,Japan.

† Correspondence should be addressed: K. Maruoka, Labo-ratory of Synthetic Organic Chemistry and Special Laboratory ofOrganocatalytic Chemistry, Department of Chemistry, GraduateSchool of Science, Kyoto University, Sakyo-ku, Kyoto 606-8502,Japan (e-mail: [email protected]).

Proc. Jpn. Acad., Ser. B 95 (2019)No. 1] 1

doi: 10.2183/pjab.95.001©2019 The Japan Academy

http://dx.doi.org/10.2183/pjab.95.001

amino acids as the starting materials and/or as theintermediates.5) These include, amoxicillin (antibi-otic), captopril, enalapril, lisinopril (hypotensivedrugs), norvir, amprenavir (anti-HIV drugs) andacyclovir (antiviral drug), etc. (Scheme 2). There-fore, amino acids are indispensable for the prepara-tion of new drugs, and have entered the mainstreamof medicinal products. Asymmetric synthesis of ,-amino acids by enantioselective phase-transfer al-kylation of a prochiral, protected glycine derivative 1using a chiral phase-transfer catalyst (PTC) hasprovided an attractive method for the preparation

of both natural and unnatural amino acids(Scheme 3).4),6)

However, in the initial stages of the work onasymmetric phase-transfer chemistry, almost allthe chiral phase-transfer catalysts that had beenobtained were cinchona alkaloid derivatives(Scheme 4). Unfortunately, the starting cinchonineand cinchonidine are not enantiomeric. Further,because of several O-hydrogens to ammonium cationin such catalysts, the Hofmann elimination takesplace under ordinary phase-transfer conditions usingbase. This constituted a major difficulty in rationallydesigning and fine-tuning of the catalysts to attainsufficient reactivity and selectivity.7) Thus, it isessential to synthesize desirable chiral phase-transfer

Scheme 1. Privileged structures of Asperlicin, and (R)-BINAP asa privileged chiral ligand.

N

SNH

CO2H

HNH2

CH3

CH3

OHO O

Amoxicillin

N

HSCH3

O

CO2H

Captopril

NH

N

CO2H

CH3EtO2C

OEnalapril

NH

N

CO2H

EtO2C

OLisinopril

H2N

N

S

H3C

H3C

N NH

HN N

HO

CH3

OH3C CH3

O OH

O

N

S

Norvir

Scheme 2. Various drugs derived from ,-amino acids.

Scheme 3. Asymmetric, phase-transfer alkylation of a prochiral,protected glycine derivative 1 catalyzed by chiral PTC or ent-PTC.

N

H

ClOH

N

N

H Ar

XOH

N

Cinchonine-derived PTC

N

Ar

N

H

OH

X

Cinchonidine-derived PTC

N

N

H

O

Br

Cin

CinCin Cin

Cin

Cin

Cinbis-PTC tris-PTC

Scheme 4. Cinchona alkaloid-derived chiral phase-transfer cata-lysts.

K. MARUOKA [Vol. 95,2

catalysts from both enantiomeric starting materials,and also without any O-hydrogens in the catalyststructure. It was against this background that thestructurally rigid, chiral spiro-ammonium salts oftype (R,R)-2 and (S,S)-2 possessing 3,3B-diarylsubstituents, which were derived from commerciallyavailable (R)- or (S)-binaphthol, respectively, weredesigned as new C2-symmetric chiral phase-transfercatalysts, and applied to the asymmetric synthesis ofent-3a and 3a, respectively (Scheme 5).8) An initialattempt on the design of efficient chiral phase-transfer catalysts was made on the benzylation ofN-(diphenylmethylene)glycine tert-butyl ester 1awith 1mol% of symmetric (S,S)-2a in 50% aqueousNaOH–benzene (volume ratio F 1:3) at room tem-perature and the corresponding benzylation product

3a was obtained in 76% yield with 73% ee. It shouldbe noted that the use of (R,S)-2a dramaticallylowered both the reactivity and enantioselectivityin the asymmetric phase-transfer benzylation. In-troduction of aromatic substituents (Ar) on the 3,3B-position of one binaphthyl subunit of the catalystafforded a beneficial effect on the enantiofacialdiscrimination, as the reaction of 1a with (S,S)-2bresulted in the formation of 3a in 43% yield with 81%ee. Moreover, the reaction in toluene as organicsolvent under the influence of (S,S)-2b was com-pleted within 30min at 0 °C with 50% KOH as anaqueous base giving the product 3a in 82% yieldwith 89% ee. Switching the catalyst to (S,S)-2c andsterically more hindered (S,S)-2d further increasedthe enantioselectivity to 96% ee and 98% ee,respectively, and virtually complete stereochemicalcontrol was achieved using (S,S)-2e as catalyst. Inthe same way, the similar catalysts (S,S)-4 possessing4,4B,6,6B-tetraaryl substituents also exhibited excel-lent enantioselectivity in the enantioselective synthe-sis of 3a.9) Interestingly, the combination of 0.05mol% of each of (R,R)-2d and 18-crown-6 at 0 °C for3 h greatly accelerated the phase-transfer alkylation,giving ent-3a in 90% yield with 98% ee.10) It shouldbe noted that without 18-crown-6 the yield issignificantly lowered (only 4%). Although the con-formationally rigid, N-spiro structure created by twochiral binaphthyl subunits is a characteristic featureof 2 and related catalyst 4, it also imposes limitationson the catalyst design due to the need to use twodifferent chiral binaphthyl moieties. Accordingly,here developed a new C2-symmetric chiral quaternaryammonium bromide 5 incorporating an achiral,conformationally flexible biphenyl subunit.11) Thephase-transfer benzylation of 1a using the catalyst(S)-5a having a O-naphthyl group on the 3,3B-positions of the flexible biphenyl moiety proceededsmoothly at 0 °C to afford 3a in 85% yield with 87%ee after 18 h (Scheme 6). The observed chiralefficiency could be ascribed to the considerabledifference in catalytic activity between the rapidlyequilibrated, diastereomeric homo- and heterochiralcatalysts; namely, homochiral (S,S)-5a is primarilyresponsible for the efficient asymmetric phase-trans-fer catalysis to produce 3a with high enantiomericexcess, whereas heterochiral (R,S)-5a displays lowreactivity and stereoselectivity. This unique phe-nomenon provides a powerful strategy for themolecular design of chiral catalysts, and quaternaryammonium bromides possessing a sterically demand-ing substituent such as (S)-5b and (S)-5c exhibited

Scheme 5. Design of new C2-symmetric, chiral phase-transfercatalysts 2 and 4.

Design of high-performance chiral phase-transfer catalysts with privileged structuresNo. 1] 3

higher enantioselectivity (92% ee and 95% ee,respectively) in the asymmetric benzylation of 1a.

Further efforts towards simplifying spiro-typephase-transfer catalysts have led to the developmentof the three-component coupling approach from thekey intermediate 7, arylboronic acid and dialkyl-amine for the design of new, mono(binaphthyl)-based, chiral phase-transfer catalysts of type 6 asillustrated in Scheme 7.12)

The chiral efficiency of such simplified, chiralphase-transfer catalysts (S)-6 was examined by

carrying out asymmetric benzylation of glycinederivatives under phase-transfer conditions. Amongvarious readily available arylboronic acids anddialkylamines investigated, 3,4,5-trifluorophenyl-substituted dibutyl- or didecylammonium bromide(S)-6Db9Dc showed excellent enantioselectivity(97% ee; Table 1).

These findings led to the conclusion that chiralquaternary ammonium bromide (S)-6Db (nowregistered as Simplified Maruoka Catalyst®), pos-sessing flexible, straight-chain alkyl groups insteadof a rigid binaphthyl moiety, functions as anunusually active chiral phase-transfer catalyst. Mostnotably, the reaction of 1a with various alkyl halides(R–X) proceeded smoothly under mild phase-trans-fer conditions in the presence of 0.01–0.05mol%of (S)-6Db to afford the corresponding alkylationproducts 3 with excellent enantioselectivities(Scheme 8).12),13)

The synthetic utility of this chiral phase-transfercatalysts was highlighted by the facile synthesis ofL-Dopa ester and its analogues, which are usuallybeen prepared by either asymmetric hydrogenation ofeneamides or enzymatic processes, and have beentested as potential drug for the treatment of

Scheme 7. Evaluation of in situ-generated catalysts (S)-6Aa9Di in the enantioselective phase-transfer benzylation of glycinederivative 1a.

Scheme 6. Design of new C2-symmetric, chiral phase-transfercatalyst 5 possessing conformationally flexible biphenyl subunit.

Table 1. Screening of in situ-generated catalysts (S)-6Aa9Di inthe enantioselective phase-transfer benzylation of glycine deriv-ative 1a

A B C D

a 12 26 1 7

b !27 43 93 97

c !17 58 96 97

d !9 22 44 7

e !7 5 31 43

f !23 33 41 20

g !19 26 78 81

h 22 3 2 6

i 15 41 75 83


Parkinson’s disease. Catalytic phase-transfer alkyla-tion of protected glycine tert-butyl ester 1a with therequisite benzyl bromide 8 in toluene-50% KOHaqueous solution proceeded smoothly at 0 °C underthe influence of (R,R)-2e (1mol%) to furnish fullyprotected L-Dopa tert-butyl ester, which was sub-sequently hydrolyzed with 1M citric acid in THF atroom temperature to afford the corresponding aminoester 9 in 81% yield with 98% ee. Debenzylation of 9under catalytic hydrogenation conditions producedthe desired L-Dopa tert-butyl ester 10 with 94% yield(Scheme 9).8b),14) In a similar manner, L-Azatyrosinecan be prepared from 1a and bromide 11 under theinfluence of chiral phase-transfer catalyst (R,R)-2dand subsequent transformation of 12.15)

In addition to chiral ,-monoalkyl-,-amino acids,nonproteinogenic, chiral ,,,-dialkyl-,-amino acidspossessing stereochemically stable, quaternary car-bon centers are also significant synthetic targets, notonly because they are often effective enzyme inhib-itors, but also because they are indispensable for theelucidation of enzymatic mechanisms. Accordingly,numerous studies have been conducted to developtruly efficient methods for their preparation, and thephase-transfer catalysis has some unique contribu-tions in this process. Since the aldimine Schiff base1b can be readily prepared from glycine, directstereoselective introduction of two different sidechains to 1b by appropriate chiral phase-transfercatalysis would provide an attractive and powerfulstrategy for the asymmetric synthesis of structurallydiverse ,,,-dialkyl-,-amino acids in one pot(Scheme 10).

It should be mentioned that asymmetric mono-alkylation of aldimine Schiff base 14 derived from an,-alkyl-,-amino acid would also provide ,,,-dialkyl-

,-amino acids as indicated in Scheme 10. Thispossibility of a one-pot, asymmetric double alkylationof the aldimine Schiff base 1b has been realized byusing an N-spiro, chiral phase-transfer catalyst oftype 2e, giving ,,,-dialkyl-,-amino acid 15 selec-tively (Scheme 11).16) In addition, asymmetric mono-alkylation of ,-alkyl-,-amino acid derivatives 14appears feasible by using (S,S)-2e8b) or (S)-6Db12b)

to furnish various types of ,,,-dialkyl-,-amino acids16 and 17, respectively (Scheme 12).

Peptide modification provides a useful strategyfor efficient target screening and optimization of lead

Scheme 8. Enantioselective phase-transfer alkylation of glycinederivative 1a with Simplified Maruoka Catalyst® (S)-6Db.

OBn

OBn

Br H2NO

OButH

OBn

OBn+

H2NO

OButH

OH

OH

0 °C, 3 h

1a

(R,R)-2e(1 mol%)

toluene50% KOH aq

citric acid

10% Pd/C

79% overall yield

98% ee

r.t., 15 h

r.t., 5 h

THF

H2, THF

8 9

10

NOSO2Ph

Br H2NO

OButH

NOSO2Ph

+

H2NO

OHH

NOH

0 °C, 5 h

1a

(R,R)-2d(1 mol%)

toluene50% KOH aq

1 N HCl

85%, 92% ee

THF11 12

13 (L-Azatyrosine)

Scheme 9. Asymmetric synthesis of L-Dopa ester and L-Azatyro-sine.

Scheme 10. New strategy for asymmetric synthesis of ,,,-dialkyl-,-amino acids.


structures in the application of naturally occurringpeptides as pharmaceuticals. The introduction of sidechains directly to a peptide backbone represents apowerful method for the preparation of unnaturalpeptides. An achiral glycine subunit has generallybeen used for this purpose. However, control of thestereochemical outcome of these transformations inan absolute sense is not easy, especially in themodification of linear peptides, and hence develop-ment of an efficient and practical approach toestablish sufficient stereoselectivity and general ap-plicability has been crucially important. Accordingly,we examined the chirality transfer in the diastereo-selective alkylation of the dipeptide, Gly-L-Phederivative 18 (Scheme 13).

Firstly, the use of tetrabutylammonium bromide(TBAB) resulted in only low diastereoselectivity (8%de). Interestingly, the reaction with catalyst (S,S)-2cor (R,R)-2c afforded DL-19 (55% de) or LL-19 (20%de), respectively, suggesting (R,R)-2c is a mis-matched catalyst for this diastereofacial differentia-tion of 18. Changing the 3,3B-aromatic substituents

(Ar) of 2 dramatically increased the stereoselectivity,and almost complete diastereocontrol (97% de) wasrealized with (S,S)-2f.17) A similar tendency is alsoobserved in the diastereoselective benzylation oftripeptide 20.

One disadvantage of the asymmetric phase-transfer alkylation of glycine derivative 1 for thesynthesis of ,-alkyl-,-amino acids is the difficulty ofusing sterically hindered, unreactive alkyl halidesfor the preparation of sterically hindered ,-alkyl-,-amino acids. In this context, efforts have beenintrigued for the development of asymmetric Streckerreactions under phase-transfer conditions. The asym-metric Strecker reaction, catalytic asymmetric cyan-ation of imines represents one of the most direct andviable methods for the asymmetric synthesis of ,-amino acids and their derivatives. Numerous recentefforts in this field have led to the establishment ofhighly efficient and general protocols, although theuse of either alkylmetal cyanide or anhydroushydrogen cyanide, generally at low temperature, isinevitable. It is worth to mention that this is the firstexample of a phase-transfer-catalyzed, highly enan-tioselective Strecker reaction of aldimines usingaqueous KCN based on the molecular design ofchiral quaternary ammonium salt (R,R,R)-22, hav-ing a tetranaphthyl backbone, as a highly efficientorganocatalyst (Scheme 14).18) This phase-transfer

Scheme 11. One-pot dialkylation sequence for asymmetric syn-thesis of ,,,-dialkyl-,-amino acids.

Scheme 12. Asymmetric synthesis of ,,,-dialkyl-,-amino acids16 and 17 by asymmetric alkylation of ,-alkyl-,-amino acidderivatives 14b.

Scheme 13. Stereoselective alkylation of peptides under asym-metric phase-transfer catalysis.


catalyzed asymmetric Strecker reaction is furtherelaborated by the use of ,-amido sulfone as aprecursor of N-arylsulfonyl imine. In this system,the reaction can be carried out with a slight excess ofpotassium cyanide (1.05 equiv) which leads tocompletion of the reaction within 2 h.18b)

Although phase-transfer catalyzed enantioselec-tive direct aldol reactions of glycine derivatives withaldehyde acceptors could provide an ideal approachfor the simultaneous construction of the primarystructure and stereochemical integrity of O-hydroxy-,-amino acids, which is a very important chiral unitsfrom the pharmaceutical viewpoint, there are onlyvery limited examples reported till date. Thus, thisreview reports an efficient, highly diastereo- andenantioselective direct aldol reaction of 1a with awide range of aliphatic aldehydes under mild phase-transfer conditions.19) Indeed, treatment of 1a with3-phenylpropanal employing N-spiro chiral quater-nary ammonium salt (R,R)-2g as a key catalystresulted in the formation of the corresponding O-hydroxy-,-amino ester 23 in 76% isolated yield withthe anti/syn ratio of 77:23, and the enantiomericexcess of the major anti isomer was determined to be91% ee. Interestingly, the use of (R,R)-2h possessing3,5-bis[3,5-bis(trifluoromethyl)phenyl]phenyl sub-stituent as a catalyst enhanced both diastereo- and

enantioselectivities (anti/syn F 92:8, 96% ee for antiisomer) (Scheme 15).

The initially developed reaction conditions using2 equiv of aqueous base (1% NaOH aq) exhibitedinexplicably limited general applicability in terms ofaldehyde acceptors. For example, reaction of glycinederivative 1a with 4-benzyloxybutanal gave the aldolproduct with low diastereoselectivity (anti/syn F

58:42; 82% ee for anti isomer). The mechanisticinvestigation revealed the intervention of an unfav-orable yet inevitable retro aldol process involvingchiral catalyst 2. Based on this information, a reliableprocedure has been established by the use of thecatalyst (R,R)-2h (2mol%) with a catalytic amountof 1% NaOH (15mol%) and ammonium chloride(10mol%), which tolerates a wide range of aldehydesto afford the corresponding anti-O-hydroxy-,-aminoesters almost exclusively in an essentially opticallypure form (Scheme 16).20)

We have developed the diastereo- and enantio-selective conjugate addition of nitroalkanes toalkylidenemalonates under mild phase-transfer con-ditions by the utilization of appropriately designedchiral quaternary ammonium bromide 2h as anefficient catalyst. This new protocol offers a practicalentry to optically active .-amino acid derivatives,from which (R)-Baclofen and (R)-Rolipram can beeasily prepared as shown in Scheme 17.21) As anextension of this research, we have also succeededin the catalytic asymmetric conjugate addition ofnitroalkanes to cyclic ,,O-unsaturated ketones underphase-transfer condition.22)

An enantioselective Michael addition of O-ketoesters to ,,O-unsaturated carbonyl compounds is

Scheme 15. Asymmetric synthesis of O-hydroxy-,-amino acidsby direct asymmetric aldol reaction.

Scheme 14. Asymmetric Strecker reaction under phase-transfercatalysis.


a useful method for the construction of denselyfunctionalized chiral quaternary carbon centers. Acharacteristic feature of designer chiral phase-trans-fer catalyst 2g in this type of transformation is that itenables the use of ,,O-unsaturated aldehydes as anacceptor, leading to the construction of quaternarystereocenter having three different functionalities ofcarbonyl origin as demonstrated in the reaction with2-tert-butoxycarbonylcyclopentanone 24a. It is of

interest that the use of fluorenyl ester 24b greatlyimproved the enantioselectivity. The addition of 24bto MVK was also feasible under similar conditionsand the desired Michael adduct was obtainedquantitatively with 97% ee (Scheme 18).23)

The combinatorial design approach for therational design of new phase-transfer catalysts(Scheme 7) is found to be quite useful to develophitherto difficult asymmetric transformations. Forexample, asymmetric conjugate addition of ,-sub-stituted-,-cyanoacetates 25 to acetylenic estersunder phase-transfer condition is quite challengingbecause of the difficulty to control the stereochemis-try of the product. In addition, despite numerousexamples of the conjugate additions to alkanoicesters, so far there are no successful asymmetricconjugate additions to acetylenic esters. In thiscontext, we recently developed a new morpholine-derived phase-transfer catalyst (S)-26a and appliedit to the asymmetric conjugate additions of ,-alkyl-,-cyanoacetates 25 to acetylenic esters. In thisasymmetric transformation, an all-carbon quaternarystereocenter can be constructed in a high enantio-meric purity (Scheme 19).24)

With this information in hand, an enantioselec-tive organocatalytic, one-pot synthesis of hexahydro-pyrrolizine and octahydroindolizine core structures27 (n F 1 or 2) was considered as the starting fromreadily available glycine esters 1c in combinationwith several different organocatalytic reactions(Scheme 20). Our key strategy is based on thedevelopment of asymmetric conjugate addition ofN-(diphenylmethylene)glycine ester 1c and ,,O-enones 30 (n F 1 or 2) by using a chiral phase

Scheme 17. Asymmetric phase-transfer conjugate addition ofnitroalkanes to alkylidenemalonates and enone.

Scheme 18. Asymmetric phase-transfer conjugate addition of O-keto esters to ,,O-unsaturated carbonyl compounds.

Ph OBut

O

NH2

OH

Pr i3SiOOBut

O

NH2

OH

CH3(CH2)4 OBut

O

NH2

OH

CH3 OBut

O

NH2

OH

98% ee(82%, anti/syn = 96:4)

97% ee(80%, anti/syn = 94:6)

99% ee(54%, anti/syn = >94:6)

98% ee(73%, anti/syn = >96:4)

Scheme 16. Asymmetric aldol synthesis.


transfer catalyst of type (S)-26a (Scheme 20).Organocatalytic intramolecular reductive aminationof conjugate adduct 29 (n F 1 or 2) with Hantzschester would proceed in a stereoselective manner togive pyrrolidine derivative 28 (n F 1 or 2) as anintermediate, which is susceptible to the subsequentcyclization with iminium ion formation and reduc-tively aminated to furnish a hexahydropyrrolizine oroctahydroindolizine core structure 27 (n F 1 or 2),respectively.

Here, we firstly examined asymmetric conjugateaddition of N-(diphenylmethylene)glycine di(tert-butyl)methyl ester 1c and ethyl vinyl ketone withK2CO3 under the influence of chiral phase-transfercatalyst (S)-26a to furnish conjugate adduct 31 withlow enantioselectivity. However, the use of chiral

phase-transfer catalyst of type (S)-26b and 10mol%of CsCl in ether at 0 °C gave conjugate adduct 31 in84% yield with 94% ee (Scheme 21).25) With theoptimal reaction condition for asymmetric conjugateaddition in hand, we further carried out intra-molecular reductive amination of 31 with Hantzschester (2 equiv) and CF3CO2H (1 equiv) in aqueousEtOH at 60 °C to furnish 2,5-disubstituted cis-pyrrolidine 32 stereospecifically in 84% yield.25)

Thus, one-pot synthesis of cis-pyrrolidine 32 withoutisolation of adduct 31 was realized in a reasonableyield.

This information was further used to develop afacile and short asymmetric synthesis of physiologi-cally active (D)-Monomorine in a highly stereo-selective manner by the way of key octahydroindo-lizine core structure 35 (Scheme 22). Accordingly,asymmetric conjugate addition of glycine ester 1bwith ,,O-enone 33 (2.0 equiv) and K2CO3 (5 equiv)under the influence of chiral phase-transfer catalyst(S)-26b and catalytic CsCl in ether at 0 °C for 8 hwas carried out to give conjugate adduct 34 in 86%yield with 93% ee. Intramolecular reductive amina-tion of the adduct 34 and subsequent iminium ionformation followed by second reductive aminationwere effected with Hantzsch ester (5 equiv) andCF3CO2H in aqueous EtOH at 60 °C for 48 h tofurnish octahydroindolizine core structure 35 in 61%yield without loss of enantioselectivity. The absoluteconfiguration of 35 was unambiguously confirmedthrough X-ray crystallographic analysis after thereduction and subsequent p-bromobenzoate forma-

Scheme 19. Asymmetric conjugate addition of ,-cyano esterswith new chiral phase-transfer catalyst (S)-26a.

Scheme 20. Retrosynthetic pathway on alkaloid core structures.

Scheme 21. One-pot synthesis of optically active pyrrolidinealkaloid core structures.


tion. The one-pot reaction of the whole reactionsequence was also realized without any difficulty bysequentially adding different reagents to afford 35in 48% overall yield. The transformation of the keyintermediate 35 to (D)-Monomorine was realized in3-step sequence as shown in Scheme 22.26)

The development of new, catalytic asymmetrictransformations by using a chiral metal-free catalystin water solvent under neutral conditions withexcellent atom economy is one of the most idealapproaches in current asymmetric synthesis in theviewpoint of green and sustainable chemistry. There-fore, this work focuses on the possibility of realizingsuch an ideal transformation, and hence to developan environmentally-benign asymmetric conjugateaddition to nitroolefins under essentially neutralconditions in order to fulfill four important factors(i.e., metal-free, water, neutral, and atom economy)as described above. Although quaternary ammoniumsalts as phase-transfer catalysts are generally be-lieved to require base additives for phase-transferreactions, in this case it is found that even withoutany base additives the enantioselective phase-trans-fer conjugate addition of 3-phenyloxindole 36 to O-nitrostyrene proceeded smoothly in the presence ofchiral bifunctional ammonium bromide (S)-37 underneutral conditions in water-rich solvent (i.e., H2O/toluene F 10:1) with both high diastereomeric andenantiomeric ratios (Scheme 23).27) This reactiondoes not work well under ordinary phase-transferconditions in aqueous basic solutions, such asaqueous KOH, K2CO3, and PhCO2K, and underhomogeneous water-free reaction conditions. Thisfinding is very surprising and unusual result in thelong-standing phase-transfer chemistry. It is quite

desirable in the green and sustainable chemistry.Specifically, both racemic and optically active con-jugate adducts derived from 3-aryloxindoles can bereadily transformed to valuable natural productsand their analogues as exemplified by the trans-formation of optically active conjugate adduct 38(90% ee) to the corresponding cyclization product39, which comprises a similar core structure withmany important natural products such as Flustr-amines and Flustramides.28) These natural productanalogues might possess some important biologicalactivity and hence are valuable for the drugindustry.

We are also interested in the development of anenvironmentally-benign asymmetric conjugate ami-nation to nitroolefins under essentially neutralconditions. This transformation allows the efficientasymmetric synthesis of chiral 1,2-diamino com-pounds as a useful chiral building block in pharma-ceutical areas. After various screening of reactionconditions, an asymmetric neutral amination tonitroolefins was found to be catalyzed by chiralbifunctional tetraalkylammonium salts of type 40awith very low catalyst loading (0.05mol%) in water-rich biphasic solvent (Scheme 24).29) Here, piperi-dine-derived catalysts (S)-40a are found to besuperior to morphorine-derived catalysts (S)-37 interms of enantioselectivity. It should be noted thatasymmetric conjugate amination does not workwell under the ordinary phase-transfer reactionconditions using aqueous base solutions, such asaqueous KOH, K2CO3, and PhCOOK solutions, andunder the homogeneous reaction conditions withoutaqueous solution. Hence, the highly enantioselective

Scheme 23. Asymmetric conjugate addition of 3-phenyloxindoleunder neutral phase-transfer conditions.

Scheme 22. Short-step synthesis of natural alkaloid, (D)-Mono-morine.


conjugate amination of nitroolefins was only achievedwhen the reaction was performed under the base-freeneutral phase-transfer conditions in water-rich bi-phasic solvent. The resulting amination products canbe readily transformed by the catalytic hydrogena-tion with Raney Ni catalyst to the corresponding1,2-diamines, which are versatile chiral buildingblocks from synthetic as well as pharmaceuticalviewpoints.

The X-ray crystal structure of chiral ammoniumamide (S)-43 provides an important structuralinformation. The bond-lengths of amide moietyindicate that the negative charge of amide anion isdelocalized on the nitrogen-carbon-oxygen atoms asshown in Scheme 25.29) Importantly, the hydrogenbonding interaction between the hydroxy group inthe binaphthyl unit and the oxygen of amide anion isclearly observed in the crystal structure of (S)-43.

A highly diastereo- and enantioselective con-jugate addition of ,-substituted nitroacetates tomaleimides in the presence of (S)-40b under base-free neutral phase-transfer conditions was developedfor the synthesis of ,,,-disubstituted ,-amino acidderivatives (Scheme 26).30)

Although a variety of chiral quaternary am-monium salts have been developed as reliablecatalysts for asymmetric phase-transfer reactions,only a few examples of chiral quaternary phosphoni-um salts as chiral phase-transfer catalysts have beenreported with some limitations. In consideration of

the wide availability of various types of commerciallyavailable chiral phosphine compounds, the presentapproach for the search of effective chiral quaternaryphosphonium salts (S)-45 relies on the use ofcommercially available chiral phosphine compounds(S)-44 as catalyst precursors. This approach allowsfacile construction of a catalyst library of chiralquaternary phosphonium salts with various struc-tures, which is successfully applied to asymmetricconjugate additions under base-free phase-transferconditions with low catalyst loading (up to 0.1mol%) (Scheme 27).31)

The fluoride-mediated generation of nucleophilesfrom organosilicon compounds for selective bond-forming reactions is very useful in organic synthesis.This approach implies the possibility of developingan asymmetric version based on the use of a chiral,nonracemic fluoride ion source as represented bychiral quaternary ammonium bifluorides of type 46.Indeed, the asymmetric nitroaldol reaction and

Scheme 25. X-ray crystal structure of chiral ammonium amide(S)-43.

Scheme 24. Asymmetric conjugate amination to nitrostyrenewith (S)-40a under neutral phase-transfer conditions.

Scheme 26. Asymmetric conjugate amination to nitrostyrenewith (S)-40b under neutral phase-transfer conditions.


conjugate addition of silyl nitronates are found tobe highly efficient under the influence of chiralquaternary ammonium bifluorides (S,S)-46a9b(Scheme 28).32),33)

Tetraalkylammonium salts are recognized asrepresentative organocatalysts and are often usedas phase-transfer catalysts for the activation ofanionic nucleophiles through the formation of anion pair with an ammonium cation. Although thestructures of tetraalkylammonium salts are com-

monly expressed as 47a, their actual ionic structureis discussed differently. Namely, the positive chargeof ammonium salts is delocalized on the ,-hydrogenatoms, which are known to interact with an anioniccounterion through hydrogen bonding, as shown in47b (Scheme 29).34)

Although the hydrogen-bonding ability of the,-hydrogen atoms on tetraalkylammonium salts isoften discussed with respect to phase-transfer cata-lysts, catalysis that utilizes the hydrogen-bond-donorproperties of tetraalkylammonium salts remainsunknown. This work successfully demonstrates hy-drogen-bonding catalysis with the newly designedtetraalkylammonium salt catalysts in Mannich-typereactions. Indeed, the Mannich-type reaction of N-acyl isoquinolines 50 with ester-derived silyl enolether 51 under the catalysis of ammonium salts 48a(the actual structure is 49) gave rise to thecorresponding Mannich product 52 in 38% yield(Scheme 30).35) It should be noted that the use ofrelated catalysts 53 and 54 gave rise to the product52 in 9% and 6%, respectively. Fortunately, switch-ing the catalyst from 48a to 48b enhanced thechemical yield to 61%, and the use of longer reactiontime (6 h) gave the Mannich product 52 in 90%yield. The structure and the hydrogen-bondingability of the new ammonium salt 48a wereinvestigated by X-ray diffraction analysis and NMRtitration studies.

Acknowledgements

KM acknowledges his coworkers for their con-tributions at various levels. He also thanks Ministryof Education, Culture, Sports, Science and Technol-ogy of Japan for the financial support for this workthrough Grant-in-Aid for Scientific Research.

Scheme 29. Structure of tetraalkylammonium salt 47.

Scheme 27. Design of effective chiral quaternary phosphoniumsalts derived from commercially available chiral phosphinecompounds as catalyst precursors.

Scheme 28. Asymmetric reaction of silyl nitronates with chiralquaternary ammonium bifluorides.


References

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(Received Sep. 8, 2018; accepted Oct. 10, 2018)


Profile

Keiji Maruoka was born in Mie, Japan in 1953. He graduated from KyotoUniversity (1976) and received his Ph.D. (1980) from University of Hawaii (ThesisDirector: Prof. H. Yamamoto). He became an assistant professor of Nagoya University(1980) and promoted as a lecturer (1985), and as an associate professor (1990)subsequently. He moved to Hokkaido University as a full professor (1995–2001), andcurrently he is a professor of chemistry in Kyoto University. He is also a part-time chairprofessor of Guangdong University of Technology. He has a wide range of researchinterests in synthetic organic chemistry, and his current research interests includebidentate Lewis acids in organic synthesis and practical asymmetric organocatalysisusing rationally designed, high-performance organocatalysts including chiral C2-symmetric phase-transfer catalysts, organoacid catalysts, bifunctional organocatalysts, and organoradicalcatalysts. He has received the Inoue Prize for Science (2000), the Ichimura Prize for Science (2002), SyntheticOrganic Chemistry Award of Japan (2003), Nagoya Silver Medal (2004), the Green and Sustainable ChemistryAward (2006), the Award by the Minister of Education, Culture, Sports, Science and Technology (2006), the JapanChemical Society Award (2007), Molecular Chirality Award (2007), Novartis Lectureship Award (2007/2008),Chunichi Cultural Prize (2010), Arthur C. Cope Scholar Awards (2011), Medal of Honor with Purple Ribbon(2011), Humboldt Research Award (2011), Torey Science & Technology Award (2012), Noyori Prize (2016), andthe Japan Academy Prize (2018). He is a chief editor of Chem. Rec., a co-chair and editor of Asian JOC, an editorof Tetrahedron Lett., and is a member of the international advisory editorial board of ChemComm, Acc. Chem.Res., Org. Biomol. Chem., Chem. Asian J., and Adv. Synth. Catal.


design of high-performance chiral phase-transfer catalysts

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