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PROLINE-CATALYZED ASYMMETRIC REACTIONS

Tetrahedron report number 613

Proline-catalyzed asymmetric reactions

Benjamin List p

Department of Molecular Biology,The Scripps Research Institute,10550N.Torrey Pines Rd.,La Jolla,CA 92037,USA

Received 2April 2002

Contents

1.Introduction

55731.1.ProlineDa universal asymmetric catalyst?55732.The Hajos±Parrish±Eder±Sauer±Wiechert reaction

55742.1.Background

55742.2.Scope and applications 55752.3.Mechanism

55763.The direct intermolecular aldol reaction

55763.1.Background

55763.2.Scope and applications 55763.3.Mechanism 55784.Mannich reactions 55785.Michael reactions

55815.1.Iminium catalysis of the Michael reaction 55815.2.Enamine catalysis of the Michael reaction 55835.3.One-pot Robinson-annulations 55846.The direct electrophilic a -amination

55857.Miscellaneous proline-catalyzed asymmetric reactions

55857.1.Diels±Alder-type dimerizations of a ,b -unsaturated aldehydes 55867.2.Baylis±Hillman reactions 55867.3.Reductions 55867.4.Oxidations 55878.Conclusions

5587

1.Introduction

Several strategies are available for enantioselective cataly-sis,including heterogeneous catalysis,Brùnsted or Lewis acid and base catalysis,homogeneous transition-metal catalysis,and biocatalysis.One remarkable molecule,the amino acid proline,has become a crucial component in examples of all of the catalytic strategies listed above.Proline can be a ligand in asymmetric transition-metal catalysis,a chiral modi?er in heterogeneously catalyzed hydrogenations,and,most importantly,proline itself can be an effective organocatalyst of several powerful asym-metric transformations,such as the aldol,Mannich,and Michael reactions.

In the focus of this review are proline-catalyzed asymmetric reactions.Covered are those reactions that are either cata-lyzed by proline alone,or by proline in combination with cocatalysts such as metal salts.Selected non-enantioselec-tive proline-catalyzed reactions have also been included.However,the present review does not cover the use of important proline-derived auxiliaries or catalysts including the Enders-hydrazones or the Corey±Bakshi±Shibata-catalyst,which have been reviewed elsewhere.1,2Further-more,other remarkable and useful amino acid-based cata-lysts such as MacMillan's iminium catalysts and Miller's peptide catalysts are beyond the scope of this review.31.1.ProlineDa universal asymmetric catalyst?There are several reasons why proline has become an impor-tant molecule in asymmetric catalysis.Not least is the

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Keywords :proline;catalysis;enamine.p

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B.List/Tetrahedron58(2002)5573±5590 5574

fact that proline is an abundant chiral molecule that is inexpensive and available in both enantiomeric forms. Additionally,there are various chemical reasons that contri-bute to proline's role in catalysis.Proline is bifunctional, with a carboxylic acid and an amine portion.These two functional groups can both act as acid or base and can also facilitate chemical transformations in concert,similar to enzymatic catalysis.While enzymes typically use several different functional groups in their catalytic machinery, bifunctional asymmetric catalysis has become a very successful strategy in the laboratory.4In addition,proline is a chiral bidentate ligand that can form catalytically active metal complexes(Fig.1).

While all of these criteria apply for all amino acids,proline is a secondary,cyclic,pyrrolidine-based amino acid.A unique consequence of this property is the increased p K a value of its amine compared to primary amino acids. Another consequence of proline's pyrrolidine portion is the bicyclo[3.3.0]octane ring system(`open book structure') of its metal complexes.The most important difference to other amino acids is proline's effective aminocatalysisDa Lewis-base-type catalysis that facilitates iminium-and enamine-based transformations.5Proline's unique nucleo-philic reactivity is primarily a consequence of the pyrroli-dine portion,which forms iminium ions and enamines with carbonyl compounds more readily than most other amines, including cyclic ones such as piperidine.6The carboxylate further contributes to proline's aminocatalysis by acting as a general Brùnsted cocatalyst.

2.The Hajos±Parrish±Eder±Sauer±Wiechert reaction 2.1.Background

The1960s witnessed a strong interest in ef?cient and economic steroid syntheses.This development was fueled by the commercial success of steroidal contraceptive agents (in1969,7.5million American women were taking the pill) and the promise of other pharmaceutically active steroids such as the`wonder drug',cortisone.The best way to synthesize steroids at the time was the Marker process,a sequence of reactions that led from diosgenin,a plant steroid isolated from Mexican wild yams,to cortisone and other important steroids such as norethindrone.7Early on,alter-native synthetic schemes that would not require the use of a potentially rare resource were envisioned.For example, racemic tetrahydroindandione1and octahydronaphtalene-dione2(the Wieland±Miescher ketone)have been resolved and used in asymmetric steroid total syntheses(Scheme1).8 Ketones1and2can be made from symmetric monocyclic triketones3and4via intramolecular aldol condensation (Scheme2).These reactions can be catalyzed by amines such as pyrrolidine,9and Spencer et al.convincingly demonstrated that they involve enamine intermediates similar to certain enzymatic reactions.10 Contemporaneous to these experiments were Yamada's studies on asymmetric synthesis with amino acids.For example,asymmetric Robinson-annulations have

been Figure1.Modes of action in

proline-catalysis.

B.List /Tetrahedron 58(2002)5573±55905575

developed that are based on preformed proline-derived enamines (Scheme 3).11

Asymmetric enamine catalysis was ?rst realized with the discovery of the proline-catalyzed asymmetric intramolecu-lar aldol reaction by two industrial groups in the early 1970s.Hajos and Parrish at Hoffmann La Roche reported proline-catalyzed intramolecular aldol reactions of tri-ketones such as 3and 4to give aldols 5and 6in good yields and ees (Scheme 4).12Acid-catalyzed dehydration furnished aldol condensation products 1and 2in a second step (Eqs.(1)and (2)).As shown by Eder,Sauer,and Wiechert at Schering,the aldol condensation products can also be obtained directly from triketones 3and 4if the cyclization is performed in the presence of proline (10±200mol%)and an acid-cocatalyst (Eqs.(3)and (4)).132.2.Scope and applications

The asymmetric proline-catalyzed intramolecular aldol

cyclization,also termed the Hajos±Parrish±Eder±Sauer±Wiechert reaction,14has been applied to several substrates since its invention over 30years ago.15A small selection of products obtained using proline-catalyzed intramolecular aldolizations is shown in Fig.2.16

The Hajos±Parrish±Eder±Sauer±Wiechert reaction has not only been used in steroid syntheses but also in several other natural product total syntheses.17The reaction has been studied using polymer-bound (S )-proline as the catalyst 18and Agami et al.described conceptually related proline-catalyzed enantiogroup differentiating aldol-cyclodehydra-tions of acyclic diketones (Table 1).19When compared to the Hajos±Parrish±Eder±Sauer±Wiechert reaction,the ef?ciency and enantioselectivity of Agami's desymmetri-zation reaction are generally

lower.

Scheme 4.Hajos±Parrish±Eder±Sauer±Wiechert

reactions.

B.List /Tetrahedron 58(2002)5573±5590

55762.3.Mechanism

While realizing that their aresults may be considered an example of a simpli?ed model of a biological system in which (S )-proline plays the role of an enzymeo,Hajos and Parrish initially rejected the aldolase-type enamine mecha-nism in their seminal work.12According to the proposed alternative mechanism,one of the enantiotopic ring carbo-nyl-groups is activated as a carbinolamine,which undergoes a C±C-bond-forming nucleophilic substitution reaction reaction with a side-chain enol (A in Fig.3).This model is consistent with the low 18O-incorporation into the product,an observation made if the reaction was conducted in the presence of 18O-labeled water.However,the Hajos-mechanism has been rejected by Jung because it involves retention of con?guration in an S N 2-like process.20Jung and later Eschenmoser et al.21?rst discussed a `one proline-mechanism'involving a side-chain enamine intermediate and Agami et al.proposed model B in which a second proline molecule is involved.22Kinetic studies and an observed non-linear effect in asymmetric catalysis supported the involvement of two proline molecules in the enantioselectivity-determining step.23Heterogeneous catalysis involving a concerted bifunctional acid/base-mechanism (C )has also been suggested as a possible mechanism on the basis of the observation that proline is often not completely soluble in organic solvents.24Using quantum mechanical calculations,Houk et al.recently proposed a new model (D )that readily explains the observed enantioselectivity.25This elegant model is also consistent with the original Spencer-mechanism of the pyrrolidine-catalyzed intramolecular aldolization.

3.The direct intermolecular aldol reaction 3.1.Background

The direct intermolecular aldol reaction between two carbonyl compounds is central to sugar metabolism.Class I aldolases catalyze this process by using an enamine mechanism.26Several early bioorganic studies appeared in which simple small molecule amines and amino acids served as aldolase models.27Aldolase-like catalytically active amines,amino acids,and amine/antibody systems have been studied by Reymond et al.28In addition,catalytic antibodies have been generated which also use an enamine mechanism.29These important studies in particular have taught us the potential of enamine catalysis for asymmetric synthesis.Lessons learnt from the aldolase antibodies,the Hajos±Parrish±Eder±Sauer±Wiechert reaction,and the discovery of non-proteinogenic,metal complex-catalyzed direct asymmetric aldol reactions,30led to the development of the ?rst proline-catalyzed direct asymmetric aldol reac-tion.31Initially,it was shown that,although proline typically reacts unproductively with aldehydes,the intermolecular reaction between a ketone and an aldehyde is possible if a large excess of the ketone donor is used.For example,acetone (20vol.%,ca.27equiv.)reacts with isobutyralde-hyde in DMSO to give the corresponding aldol in excellent yield and ee (Scheme 5).

3.2.Scope and applications

Several other aldehydes have been used in proline-catalyzed aldol reactions with acetone (Table 2).In general,aromatic aldehydes furnish aldols with ees of around 70%and in varying yields (54±94%).Higher enantioselectivities and yields were obtained when a -branched aldehydes were used and tertiary aldehydes gave exceptionally high ees of up to .99%.The only signi?cant side-product in these reactions (and also in the Hajos±Parrish±Eder±Sauer±Wiechert reaction)is the aldol-condensation product.

Table 1.Agami's enantiogroup differentiating aldol

cyclodehydration

R ee (%)Ph

47n -C 5H 1120Me 42i -Pr 8t -Bu

B.List/Tetrahedron58(2002)5573±55905577

a-Unbranched aldehydes turned out to be a dif?cult substrate class and did not provide the corresponding aldol products under standard conditions.Only homo-aldol-addition-and condensation of the aldehyde or elimination of the cross-aldol product to the a,b-unsaturated ketone were observed in https://www.wendangku.net/doc/292283014.html,ing acetone or acetone/CHCl3 mixtures as solvents and10±20mol%of proline as the catalyst allowed isolation of the cross-aldol products in modest yields and good enantioselectivities(Table3).32Observed side-products are the cross-aldol condensation products and the homo-aldol addition product of acetone.

The proline-catalyzed aldol reaction of acetone with a-unbranched aldehydes has been used in a short synthesis of the natural pheromone(S)-ipsenol(Scheme6).

Recently,the proline-catalyzed intermolecular aldol reaction with acetone has been applied to the highly dia-stereoselective synthesis of complex sugar derivatives (Scheme7).33

Table2.Proline-catalyzed direct asymmetric aldol reactions using acetone as the donor

Product Yield(%)ee

(%)

9796

81.

85.99

Table3.Proline-catalyzed direct asymmetric aldol reactions using a-

unbranched aldehydes as acceptor

Product Yield(%)ee

(%)

Scheme6.Catalytic asymmetric total synthesis of(S

)-ipsenol.

Table4.The proline-catalyzed intermolecular aldol reaction using cyclic

ketones as donors

Product Yield(%)

1:1

7:1

68.

20:1

77 2.5:1

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5578A general limitation of the method is the scope of the ketone component.Since a large excess of the ketone is often required,small and inexpensive ketones such as acetone,butanone,and cyclohexanone are typically used.Selected reaction products from proline-catalyzed aldol reactions with ketones other than acetone are provided in Table 4.Other ketones such as 3-pentanone and cetophenone have not been successfully used yet.

Excellent results have also been obtained with hydroxy-acetone as the donor.In this case,anti-diols are formed in high regioselectivities,diastereoselectivities and enantio-selectivities (Table 5).

Several proline-catalyzed intermolecular aldol reactions have recently been successfully repeated,both with proline itself and with poly(ethylene glycol)-supported proline.34,35In addition to serving as acceptors in proline-catalyzed aldol reactions,aldehydes can also act as donors under certain conditions.For example,acetaldehyde trimerizes in the presence of (S )-proline to give aldehyde 7in low yield but relatively high enantioselectivity (Scheme 8).36

Furthermore,it was found that several a -unbranched alde-

hydes react with activated non-enolizable ketones to give aldols in good yields and ees (Table 6).373.3.Mechanism

The originally proposed mechanism of the proline-catalyzed intermolecular aldol reaction 31was based on the established class I aldolase-mechanism that involves carbinolamine,imine or iminium,and enamine intermediates.26The catalytically active functional groups in class-I aldolases are an 1-amino group of a lysine residue and,depending on the enzyme subtype,a set of Brùnsted cocatalysts required for the various proton-transfers of the multi-step reaction mechanism.In the proline-catalyzed version,the catalytic amine is proline's pyrrolidine.The carboxylate could function as a multi-purpose Brùnsted cocatalyst for the proton-transfers (Scheme 9).

The enantioselectivity was explained with a transition state (E )that can be described as a metal-free version of the classical Zimmermann±Traxler model (F ),38which successfully explains stereoselectivities of metal enolate aldol reactions.Furthermore,model E is similar to Houk's recently calculated transition state of the Hajos±Parrish±Eder±Sauer±Wiechert reaction (D ).25However,according to these calculations,an N±H hydrogen bond does not lower the energy of the transition state and model E has consequently been advanced to model G ,5which is superimposable to the calculated transition state of the proline-catalyzed intermolecular aldol reaction (Fig.4).The proposed multi-step reaction mechanism (Scheme 9)has very recently been con?rmed using density functional theory calculations.39a Moreover,the validity of transition state G has been demonstrated by using density functional theory predictions followed by experimental veri?cation of stereoselectivities of proline-catalyzed aldol reactions.39b

4.Mannich reactions

Proline-catalysis has recently been extended to the direct asymmetric three-component Mannich reaction of ketones,aldehydes,and amines to give b -amino ketones in high yields and enantioselectivities (Scheme 10).40

Prior examples of catalytic asymmetric Mannich reactions

Table 5.The proline-catalyzed intermolecular aldol reaction using hydroxyacetone as the donor Product

Yield (%)

(%)

60.20:1.

62.20:1.

51.20:1.

95 1.5:1

38 1.7:1.

402:1.

Table 6.The proline-catalyzed direct asymmetric intermolecular aldol reaction using aldehydes as

donors

Yield (%)

ee (%)

Me 9090Et 9185i -Pr

8885CH 2CH v CH 29488n -C 6H 139184Ph 970

B.List /Tetrahedron 58(2002)5573±55905579

typically were indirect and required the use of preformed imine-and enol equivalents.41In contrast,the proline-catalyzed version constitutes a rare example of a catalytic asymmetric multi-component reaction.The substrate scope of this reaction has recently been explored.42Various ketones can be employed in proline-catalyzed Mannich reactions with p -anisidine (PMPNH 2)and p -nitrobenzalde-hyde with excellent results (Table 7).

Catalyst and amine-component have also been varied and so far proline seems to be the optimal catalyst while p -anisi-dine turned out to be the most useful amine-component.A remarkable aspect of the reaction is its tolerance to a broad range of diverse aldehydes as substrates.Both aromatic and aliphatic aldehydes can be used.Aromatic aldehydes generally give the Mannich products in high ees yet modest yields.43Most importantly,and in contrast to the proline-catalyzed aldol reactions and to all other catalytic asym-metric Mannich reactions,a -unbranched aldehydes

were

Scheme 9.Originally proposed mechanism of the proline-catalyzed direct asymmetric aldol

reaction.

Figure 4.Transition

states.

Table 7.Proline-catalyzed direct asymmetric Mannich reactions varying the ketone

component

Ketone Products Yield (%)

de (%)ee

(%)50

96.9599

93.95

92.95.99

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5580ef?cient substrates in the proline-catalyzed variant.Here,acetone or a chloroform/acetone mixture was used as the solvent instead of the commonly used DMSO (Table 8).Recently,ethyl glyoxylate has been added to the list of aldehydes that may be used.44Functionalized a -amino acid esters were obtained in high stereoselectivities in such reactions if the preformed imine of ethyl glyoxylate was used.Both ketones and a -unbranched aldehydes could be utilized as donors to give the products in high enantio-selectivities (Table 9).

Because of the exceptionally high regio-,diastereo-,and enantioselectivities observed in the Mannich reaction with hydroxyacetone,reactions with this ketone as the donor component were studied with several different aromatic aldehydes and isobutyraldehyde (Table 10).42

Good yields and diastereoselectivities and excellent regio-selectivities were generally observed.Enantioselectivities were typically very high (up to .99%),yet dependent on the electronic nature of the aldehyde component.A good

Table 8.Proline-catalyzed direct asymmetric Mannich reactions varying the aldehyde

component

R Yield (%)

(%)747

390

9382

7560

8080

5670

Table 9.Proline-catalyzed asymmetric Mannich reactions involving an ethyl glyoxylate derived

imine

R R 0Yield (%)

dr ee (%)Me

H 86±

99Me Me 72.19:1.99Et Me 47.19:1.99Me OH 62.19:199H i -Pr 81.10:193H Me 72 1.1:199H n -Bu 813:199H

n -Pent

.19:1

,99

Table 10.Proline-catalyzed direct asymmetric Mannich reactions invol-ving hydroxyacetone as the

donor

R Yield (%)

dr ee

(%)92

20:1

8815:1

9015:1

798:1

839:1

855:1

883:1

5717:1

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correlation of enantioselectivities with Hammett s p-values was observed,and a linear Hammett plot was obtained with a reaction constant r for the proline-catalyzed three-component Mannich reaction of1.36(R2 0.95)(Fig.5).

The positive reaction constant is consistent with partial negative charge formation in the transition state and with the proposed mechanism that involves nucleophilic addition of a proline±enamine to an imine(Scheme11).

According to the mechanistic proposal,a proline±enamine reacts with an imine in the C±C-bond forming and enantio-selectivity-determining step.Both the imine and enamine intermediates are formed in situ from an aldehyde and a ketone in two separate pre-equilibria.

One of the intriguing aspects of the proline-catalyzed Mannich reaction is its stereoselectivity.Diastereo-and enantioselectivities are opposite to those observed in proline-catalyzed intermolecular aldol reactions.This result was initially explained with transition states that involved (Z)-imines.However,(E)-aldimines strongly predominate equilibria with the corresponding(Z)-imines.For example, only the(E)-aldimine can be detected1H NMR-spectro-scopically in the reaction of p-nitrobenzaldehyde with p-anisidine in DMSO-d6.42b Therefore,although(Z)-imines cannot be excluded,it seems more likely that(E)-imines are involved in the reaction mechanism.The currently preferred transition state models for the proline-catalyzed Mannich reaction(H)and intermolecular aldol reaction(G)are shown in Fig.6.

The assumed transition states reˉect the fact that enantio-faciality of the electrophile(imine si vs aldehyde re),but not that of the enamine,is reversed in aldol vs Mannich reactions and in order to allow for protonation of its lone pair,an(E)-imine has to approach the enamine with its si-face to avoid unfavorable steric interactions between the pyrrolidine and aromatic ring.

5.Michael reactions

The Michael addition is a particularly interesting reaction because proline-catalysis may proceed by both amino-catalytic pathways,iminium(a)and enamine catalysis(b) (Scheme12);both reaction types have been realized.

5.1.Iminium catalysis of the Michael reaction Yamaguchi et al.found the Michael addition of malonates to a,b-unsaturated aldehydes to be catalyzed by secondary amines,including(S)-proline.45For example,dimethyl malonate reacts with hex-2-enal in the presence of pyrrolidine or proline to furnish Michael adduct8.It was noted that triethylamine and N-methyl proline are inactive and that lithium prolinate is superior to proline itself (Table

11).

Table11.Initial study by Yamaguchi et al.on iminium catalysis of the Michael

reactions

Catalyst Yield(%)

NEt3No reaction

Pyrrolidine33

(S)-Proline44

(S)-Proline Li salt93

(S)-Valine Li salt32

Table12.Studied metal

prolinates

M Cat.mol%Yield(%)ee(%)Abs.con?g. Li1002328(S)

Na57229(R)

251(R)

Rb59159(R)

Cs57356(R)

Mg1/2200831(S)

Ca1/2204122(S)

Sr1/2203912(S)

Ba1/220481(S)

Nme4103341(R)

B.List/Tetrahedron58(2002)5573±5590 5582

The lithium prolinate-catalyzed reaction has been performed with several different a,b-unsaturated aldehydes in good yields.However,only racemic products were obtained.The authors proposed iminium intermediates to be involved in the mechanism of this novel Michael https://www.wendangku.net/doc/292283014.html,ter,the same group observed asymmetric induc-tion if the reactions were performed in chloroform instead of methanol.After screening several different metal and ammonium prolinates as catalysts for the Michael addition of diisopropyl malonate to cycloheptenone,it was found that enantioselectivity and yield were optimal with the rubidium salt(Table12).46Interestingly,the lithium and alkaline earth metal prolinates provided the product with reversed absolute con?guration.The optimized conditions with rubidium prolinate as the catalyst have been applied to Michael additions of diisopropyl malonate and also of nitroalkanes to a variety of unsaturated ketones and alde-hydes to give the products in good yields and ees(Tables13 and14).47

Recently,an industrial group applied the Yamaguchi±Michael addition to an elegant yet only modestly enantio-selective synthesis of the selective serotonine re-uptake inhibitor(SSRI)(2)-paroxetine(Scheme13).48

The rubidium prolinate-catalyzed Michael addition of a malonamide9to cinnamic aldehyde10gave trans-piperi-dinone11,which was reduced to give piperidine12in 30%ee.(2)-Paroxetine was obtained from piperidine12 straightforwardly.

Yamaguchi et al.further demonstrated that the enantioselec-tivities of the malonate Michael additions could be further improved by using di(tert-butyl)malonate as the donor and cesiumˉuoride as a cocatalyst.47b Related conditions have been used in Merck's approach to the synthesis of substituted proline-derivatives(Scheme14).49

Accordingly,treating a,b-unsaturated aldehydes with diethylacetamidomalonate furnished pyrrolidines such as 13.These can be converted to3-substituted proline deriva-tives in three steps.As has been noted before by Yamaguchi et al.,addition of a small amount of water to the Michael reaction mixture was found to be essential for effective catalysis to occur.

High enantioselectivities(up to93%ee)in prolinate-cata-lyzed Michael additions of nitroalkanes to enones have recently been obtained by Hanessian and Pham by using a combination of proline(3±7mol%)with a stoichiometric amount of trans-2,5-dimethylpiperazine as the catalyst (Table15).50

It is likely that these reactions and those that are catalyzed by metal prolinates are facilitated by an iminium mechan-ism.Evidence obtained by Yamaguchi et al.includes that tertiary amines such as N-methyl proline are inactive,and that in contrast to(E)-4-phenyl-3-buten-2-one,its iminium salt readily undergoes a Michael reaction with dimethyl malonate.Proline's function could be two-fold in providing

Table13.Rubidium prolinate-catalyzed Michael additions of diisopropyl malonate

Enone or enal Product Yield(%)ee

(%)

5841

Table14.Rubidium prolinate-catalyzed Michael additions of

nitroalkanes

Enone or enal Product Yield(%)ee

(%)

Scheme13.Catalytic asymmetric synthesis of(2)-paroxetine.

B.List /Tetrahedron 58(2002)5573±55905583

a secondary amine for iminium catalysis as well as the carboxylate as a cocatalyst that helps in binding the nucleo-philic nitronate or malonate anion via the metal (or ammonium ion).In turn,this could determine the enantio-facial selectivity (Scheme 15).

An explanation of why different metals furnish enantio-meric products is not provided by this mechanism.However,it should be noted that the enantiofacial selec-tivity could readily reverse if the geometry of the presumed iminium ion was switched from (E )to (Z ).5.2.Enamine catalysis of the Michael reaction

Intramolecular proline-catalyzed Michael reactions of unac-tivated ketones to a ,b -unsaturated carbonyl compounds have been described by Kozikowski et al.51(Eqs.(5)and (6))and Momose et al.52(Eqs.(7)and (8))(Scheme 16).These reactions require a stoichiometric amount of the catalyst,long reaction times,and provide cyclic Michael products in only modest ees.In analogy to the Hajos±Parrish±Eder±Sauer±Wiechert reaction,a proline

enamine

Scheme 14.Merck's synthesis of substituted prolines.

Table 15.Proline-catalyzed asymmetric Michael reactions that use an organic base as the

cocatalyst

Enone or enal Product Yield (%)ee

(%)n.r.

Scheme 15.Possible iminium catalysis mechanism of proline-catalyzed Michael

reactions.

Scheme 16.Proline-catalyzed intramolecular Michael reactions.

B.List /Tetrahedron 58(2002)5573±5590

5584intermediate has been proposed to be involved in the mechanism.

The ?rst proline-catalyzed enantioselective intermolecular Michael reactions that use simple unactivated ketones as donors have recently been described.53Reacting selected small ketones (in excess)with nitro ole?ns and (S )-proline (15mol%)in DMSO gave the corresponding Michael adducts in generally high yields but only low enantio-selectivities (#23%)(Method A,Table 16).Enders et al.could further improve the enantioselectivity of the process by using methanol as the solvent (Method B).54

A novel proline-catalyzed three-component reaction between ketones,aldehydes,and Meldrum's acid has also been developed.55,56The reaction presumably involves a Knoevenagel reaction followed by a non-enantioselective Michael-type hetero-Diels±Alder reaction (Table 17).Why proline-catalyzed enamine catalytic Michael reactions (in contrast to Yamaguchi's iminium catalytic Michael reac-tions)generally showed lower enantioselectivities than the corresponding Mannich and aldol processes remains an open question.The basic lone pair of aldehydes and imines may be partially responsible for p -facial enantioselectivity by providing an additional point of interaction with the chiral proline enamine intermediate through hydrogen bonding to proline's carboxylic acid.Consistent with this concept is the fact that enantioselectivities in aldol and Mannich reactions are reduced in protic solvents such as methanol.Interestingly,improved enantioselectivities were observed in proline-catalyzed Michael reactions in methanol.

5.3.One-pot Robinson-annulations

The ?rst proline-catalyzed asymmetric Robinson-annu-lation (intermolecular Michael reaction followed by intramolecular aldol reaction)has been developed by Swaminathan et al.57Reacting 2-formylcyclohexanone with methyl vinylketone (MVK)directly gave spirocyclic product 14in modest enantioselectivity (Eq.(1)in Scheme 17).The scope of the reaction has been extended to other cyclic formylketones.58Wicha et al.found the proline-catalyzed reaction of diketone 15with unsaturated ketone 16to directly give Hajos±Parrish±Eder±Sauer±Wiechert-type product 17(Eq.(2)).59This reaction has recently been extended to the Wieland±Miescher-ketone (Eq.(3)).60While the proline-catalyzed one-pot Robinson-annulations are experimentally simpler than the original two-step

Table 16.The proline-catalyzed intermolecular Michael reaction of unac-tivated ketones with nitro

ole?ns

Product Yield (%)Selectivity

Method 977%ee A 9312%ee

B 30

42%ee

94dr .20:1,23%ee A 79dr .20:1,57%ee

4dr 16:1,76%ee

dr 10:1,19%ee A

Table 17.A novel proline-catalyzed three-component

reaction

R 1R 2R 3Yield (%)

de (%)

H 78H

H 83H

H 79H

H 51H

6569.

9575

B.List /Tetrahedron 58(2002)5573±55905585

processes,it has been pointed out that the two-step pro-cedures require signi?cantly less catalyst and generally provide better yields and ees.58

6.The direct electrophilic a -amination

Proline-catalysis in aldol,Mannich,and Michael reactions can be rationalized with a general enamine catalysis cycle (Scheme 18).5

Accordingly,carbonyl compounds react with proline to generate an enamine intermediate and water.This enamine

reacts with an electrophile X Y,which may be an alde-hyde,an imine,or an activated ole?n in an aldol,Mannich,or Michael reaction.Hydrolysis of the iminium intermediate then gives the product under regeneration of the proline catalyst.An alternative electrophilic species could be a dialkyl azodicarboxylate (X Y:RCO 2N v NCO 2R).The overall transformation would result in an electrophilic a -amination of the carbonyl compound.61The products of this reaction,if produced enantioselectively,could be useful precursors for various amino acid derivatives.

Very recently,this reaction has been realized for the ?rst time.62It was found that proline catalyzes the direct electro-philic a -amination of unbranched aldehydes highly effectively and enantioselectively.Because the produced a -hydrazino aldehydes are con?gurationally labile,they were in situ reduced to the corresponding alcohols (Table 18).

The potential of the produced amino alcohol derivatives as precursors for the asymmetric synthesis of a -amino acid derivatives was demonstrated with a straightforward syn-thesis of Evans-type oxazolidinone 18via hydrogenation and work-up with phosgene (Scheme 19).The hydro-genation removes both Cbz-protecting groups and simul-taneously cleaves the N±N bond.

The observed stereoselectivity can be explained with tran-sition state J (Fig.7),which again is superimposable with Houk's transition states of the Hajos±Parrish±Eder±Sauer±Wiechert reaction (D )and Agami's diketone-cyclization (D 0).A comparison of the assumed preferred transition states of the proline-catalyzed enamine-involving intra-molecular aldol reaction (D ,D 0),25intermolecular aldol reaction (G ),5Mannich reaction (H ),42Michael reaction (I ),53,54and a -amination (J )62reveals three important and general structural elements:(1)The assumed proline±enamine is always in a conformation in which the car-boxylate is anti to the enamine±ole?n.(2)The enamine±ole?n geometry is always (E ).(3)The carboxylic acid protonates the electrophile to compensate negative charge formation.A generalized transition state (K )that combines these elements may be constructed (Fig.7).

7.Miscellaneous proline-catalyzed asymmetric reactions In addition to aldol,Mannich-,Michael and electrophilic a -amination reactions,proline has been used as a catalyst in several other asymmetric transformations such as allylic oxidations,transfer-hydrogenations,and Diels±Alder-type reactions.In these reactions,proline is not only used as an aminocatalyst but also as a chiral ligand in metal-mediated asymmetric

processes.

Scheme 18.The enamine catalysis cycle.

Table 18.The ?rst direct catalytic asymmetric electrophilic a -amination of

aldehydes

Product R Yield (%)

ee (%)1i -Pr 99962n -Pr 93.953n -Bu 94974Me 97.955

Scheme 19.Synthesis of an

Evans-auxiliary.

B.List /Tetrahedron 58(2002)5573±5590

55867.1.Diels±Alder-type dimerizations of a ,b -unsaturated aldehydes

Asato and Liu et al.63found that upon treating a ,b -unsatu-rated aldehydes with (S )-proline in ethanol,cyclic optically active dimers were obtained (Table 19).

Such dimerizations were known to occur under basic condi-tions,and to give racemic products.64The proline-catalyzed reactions furnish the products in encouraging enantioselec-tivity and it may be worthwhile to study other chiral amines as potential catalysts for this interesting reaction.Mechanistically,the reaction could proceed via dienamine 19and/or iminium ion 20.These intermediates may undergo

a Diels±Alder-reaction followed by elimination and hydrolysis to give the observed products (Fig.8).7.2.Baylis±Hillman reactions

Very recently,a mixture of proline and imidazole (each 30mol%)has been found to catalyze Baylis±Hillman reactions of aldehydes with MVK (Table 20).65

Essentially,no asymmetric induction was observed (ees 5±10%).According to the proposed mechanism,proline activates MVK as the iminium ion,facilitating conjugate addition of the imidazole.The resulting enamine reacts with the aldehyde in an aldol reaction.The Baylis±Hillman product is then formed via elimination and hydrolysis.That imidazole alone (in contrast to other nucleophiles such as DABCO)is not suf?ciently reactive to induce the Baylis±Hillman process can be interpreted as evidence for the proposed iminium catalysis (Scheme 20).It will be interest-ing to note whether the use of other chiral amines or dif-ferent reaction conditions may lead to a new catalytic asymmetric Baylis±Hillman variant.

7.3.Reductions

Several reductions involving proline as the source for asym-metric induction have been developed.These include hydrogenations,epoxide reductions,borane and boranate reductions,and ruthenium-catalyzed transfer hydro-genations.

Ethyl acetoacetate has been enantioselectively reduced with

Table 19.Dimerizations of unsaturated aldehydes (n.r. not

reported)

R Yield (%)ee (%)CH 3

n.r.

±n.r.

n.r.

Figure 8.Possible intermediates.

Table 20.Proline-catalyzed Baylis±Hillman

reactions

R Yield

(%)

Scheme 20.A mechanism of the proline/imidazole-catalyzed Baylis±Hill-man

reaction.

Scheme 21.Proline-catalyzed asymmetric hydrogenation.

B.List /Tetrahedron 58(2002)5573±55905587

a Raney Cu-catalyst modi?ed with (S )-proline.66Other heterogeneous catalysts in combination with proline have also been used,but typically reduce ketones with low

enantioselectivities.

Tungler et al.described the Pd/C-catalyzed reduction of isophorone in the presence of (S )-proline to give saturated ketone 22in low yield and ca.60%ee.The main side product results from a reductive amination of ketone 22with proline.The reaction may involve iminium intermediate 21(Scheme 21).68

An equimolar mixture of NaBH 4and (S )-proline in THF reduces ketones to secondary alcohols in ees of up to 62%.69Martens et https://www.wendangku.net/doc/292283014.html,ed a mixture of borane with proline for the similar reactions and obtained enantioselectivities of up to .95%.70Presumably,proline is initially converted to prolinol,which then forms an oxazaborolidine,derivative of the well-known CBS-reduction catalyst.

Racemic epoxides have been reductively cleaved with a mixture of zirconium tetrachloride,sodium borohydride,and (S )-proline to give enantioenriched alcohols (Scheme 22).71Apparently,these reactions are not kinetic resolutions and the authors speculate that they may involve zirconium enolates.

An interesting Noyori-type asymmetric transfer hydrogena-tion has been developed by Furukawa et al.72The catalyst is prepared by mixing potassium prolinate with RuCl 2(p -cymene)2,and reduces aromatic ketones with isopropa-nol to give secondary alcohols in good yields and ees (Table 21).7.4.Oxidations

One of the ?rst catalytic asymmetric allylic oxidations was based on a copper catalyst combined with (S )-proline.Disclosed in a patent by Sumitomi Chemical Co.,Ldt.,73this system was investigated by Muzart and Ferringa.74An example is the oxidation of cyclohexene with PhCO 3t -Bu in the presence of propionic acid and catalytic amounts of Cu(OAc)2and (S )-proline to give ester 24in acceptable enantioselectivity (Scheme 23).Improved catalyst systems have recently been described.75

8.Conclusions

It is remarkable that despite the diversity of reactions discussed in this review,ranging from carbon±carbon bond-forming aldol-,Mannich-,and Michael reactions,to electrophilic aminations,transfer-hydrogenations,and allylic oxidations,the catalytically active species and source of asymmetry is a small and simple amino acid.While proline may not be the `universal asymmetric catalyst'for all reactions,it clearly is a privileged molecule for enantio-selective synthesis.Not only is proline inexpensive,avail-able in both enantiomeric forms,stable,non-toxic,and a powerful catalyst for a number of asymmetric reactions;it also has a multifaceted mechanistic complexity hidden underneath its `simple'structure.It would seem daring to expect anything less than the discovery of several new proline-catalyzed reactions in the future.

9.Note added in proof

Three important publications that highlight the vitality of the reviewed ?eld have appeared while proof reading this article:MacMillan et al.describe proline-catalyzed highly enantioselective intermolecular aldol reactions between two aldehydes (Northrup,A.B.;MacMillan,D.W.C.J.Am.Chem.Soc.2002,124,ASAP ),and Jùrgensen and coworkers describe proline-catalyzed electrophilic alpha-amination reactions (also see chapter six)of both aldehydes (Angew.Chem.Int.Ed.2002,41,1790±1793)and ketones (J.Am.Chem.Soc.2002,124,

6254±6255).

Table 21.Proline-catalyzed asymmetric transfer

hydrogenation

Product Yield (%)

(%)72

Scheme 23.Proline-catalyzed asymmetric allylic oxidation.

B.List/Tetrahedron58(2002)5573±5590 5588

Acknowledgements

Some of the experiments described herein were done in the laboratories of the reviewer and would not have been possi-ble without the dedication and enthusiasm of his co-workers William Biller,Chris Castello,David Goldsheft,Linh Hoang,Harry Martin,Wolfgang Notz,and Peter Pojarliev. We gratefully acknowledge our collaborator K.N.Houk and his colleagues at the University of California,Los Angeles for sharing the results of their brilliant compu-tational studies.We further thank Richard A.Lerner for his support and inspiration and the National Institutes of Health for generous funding of our studies.

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Biographical sketch

Benjamin List was born in Germany in1968.He studied chemistry at the

Free University of Berlin where he obtained a Diploma(summa cum laude)

in1993.He received his PhD(summa cum laude)in1997from the J ohann

Wolfgang Goethe University in Frankfurt working in the?eld of natural

product synthesis under the supervision of Professor J.Mulzer.He spent

nearly two years as a postdoctoral research associate in the laboratories of

Professor R.A.Lerner at the Scripps Research Institute studying catalytic

antibodies.In January1999,he became an Assistant Professor at Scripps.

His research interests include catalysis,new reaction methodologies,and

bioorganic chemistry.

16_Sharpless Asymmetric Epoxidation Reaction哈佛有机化学讲义

R 2 R 1 R 3 HO O R 3 OH OH OH OH OH OH OH 2 Myers Sharpless Asymmetric Epoxidation Reaction Chem 215 Reviews: Katsuki, T.; Martin, V. S. Org. React. 1996, 48, 1-300. Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric Synthesis , Ojima, I., Ed.; VCH: New York, 1993, pp. 103-158. Johnson, R. A.; Sharpless, K. B. In Comprehensive Organic Synthesis , Trost, B. M.; Fleming, I., Eds., Pergamon Press: New York, 1991, Vol. 7, pp. 389-436. Pfenninger, A. Synthesis 1986, 89-116. Asymmetric Epoxidation of Allylic Alcohols: R Substitution patterns: ? Z -disubstituted olefins are least reactive and selective. OH Examples of Sharpless Epoxidation: 3 R 2 OH R 1 Ti(O i-Pr)4,(+)-DET t -BuOOH, 3?-MS CH 2Cl 2, –20 °C R 2 OH R 1 OH ? 5-10 mol% catalyst in the presence of 3 or 4 ?-MS. (+)-DET = EtO C CO 2Et ? 10-20 mol% excess tartarate vs. Ti(O i Pr)4 required. ? (+)- and (–)-DET are readily available and i nexpensive. OH 4.7 ? (+)- and (–)-DIPT, diisopropyl tartarate, are also available and sometimes lead to higher selectivity. Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.; Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765-5780. Mnemonic for selectivity: L-(+)-DET "O" H 3C BnO O CH 3 OH O OH 100 (+)-DET (142) –20 14 80 80 D-(–)-DET "O" Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974-5976. CH 3 CH 3 O CH 3 5 (+)-DET (7.4) –20 0.75 95 91 Application of Mnemonic: CH 3 CH 3 CH 3 Ph OH Ph 120 (–)-DET (150) –20 5 90 94 O OH AE-(–)-DET OH AE-(+)-DET O OH From: Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.; Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765-5780 and Johnson, R. A.; Sharpless, K. B. In Catalytic 97%, 86% ee 97%, 86% ee Asymmetric Synthesis , Ojima, I., Ed.; VCH: New York, 1993; pp. 103-158. M. Movassaghi product Ti(%) tartarate (%) °C h yield (%) ee (%) O OH 5 (+)-DIPT (6.0) 2 65 90 Ph O OH 5 (+)-DIPT (7.5) –20 3 89 >98 Pr O OH (+)-DET (5.9) –12 11 88 95 O OH 10 C 7H 15 (+)-DET (14) –10 29 74 86 CH 3 Ph O OH 5 (+)-DIPT (7.5) –35 2 79 >98

经济学名词解释中英文对照

1、绝对优势(Absolute advantage ) 如果一个国家用一单位资源生产的某种产品比另一个国家多，那么，这个国家在这种产品的生产上与另一国相比就具有绝对优势。 2、逆向选择( Adverse choice ) 在此状况下，保险公司发现它们的客户中有太大的一部分来自高风险群体。 3、选择成本(Alternative cost ) 如果以最好的另一种方式使用的某种资源，它所能生产的价值就是选择成本，也可以称之为机会成本。 4、需求的弧弹性( Arc elasticity of demand ) 如果P1和Q1分别是价格和需求量的初始值，P2和Q2为第二组值，那么，弧弹性就等于 -(Q1-Q2)( P1 + P2 ) / ( P1-P2 ) (Q1 + Q2) 5、非对称的信息( Asymmetric information ) 在某些市场中，每个参与者拥有的信息并不相同。例如，在旧车市场上，有关旧车质量的信息，卖者通常|要比潜在的买者知道得多。 6、平均成本(Average cost ) 平均成本是总成本除以产量。也称为平均总成本。 7、平均固定成本(Average fixed cost ) 平均固定成本是总固定成本除以产量。 8、平均产品(Average product ) 平均产品是总产量除以投入品的数量。 9、平均可变成本(Average variable cost ) 平均可变成本是总可变成本除以产量。 10、投资的R Beta ) B度量的是与投资相联的不可分散的风险。对于一种股票而言，它表示所有现行股票的收益发生变化时，一种股票的收益会如何敏感地变化。 11、债券收益(Bond yield ) 债券收益是债券所获得的利率。 12、收支平衡图(Break —even chart ) 收支平衡图表示一种产品所岀售的总数量改变时总收益和总成本是如何变化的。收支平衡点是为避免损失而必须卖岀的最小数量。 13、预算线(Budget line ) 预算线表示消费者所能购买的商品X和商品Y的数量的全部组合。它的斜率等于商品X的价格除以商品Y 的价格再乘以一1。 14、捆绑销售(Bundling ) 捆绑销售指这样一种市场营销手段，岀售两种产品的厂商，要求购买其中一种产品的客户，也要购买另一种产品。 15、资本(Capital ) 资本是指用于生产、销售及商品和服务分配的设备、厂房、存货、原材料和其他非人力生产资源。 16、资本收益(Capital gain ) 资本收益是指人们卖岀股票(或其他资产)时所获得的超过原来为它支付的那一部分。 17、资本主义(Capitalism ) 资本主义是一种市场体系，它依赖价格体系去解决基本的经济问题：生产什么？如何生产？怎样分配？经济增长率应为多少？ 18、基数效用(Cardinal utility ) 基数效用是指像个人的体重或身高那样在基数的意义上可以度量的效用(它意味着效用之间的差别，即边际效用，是

西方经济学名词解释总结(考研必备)

西方经济学名词解释总结（考研必备） 1、绝对优势（Absolute advantage）如果一个国家用一单位资源生产的某种产品比另一个国家多，那么，这个国家在这种产品的生产上与另一国相比就具有绝对优势。 2、逆向选择（Adverse choice）在此状况下，保险公司发现它们的客户中有太大的一部分来自高风险群体。 3、选择成本（Alternative cost）如果以最好的另一种方式使用的某种资源，它所能生产的价值就是选择成本，也可以称之为机会成本。 4、需求的弧弹性（ Arc elasticity of demand）如果P1和Q1分别是价格和需求量的初始值，P2 和Q2 为第二组值，那么，弧弹性就等于 -（Q1-Q2）（P1＋P2）/（P1-P2）（Q1＋Q2） 5、非对称的信息（Asymmetric information）在某些市场中，每个参与者拥有的信息并不相同。例如，在旧车市场上，有关旧车质量的信息，卖者通常要比潜在的买者知道得多。 6、平均成本（Average cost）平均成本是总成本除以产量。也称为平均总成本。 7、平均固定成本( Average fixed cost）平均固定成本是总固定成本除以产量。 8、平均产品（Average product）平均产品是总产量除以投入品的数量。 9、平均可变成本（Average variable cost）平均可变成本是总可变成本除以产量。 10、投资的β(Beta） β度量的是与投资相联的不可分散的风险。对于一种股票而言，它表示所有现行股票的收益发生变化时，一种股票的收益会如何敏感地变化。 11、债券收益(Bond yield）债券收益是债券所获得的利率。 12、收支平衡图（Break－even chart）收支平衡图表示一种产品所出售的总数量改变时总收益和总成本是如何变化的。收支平衡点是为避免损失而必须卖出的最小数量。 13、预算线(Budget line）预算线表示消费者所能购买的商品X和商品Y的数量的全部组合。它的斜率等于商品X的价格除以商品Y的价格再乘以一1。 14、捆绑销售（Bundling）捆绑销售指这样一种市场营销手段，出售两种产品的厂商，要求购买其中一种产品的客户，也要购买另一种产品。 15、资本（Capital）资本是指用于生产、销售及商品和服务分配的设备、厂房、存货、原材料和其他非人力生产资源。16、资本收益（Capital gain）资本收益是指人们卖出股票（或其他资产）时所获得的超过原来为它支付的那一部分。 17、资本主义（Capitalism）资本主义是一种市场体系，它依赖价格体系去解决基本的经济问题：生产什么？如何生产？怎样分配？经济增长率应为多少？

常用统计学英文名词[整理版]

常用统计学英文名词[整理版] 常用统计学英文名词(英汉对照) Absolute deviation 绝对离差 Absolute number 绝对数 Absolute residuals 绝对残差 Acceleration normal 法向加速度 Acceleration space dimension 加速度空间的维数 Acceleration tangential 切向加速度Acceleration vector 加速度向量 Acceptable hypothesis 可接受假设Accumulation 累积 Accuracy 准确度 Actual frequency 实际频数 Actual value 实际数 Adaptive estimator 自适应估计量 Addition 相加 Addition theorem 加法定理 Additivity 可加性 Adjusted rate 调整率 Adjusted value 校正值Admissible error 容许误差 Alternative hypothesis 备择假设 Among groups 组间 Amounts 总量 Analysis of correlation 相关分析 Analysis of covariance 协方差分析 Analysis of regression 回归分析 Analysis of time series 时间序列分析 Analysis of variance 方差分析 Angular transformation 角转换 ANOVA (analysis of variance) 方差分析 ANOVA Models 方差分析模型Arcing 弧/弧旋 Arcsine transformation 反正弦变换 Area under the curve 曲线面积 Arithmetic grid paper 算术格纸 Arithmetic mean 算术平均数Assessing fit 拟合的评估 Associative laws 结合律 Asymmetric distribution 非对称分布 Asymptotic bias 渐近偏倚 Asymptotic efficiency 渐近效率 Asymptotic variance 渐近方差 Attributable risk 归因危险度 Attribute data 属性资料Attribution 属性 Autocorrelation 自相关 Autocorrelation of residuals 残差的自相关 Average 平均数 Average confidence interval length 平均置信区间长度 Average growth rate 平均增长率 Bar chart 条形图 Bar graph 条形图

rfc5958.Asymmetric Key Packages

Internet Engineering Task Force (IETF) S. Turner Request for Comments: 5958 IECA Obsoletes: 5208 August 2010 Category: Standards Track ISSN: 2070-1721 Asymmetric Key Packages Abstract This document defines the syntax for private-key information and a content type for it. Private-key information includes a private key for a specified public-key algorithm and a set of attributes. The Cryptographic Message Syntax (CMS), as defined in RFC 5652, can be used to digitally sign, digest, authenticate, or encrypt the asymmetric key format content type. This document obsoletes RFC 5208. Status of This Memo This is an Internet Standards Track document. This document is a product of the Internet Engineering Task Force (IETF). It represents the consensus of the IETF community. It has received public review and has been approved for publication by the Internet Engineering Steering Group (IESG). Further information on Internet Standards is available in Section 2 of RFC 5741. Information about the current status of this document, any errata, and how to provide feedback on it may be obtained at https://www.wendangku.net/doc/292283014.html,/info/rfc5958. Copyright Notice Copyright (c) 2010 IETF Trust and the persons identified as the document authors. All rights reserved. This document is subject to BCP 78 and the IETF Trust’s Legal Provisions Relating to IETF Documents (https://www.wendangku.net/doc/292283014.html,/license-info) in effect on the date of publication of this document. Please review these documents carefully, as they describe your rights and restrictions with respect to this document. Code Components extracted from this document must include Simplified BSD License text as described in Section 4.e of the Trust Legal Provisions and are provided without warranty as described in the Simplified BSD License. Turner Standards Track [Page 1]

Asymmetric Catalysis Science and Opportunities (Nobel Lecture)

1.Prologue Chirality(handedness;left or right)is an intrinsic universal feature of various levels of matter.[1]Molecular chirality plays a key role in science and technology.In particular,life depends on molecular chirality,in that many biological functions are inherently dissymmetric.Most physiological phenomena arise from highly precise molecular interactions, in which chiral host molecules recognize two enantiomeric guest molecules in different ways.There are numerous examples of enantiomer effects which are frequently dramat-ic.Enantiomers often smell and taste different.The structural difference between enanatiomers can be serious with respect to the actions of synthetic drugs.Chiral receptor sites in the human body interact only with drug molecules having the proper absolute configuration,which results in marked differ-ences in the pharmacological activities of enantiomers.A compelling example of the relationship between pharmaco-logical activity and molecular chirality was provided by the tragic administration of thalidomide to pregnant women in the1960s.(R)-Thalidomide has desirable sedative properties,while its S enantiomer is teratogenic and induces fetal malformations.[2,3]Such problems arising from inappropriate molecular recognition should be avoided at all costs.Never-theless,even in the early1990s,about90%of synthetic chiral drugs were still racemic–that is,equimolar mixtures of both enantiomers,which reflects the difficulty in the practical synthesis of single-enantiomeric compounds.[4]In1992,the Food and Drug Administration in the U.S.introduced a guideline regarding?racemic switches∫,in order to encourage the commercialization of clinical drugs consisting of single enantiomers.[5]Such marketing regulations for synthetic drugs,coupled with recent progress in stereoselective organic synthesis,resulted in a significant increase in the proportion of single-enantiomer drugs.In2000,the worldwide sales of single-enantiomer compounds reached123billion U.S.dol-lars.[6]Thus,gaining access to enantiomerically pure com-pounds in the development of pharmaceuticals,agrochem-icals,and flavors is a very significant endeavor. Discovery of truly efficient methods to achieve this has been a substantial challenge for chemists in both academia and industry.Earlier,enantiomerically pure compounds were obtained by the classical resolution of a racemate or trans-formation of readily accessible,naturally occurring chiral compounds such as amino acids,tartaric and lactic acids, carbohydrates,terpenes,or alkaloids.Even though stereo-selective conversion of a prochiral compound to a chiral product,namely through an asymmetric reaction,is the most attractive approach,practical access to pure enantiomers relied largely on biochemical or biological methods.However, Asymmetric Catalysis:Science and Opportunities(Nobel Lecture)** Ryoji Noyori* [*]Prof.Dr.R.Noyori Department of Chemistry Nagoya University Chikusa,Nagoya464-8602(Japan) Fax:( 81)52-783-4177 E-mail:noyori@chem3.chem.nagoya-u.ac.jp [**]Copyright1The Nobel Foundation2002.We thank the Nobel Foundation,Stockholm,for permission to print this lecture. REVIEWS

abaqus结构分析单元类型

;this wordfile adds the code folding function which is useful to ignore rows of nu mbers,enjoy~ ;updated in , based on the wordfile "abaqus_67ef()" ;Syn tax file for abaqus keywords ,code fold ing en abled ;add *ANISOTROPIC *ENRICHMENT *LOW -DISPLACEMENT HYPERELASTIC ;n ewly add /C"Eleme ntType" ;delete DISPLACEMENT ;delete MASS in /C2"Keywords2" /L29"abaqus_612" Nocase File Exte nsions = inp des dat msg /Delimiters = ~!@$%A&()_-+=|V{}[]:;"'<>，./ /Fun ction Stri ng = "%[ At]++[ps][a-z]+ [a-z0-9]+ A(*(*)A)*{$" /Fu nction Stri ng 1 = "%[ At]++[ps][a-z]+ [a-z0-9]+ A(*(*)A)[人屮+$“ /Member Stri ng = "A([A-Za-zO-9_:.]+A)[人广&]+$S[人屮+[(=);,]" /Variable Stri ng = "A([A-Za-zO-9_:.]+A)[人甘&]+$S[人屮+[(=);,]" /Open Fold Stri ngs = "*" "**""***" /Close Fold Strings = "*" "**""***" /C1"Keywords1" STYLE_KEYWORD *ACOUSTIC *ADAPTIVE *AMPLITUDE *ANISOTROPIC *ANNEAL *AQUA *ASSEMBLY *ASYMMETRIC *AXIAL *BASE *BASELINE *BEAM *BIAXIAL *BLOCKAGE*BOND *BOUNDARY*BRITTLE *BUCKLE *BUCKLING *BULK *C *CAP *CAPACITY *CAST *CAVITY *CECHARGE *CECURRENT *CENTROID *CFILM *CFLOW *CFLUX *CHANGE *CLAY *CLEARANCE *CLOAD *CO *COHESIVE *COMBINED *COMPLEX *CONCRETE *CONDUCTIVITY *CONNECTOF*CONSTRAINT *CONTACT *CONTOUR *CONTROLS *CORRELATION *COUPLED *COUPLING *CRADIATE *CREEP *CRUSHABLE *CYCLED *CYCLIC *D *DAMAGE *DAMPING *DASHPOT *DEBOND *DECHARGE*DECURRENT *DEFORMATION*DENSITY *DEPVAR *DESIGN *DETONATION*DFLOW *DFLUX *DIAGNOSTICS *DIELECTRIC *DIFFUSIVITY *DIRECT *DISPLAY *DISTRIBUTING *DISTRIBUTION *DLOAD*DRAG*DRUCKERDSA *DSECHARGE *DSECURRENT *DSFLOW *DSFLUX *DSLOAD *DYNAMIC *EL *ELASTIC *ELCOPY *ELECTRICAL *ELEMENT *ELGEN *ELSET *EMBEDDED *EMISSIVITY *END *ENERGY *ENRICHMENT *EOS *EPJOINT *EQUATION *EULERIAN *EXPANSION *EXTREME *FABRIC *FAIL *FAILURE *FASTENER *FIELD *FILE *FILM *FILTER *FIXED *FLOW *FLUID *FOUNDATION *FRACTURE *FRAME *FREQUENCY *FRICTION *GAP *GASKET *GEL *GEOSTATIC *GLOBAL *HEADING *HEAT *HEATCAP *HOURGLASS *HYPERELASTIC *HYPERFOAM *HYPOELASTIC *LATENT *LOAD *LOADING *LOW *M1 *M2 *MAP *MASS *MATERIAL *MATRIX *MEMBRANE *MODAL PAIR PARAMETER PART PARTICLE PATH PENETRATION PLASTIC PLASTICITY POINT POINTS CPE4I CPE4IH WARP2D3 WARP2D4