The asymmetric hydrogenation of n,ndialkyl and nalkylnaryl enamines to chiral tertiary amines was studied. Here, we report an efficient biocatalytic process to replace a recently implemented rhodiumcatalyzed asymmetric enamine hydrogenation for the largescale manufacture of the antidiabetic compound sitagliptin. The development of a planarchiral catalyst for the enantioselective additions of hn3 to hindered ketenes was investigated. Key words copper catalysis, asymmetric synthesis, allenols, propar. Journal of the american chemical society 2018, 140 2, 598601. Synthesis of chiral amines by asymmetric additions to tertbutylsulfinimines ellman auxiliary additions to tertbutylsul. Myers synthesis of chiral amines by asymmetric additions. Chiral tertiary alcohols and rtertiary amines are important building blocks of naturally occurring and artificial biologi cally active molecules. Myers synthesis of chiral amines by asymmetric additions to. Enantioselective organocatalytic amineisocyanate capture. Catalytic asymmetric synthesis of allcarbon quaternary stereocenters. Oct 24, 20 chiral amines are prevalent in many bioactive molecules, including amino acids and pharmaceutical agents.
Organic chemistry catalytic asymmetric hydroamination va of. Asymmetric synthesis of amines using tert butanesulfinamide. Being chiral amines less numerous than amino acids, of the twenty four alkyl amines with one to fivecarbon chain that can be derivatized with tfa i. One of the challenges of preparing chiral amines in enantiomerically pure form is the development of costeffective and sustainable catalytic methods that are able to address the requirement for the entire range of primary, secondary and tertiary amines. Spontaneous absolute asymmetric synthesis promoted by achiral amines in conjunction with asymmetric autocatalysis, journal of systems chemistry, 2010, pp. Rhodiumcatalyzed asymmetric hydroamination of allyl amines. Process considerations for the asymmetric synthesis of chiral.
Chiral amines are very important compounds industrially, for example, they are used as medicine chemical intermediates and chiral reagents for diastereomeric salt formation method. Asymmetric synthesis of primary amines catalyzed by. This is one property that many strategies in asymmetric synthesis have in common. Other readers will always be interested in your opinion of the books youve read. Catalytic asymmetric 3,3rearrangements of allylic acetimidates. This first comprehensive presentation of this hot and important topic compiles the most uptodate methods for chiral amine synthesis. Asymmetric synthesis of amines with tertbutanesulfinamide. Spontaneous absolute asymmetric synthesis promoted by achiral. The auxiliary can then be typically recovered for future use. Synthesis of asymmetric secondary and tertiary amines from. The use of 2bornanethiol for the asymmetric synthesis of.
Asymmetric synthesis of less accessible tertiary amines from. Butanesulfinyl imines are exceedingly versatile intermediates for the asymmetric synthesis of amines. The use of 2bornanethiol for the asymmetric synthesis of amines. Essa hu, asymmetric catalysis with chiral lewis bases part iii, march 2001. The international list of authors reads like a whos who of the subject, providing a large array of highly practical information concentrated into the useful and essential methods. Aug 19, 2009 stereoselective synthesis of fluorinated chiral amines based on the use of ntertbutylsulfinyl imines has been accomplished by two major strategies. Unified access to cyclic ureas of tertiary and secondary amines in. They are used directly as resolving agents, building blocks or chiral auxiliaries. Nov 26, 20 enantiomerically pure chiral amines are valuable building blocks for the synthesis of pharmaceutical drugs and agrochemicals. A chiral auxiliary is a stereogenic group or unit that is temporarily incorporated into an organic compound in order to control the stereochemical outcome of the synthesis. Control of chemoselectivity in asymmetric tandem reactions. Turner a chiral primary amines are important intermediates in the synthesis of pharmaceutical compounds. Aldimines 15 and ketimines 16 are prepared in high yields under mild conditions by condensing enantiomerically pure tertbutanesulfinamide 10, either enantiomer of which is readily synthesized in large scale from inexpensive reagents, with a wide range of. One of the challenges of preparing chiral amines in.
The chirality present in the auxiliary can bias the stereoselectivity of one or more subsequent reactions. Over the past several years, we have developed a method for the asymmetric synthesis of a broad range of amines using the extremely versatile chiral amine reagent, tertbutanesulfinamide fig. Chiral primary amines play an essential role in the preparation of natural products, active pharmaceutical ingredients, and other important derivatives because of their synthetic flexibility figure 1a. Asymmetric synthesis of less accessible tertiary amines.
Asymmetric sequential auichiral tertiary amine catalysis. Biocatalytic asymmetric synthesis of chiral amines from. Bibliography includes bibliographical references and index. Indeed it is estimated that currently 40 % of pharmaceuticals contain a chiral amine component in their structure. A highly stereoselective synthesis of hitherto less accessible chiral tertiary amines with multiple structurally similar linear carbon chains was achieved through chiral auxiliary mediated addition of organolithium reagents to the geometrically well. Chiral amines have found widespread application in asymmetric synthesis serving, for instance, as chiral bases in enantioselective deprotonation reactions 1 or being valuable substances for resolving racemic mixtures of acids. Asymmetric catalysis with chiral primary aminebased. Herein, we report a general asymmetric route for the onepot synthesis of chiral. Process considerations for the asymmetric synthesis of. Enantiomerically pure chiral amines are valuable building blocks for the synthesis of pharmaceutical drugs and agrochemicals.
The power of catalytic asymmetric tandem reactions is particularly compelling in providing direct transformations of readily available achiral starting materials into. The catalytic asymmetric synthesis of tertiary alcohols and. Pharmaceutical synthesis can benefit greatly from the selectivity gains associated with enzymatic catalysis. Whether youve loved the book or not, if you give your honest and detailed thoughts then people will find new books that are right for them. Access to chiral tertiary amines via the iridiumcatalyzed. Catalytic asymmetric tandem reactions are recognized as an optimal strategy for the synthesis of complex chiral compounds 1. Organic chemistry catalytic asymmetric hydroamination. Nucleophilic chiral amines as catalysts in asymmetric synthesis stefan france, david j. The aim being to convert enantiomers into diastereomers. Chiral tertiary diamines in asymmetric synthesis request pdf. Since then, chiral secondary amines catalysts shown in scheme 1a. The amount of chiral ligand used in this transformation can be as low as 2. Chiral tertiary amine noxides in asymmetric epoxidation of. Asymmetric total synthesis of bioactive natural products and pharmaceuticals.
Chiral auxiliaries are incorporated into synthetic routes to control the absolute configuration of stereogenic centers. After the reaction between pyrimidine5carbaldehyde 1 and ipr 2 zn in the presence of achiral amines, asymmetric autocatalysis amplified the spontaneously generated small fluctuation of ee to afford the enantiomerically. Secondary amines as coupling partners in direct catalytic. The methods developed using the reagent tertbutanesulfinamide as well as those involving camphorderived auxiliaries have produced chiral amines in high yields and stereoselectivities, which is very important to pharmaceutical industries. Catalytic asymmetric synthesis of allcarbon quaternary stereocenters christopher j. While classically available through racemic resolution with optically active acids, biotechnological approaches also open a way to chiral amines. Catalytic asymmetric synthesis of allcarbon quaternary. A chemoenzymatic route to enantiomerically pure cyclic tertiary amines journal of the american chemical society.
In particular, we obtained conversions of 80% or up to 96% for the asymmetric synthesis of rphenoxy2propylamine from. The use of weakly coordinating metal counterions such as lithium, certain lewis acid or base additives, or the presence of lewis basic functional groups within the sul. Ureas of chiral diamines are prominent features of therapeutics, chiral auxiliaries, and intermediates in complex molecule synthesis. Tertiary amine promoted asymmetric aldol reaction of. One is the stereoselective addition or asymmetric reduction of fluorinated n tert butylsulfinyl imines and their derivatives. Furthermore, chiral versions of common amines, such as dmap derivatives 1 and noncinchona derivatives of quinuclidine 2,19 have been successfully developed for use in asymmetric synthesis figure 1.
Other amine catalysts, both simple and complex, have been synthesized and screened in asymmetric reactions, such as dabco derivatives 3, pyrrolidines 4, as well as a library of chiral bicyclic amines 5. Abstract a highly stereoselective synthesis of hitherto less accessible chiral tertiary amines with multiple structurally similar linear carbon. Nucleophilic chiral amines as catalysts in asymmetric. Vaporphase reactions ofnpentan1ol with 2ethylhexyiamine and ofnheptan1ol with cyclohexylamine occurring in the presence of an industrial oxide copperzincaluminum catalyst snm1 at 175185c have been found to afford the corresponding asymmetric secondary and tertiary amines in yields of 5999 % and 549 %, respectively. Biocatalytic approaches to the synthesis of enantiomerically. Request pdf on sep 1, 2003, stefan france and others published nucleophilic chiral. Additionally, chiral amines are prevalent, essential parts of many drugs and drug candidates. A practical electrophilic nitrogen source for the synthesis. Steven malcolmson presents the cucatalyzed synthesis of 1,2amino tertiary alcohols. Mar 22, 2018 herein, we report a general asymmetric route for the onepot synthesis of chiral. Chiral amines are also widely used as resolving agents for diastereomeric salt crystallization. Jan 28, 2006 deracemization of racemic chiral tertiary amines has been achieved by combination of an enantioselective amine oxidase, obtained through directed evolution, and ammonia borane in a onepot process. Amino acids and peptides as asymmetric organocatalysts, tet. Asymmetric synthesis of primary amines catalyzed by thermotolerant fungal reductive aminases juan mangassanchez, a mahima sharma, b sebastian c.
Aldol reactions organocatalysis enantioselectivity asymmetric synthesis aldoses the direct asymmetric selfaldol reactions of various. One is the stereoselective addition or asymmetric reduction of fluorinated ntertbutylsulfinyl imines and their derivatives. Enantioselective synthesis of an nk 1 antagonist 16. With our dedicated isocertified plant for optically active amines we can provide more than 1,000 metric tons of our enantiomerically pure amines for your applications. For symmetrical amines, the di or tri prefix is used depending on whether there are 2 or 3 substituents. The development of a planar chiral catalyst for the enantioselective additions of hn3 to hindered ketenes was investigated. A chemoenzymatic route to enantiomerically pure cyclic.
Radical addition chiral nacylhydrazones asymmetric catalysis of radical addition closing remarks enantioselective synthesis of amines by chiral bronsted acid catalysts introduction carboncarbon bond forming reactions carbonhydrogen bond forming reactions carbonheteroatom. Chiral amines continue to play a pivotal role in the area of asymmetric reactions as ligands and catalysts. The broadest portfolio of chiral amines in industry technology. All the n,pligated iridium complexes investigated were active catalysts for the reaction, but only those with bicyclesupported oxazolinephosphine ligands gave reasonable stereoinduction. It was demonstrated that a new planar chiral catalyst 1. Synthesis of asymmetric secondary and tertiary amines from a. Miller, and thomas lectka, department of chemistry, johns hopkins university, 3400 north charles street, baltimore, maryland 21218, and department of chemistry.
Jul 16, 2010 pharmaceutical synthesis can benefit greatly from the selectivity gains associated with enzymatic catalysis. Chiral amines are prevalent in many bioactive molecules, including amino acids and pharmaceutical agents. Chiral tertiary amine noxides in asymmetric epoxidation. Tertiary amine promoted asymmetric aldol reaction of aldehydes. Tertiary amine promoted asymmetric aldol reaction of aldehydes bartosz guta and jacek mlynarskia,b keywords. For example, dipropylamine is a secondary amine, and triphenylamine is a tertiary amine. Asymmetric synthesis of amines by the catalytic enantioselective additions of hydrazoic acid to ketenes by takashi nakai submitted to the department of chemistry on august 31, 2007 in partial fulfillment of the requirements for the degree of master of science in organic chemistry at the massachusetts institute of technology abstract the. For asymmetric amines, the parent chain gets the amine suffix. Starting from an enzyme that had the catalytic machinery to perform the. For this reason, the asymmetric synthesis of amines is of fundamental importance to many synthesis applications. Deracemization of racemic chiral tertiary amines has been achieved by combination of an enantioselective amine oxidase, obtained through directed evolution, and ammonia borane in a onepot process. In the past few years, primary amine catalysts derived from natural amino acids, cinchona alkaloids and other chiral amines have emerged as readily available. Chiral amines play an important role in stereoselective organic synthesis.
We found that in the presence of 2butene, a wide range of hydroxylamine esters could be effectively converted into the corresponding chiral tertiary amines in a highly enantioselective manner. It was demonstrated that a new planarchiral catalyst 1. Synthesis of 1,2amino tertiary alcohols by cucatalyzed enantioselective reductive couplings with ketones. Abstract a facile cuicatalyzed asymmetric synthesis of chiral tertiary allenols with up to 95% ee starting from common tertiary propargylic alcohols and aldehydes has been developed. Stereoselective synthesis of fluorinated chiral amines based on the use of ntertbutylsulfinyl imines has been accomplished by two major strategies.
Parallel interconnected kinetic asymmetric transformation. Organic chemistryamines wikibooks, open books for an open. Overman department of chemistry, university of california, irvine, ca 926972025 contributed by larry e. David evans synthesis of the macrolide cytovaricin, considered a classic, utilizes oxazolidinone chiral auixiliaries for one asymmetric alkylation reaction and four asymmetric aldol reactions, setting the absolute stereochemistry of nine stereocenters. The successes reported in the asymmetric hydrogenation of enamines suggest that it is a viable route to chiral tertiary amines, and the reaction is especially attractive considering the straightforward substrate synthesis. Preface stereoselective synthesis of alphabranched amines by nucleophilic addition of unstabilized carbanions to imines introduction overview of the methods for the preparation of imines chiral auxiliarybased approaches catalytic asymmetric nucleophilic addition to achiral imines conclusion asymmetric methods for radical. Spontaneous absolute asymmetric synthesis promoted by. An unprecedented sequential goldcatalyzed enoneformation and bifunctional tertiary amine mediated asymmetric cyanosilylation reaction is developed, allowing the highly enantioselective synthesis of 3alkenyloxindoles from diazooxindoles, furans and trimethylsilyl cyanide tmscn. Jan 16, 2019 efficient strategies toward the synthesis of chiral amines are highly desirable as these frameworks are present in an estimated 45% of pharmaceutical drug candidates. This stereoselective nucleophilic addition offers a general approach to the asymmetric synthesis of. Accurate and simple methods by hplc for determination of enantiomeric excess of chiral amines are therefore required. The invention discloses a process for the asymmetric synthesis of chiral amines by using transaminase to facilitate transamination of an amino group from an amino donor to an amino acceptor, thereby forming the desired product.
Catalytic asymmetric synthesis of chiral allylic amines. Pizzarello, department of chemistry and biochemistry, arizona state university, tempe, az 85287. Applications of tertbutanesulfinamide in the asymmetric. Advances in the asymmetric total synthesis of natural products. Synthesis of fluorinated chiral amines using ntert. Jonathan william medley myers synthesis of chiral amines by asymmetric additions to tertbutylsulfinimines ellman auxiliary chem 115 the use of cuso4 as a lewis acidic promoter gives a high yield of the tertbutylsul. Asymmetric synthesis of pyrimidyl alkanol in the presence of achiral amines without the addition of a chiral substance. Asymmetric synthesis of tertiary alcohols and thiols via. Chiral amines are widely used as building block for. Nucleophilic chiral amines as catalysts in asymmetric synthesis. Chiral amines are widely presented in biologically active natural products and synthetic molecules.
The development of methods for the enantioselective construction of amines is an important objective in synthetic chemistry, and cc bondforming reactions are a critical subset, as highly functionalized molecules may be assembled quickly by the union of two. Secondary amines as coupling partners in direct catalytic asymmetric reductive amination zitong wu,a shaozhi du,a guorui gao,b wenkun yang,a xiongyu yang,a haizhou huanga and mingxin chang a the secondary amine participating asymmetric reductive amination remains an unsolved problem in. Great strides have been made in the development of efficient catalytic asymmetric cc bondforming nucleophilic additions to imines for the direct generation of chiral amines bearing either a sole stereocenter or two adjacent stereocenters 25. Enantiomeric separation of chiral amines and amino. Chiral 1,2diamines represent an important subclass of chiral amines that are not only prevalent in pharmaceuticals figure 1 but also represent a class of privileged ligands for asymmetric catalysis. One very promising alternative is the kinetic resolution of racemic amines and especially the asymmetric synthesis of amines from corresponding ketones hohne and bornscheuer, 2012.
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