KR101871567B1 - METHOD FOR SYNTHESIZING β-AMINO-DITHIOESTER COMPOUND AND β-AMINO-DITHIOESTER COMPOUND SYNTHESIZED BY THE METHOD - Google Patents
METHOD FOR SYNTHESIZING β-AMINO-DITHIOESTER COMPOUND AND β-AMINO-DITHIOESTER COMPOUND SYNTHESIZED BY THE METHOD Download PDFInfo
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Abstract
A process for preparing N-protected-beta-amino-dithioester compounds is disclosed. In order to prepare an N-protected-beta-amino-dithioester compound, dithiomalonate and N-proteced according to the Mannich reaction in the presence of a chiral catalyst comprising a quadrature and quinuclidine functional group -Imine or N-protected-alpha-amidosulfone can be asymmetrically reacted. According to this preparation method, a chiral N -protected-beta-amino-dithioester can be synthesized with high optical selectivity at a high yield by using a catalyst which is remarkably inexpensive and safe as compared with a conventional metal catalyst.
Description
The present invention relates to a process for preparing a β-amino-dithioester compound and a chiral β-amino-dithioester compound prepared by the process, Amino-dithioester compounds are prepared.
To synthesize new materials, the creation of carbon-carbon bonds is a fundamental approach in all organic synthesis reactions. In particular, the asymmetric Mannich reaction, which includes an amine functional group and produces a chiral beta-amino-ester compound through a new carbon-carbon bond, is one of the most important reactions for synthesizing a beta-amino acid precursor.
The Mannich reaction for synthesizing the chiralic beta-amino-ester compounds known so far is generally referred to as an " in-direct method ", in which the activated silyl-enol-ether in the presence of a chiral catalyst is used as the ester enolate nucleophile There is a way. For this purpose, alkyl esters are protected with a silyl group in the presence of very strong bases, which requires the synthesis of unstable silyl-enol-ethers in water and air. Another method is a " direct method ", which utilizes a commercially available malonate type compound as a precursor of a nucleophile without any particular modification. However, the low reactivity of malonate necessitates the use of a relatively large amount of catalyst.
It is an object of the present invention to provide a process for preparing chiral beta-amidosulfur compounds by asymmetric reaction of dithiomalonate with N-protected-imine or its precursor N-protected-alpha-amidosulfone according to the Mannich reaction in the presence of a bifunctional chiral catalyst, Amino-dithioester compounds. ≪ Desc / Clms Page number 2 >
Another object of the present invention is to provide a beta-amino-dithioester compound prepared by the above method.
A method for producing an amino dithioester compound according to an embodiment of the present invention comprises reacting a dithiomalonate compound represented by the following formula 3 with an imine compound represented by the following formula 4 in the presence of a bifunctional chiral catalyst compound represented by the following formula 1 or 2: Or an α-amidosulfone compound represented by the following formula (5) asymmetrically to synthesize a chiral amino dithioester compound represented by the following formula (6).
[Chemical Formula 1]
(2)
(3)
[Chemical Formula 4]
[Chemical Formula 5]
[Chemical Formula 6]
Wherein R is an ethyl group or a vinyl group, R 'is hydrogen or a methoxy group, n is 0 or 1, Ar is substituted Or an unsubstituted aryl group. In the above Chemical Formulas 3 to 6, R 1 is one of a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group and a substituted or unsubstituted benzyl group, R 2 is selected from the group consisting of hydrogen and a substituted or unsubstituted alkyl group And R 3 is one of a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group, and R 4 may be an amine protecting group.
In one embodiment, in Formula 1 and Formula 2, Ar may include a substituted or unsubstituted aryl group having 6 to 16 carbon atoms. For example, the Ar is 3,5-bis (trifluoromethyl) benzene (C 8 H 4 F 6) , ortho-toluene (C 7 H 8), meta-toluene (C 7 H 8), p- divinylbenzene (C 10 H 10), 1- naphthalene (C 10 H 8), 2- naphthalene (C 10 H 8), phenyl (C 6 H 5), and pyrenyl (C 16 H 9) selected from the group consisting of One can be included.
In one embodiment, the bifunctional chiral catalyst compound of Formula 1 may include at least one member selected from the group consisting of compounds represented by Formulas 1-1 to 1-8, and the bifunctional chiral catalyst compound of Formula 2 May contain at least one member selected from the group consisting of compounds represented by the following general formulas (2-1) to (2-6).
[Formula 1-1]
[Formula 1-2]
[Formula 1-3]
[Formula 1-4]
[Formula 1-5]
[Chemical Formula 1-6]
[Chemical Formula 1-7]
[Chemical Formula 1-8]
[Formula 2-1]
[Formula 2-2]
[Formula 2-3]
[Chemical Formula 2-4]
[Chemical Formula 2-5]
[Chemical Formula 2-6]
In one embodiment, R 1 is a substituted or unsubstituted alkyl group having 1 to 12 carbon atoms, an alkoxy group having 1 to 12 carbon atoms, a halogen and a nitrile, , An aryl group having 6 to 16 carbon atoms and a benzyl group having 7 to 17 carbon atoms, and R 2 may be an alkyl group having 1 to 12 carbon atoms, an alkoxy group having 1 to 12 carbon atoms, a halogen atom, An alkyl group having 1 to 12 carbon atoms which is unsubstituted or substituted with at least one functional group selected from the group consisting of hydrogen, halogen, and nitrile, or hydrogen. For example, the dithiomalonate compound of Formula 3 may include one or more compounds selected from the group consisting of compounds represented by the following Formulas 3-1 to 3-6.
[Formula 3-1]
[Formula 3-2]
[Formula 3-3]
[Chemical Formula 3-4]
[Formula 3-5]
[Chemical Formula 3-6]
In one embodiment, R 3 is an alkyl group having 1 to 12 carbon atoms, an alkoxy group having 1 to 12 carbon atoms, a halogen and a nitrile, A cycloalkyl group having 3 to 6 carbon atoms, an aryl group having 6 to 16 carbon atoms, and a heteroaryl group having 4 to 10 carbon atoms. For example, the imine compound of Formula 4 may include at least one member selected from the group consisting of compounds represented by the following Formulas 4-1 to 4-12.
[Formula 4-1]
[Formula 4-2]
[Formula 4-3]
[Formula 4-4]
[Formula 4-5]
[Formula 4-6]
[Formula 4-7]
[Formula 4-8]
[Chemical Formula 4-9]
[Formula 4-10]
[Formula 4-11]
[Formula 4-12]
In one embodiment, R 3 is an alkyl group having 1 to 12 carbon atoms, an alkoxy group having 1 to 12 carbon atoms, a halogen and a nitrile, A cycloalkyl group having 3 to 6 carbon atoms, an aryl group having 6 to 20 carbon atoms, and a heteroaryl group having 4 to 10 carbon atoms. For example, the N-protected-alpha-amidosulfone compound of Formula 5 may include at least one compound selected from the group consisting of compounds represented by the following Formulas 5-1 to 5-9.
[Formula 5-1]
[Formula 5-2]
[Formula 5-3]
[Formula 5-4]
[Formula 5-5]
[Formula 5-6]
[Formula 5-7]
[Formula 5-8]
[Formula 5-9]
In one embodiment, the reaction of the dithiomalonate compound of Formula 3 with the imine compound of Formula 4 or the alpha-amidosulfone compound of Formula 5 may occur in a solvent, An organic solvent, an aqueous solution or a mixed solution thereof may be used. For example, the organic solvent may include at least one member selected from the group consisting of dichloromethane, chloroform, toluene, tetrahydrofuran, acetone, and ethyl acetate, and the aqueous solution includes water or an aqueous solution of sodium chloride (NaCl) . As one example, dichloromethane may be used alone as the solvent, or a mixed solution of dichloromethane and an aqueous solution of sodium chloride (NaCl) may be used.
In one embodiment, the dithiomalonate compound of Formula 3 and the imine compound of Formula 4 or the alpha-amidosulfone compound of Formula 5 are reacted in the solvent at a temperature ranging from -80 to 60 ° C .
In one embodiment, the bifunctional chiral catalyst compound of Formula 1 or Formula 2 may be added in an amount of 0.1 to 100 mol% based on the imine compound of Formula 4 or the α-amidosulfone compound of Formula 5.
In one embodiment, the dithiomalonate compound of Formula 3 may be used in an amount of 1 to 3 equivalents based on the imine compound of Formula 4 or the alpha-amidosulfone compound of Formula 5.
The chiral amino dithioester compound according to an embodiment of the present invention is a compound for preparing a pharmacological agent and may have a molecular structure represented by the following formula (6).
[Chemical Formula 6]
Wherein R 1 is an alkyl group or an aryl group, R 2 is a hydrogen or an alkyl group, R 3 is a group selected from the group consisting of an alkyl group, a cycloalkyl group, an aryl group and a heteroaryl group, and R 4 is an amine protecting group have.
In one embodiment, the chiral aminodithioester compound may include at least one member selected from the group consisting of compounds represented by the following formulas (6-1) to (6-24).
[Formula 6-1]
[Formula 6-2]
[Formula 6-3]
[Formula 6-4]
[Formula 6-5]
[Formula 6-6]
[Formula 6-7]
[Formula 6-8]
[Formula 6-9]
[Chemical Formula 6-10]
[Chemical Formula 6-11]
[Chemical Formula 6-12]
[Formula 6-13]
[Chemical Formula 6-14]
[Chemical Formula 6-15]
[Chemical Formula 6-16]
[Chemical Formula 6-17]
[Chemical Formula 6-18]
[Chemical Formula 6-19]
[Chemical Formula 6-20]
[Chemical Formula 6-21]
[Chemical Formula 6-22]
[Chemical Formula 6-23]
[Chemical Formula 6-24]
According to the present invention, the asymmetric Mannich reaction of N-protected-imine or N-protected-alpha-amidosulfone with dithiomalonate occurring in the presence of a bifunctional chiral catalyst provides chiral N-proton Can be synthesized with a very high enantiomeric selectivity.
In addition, the various chiral thiosters prepared through the present invention can be used to synthesize stereochemically or pharmaceutically useful chiral compounds according to conventional processes.
Hereinafter, embodiments of the present invention will be described in detail. It is to be understood that the invention is not limited to the disclosed embodiments, but, on the contrary, is intended to cover various modifications and similarities. It should be understood, however, that the present invention is not intended to be limited to any particular type of disclosure, but includes all modifications, equivalents, and alternatives falling within the spirit and scope of the present invention.
The terms first, second, etc. may be used to describe various components, but the components should not be limited by the terms. The terms are used only for the purpose of distinguishing one component from another. For example, without departing from the scope of the present invention, the first component may be referred to as a second component, and similarly, the second component may also be referred to as a first component.
The terminology used in this application is used only to describe a specific embodiment and is not intended to limit the invention. The singular expressions include plural expressions unless the context clearly dictates otherwise. In the present application, the term " comprises " or " having " is intended to designate the presence of stated features, elements, etc., and not one or more other features, It does not mean that there is none.
Unless defined otherwise, all terms used herein, including technical or scientific terms, have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Terms such as those defined in commonly used dictionaries are to be interpreted as having a meaning consistent with the contextual meaning of the related art and are to be interpreted as either ideal or overly formal in the sense of the present application Do not.
In the present invention, the 'Mannich reaction' is defined as a reaction involving the addition of an activated hydrogen-bearing carbon to an imine to synthesize an aminoalkylated derivative.
The process for preparing a chiral N-protected beta-amino dithioester according to an embodiment of the present invention comprises reacting N-protected-imine or N-protected-alpha-amidosulfone with dicyclopentadiene in the presence of a bifunctional chiral catalyst, Lt; RTI ID = 0.0 > malalonate. ≪ / RTI > For example, the N-protected-imine or N-protected-alpha-amidosulfone and the dithiomalonate may react with each other according to an asymmetric Mannich reaction.
The chiral catalyst may include a compound of the following formula (1) or a compound of the following formula (2). The chiral catalysts of formulas (1) and (2) are N-protected-imine or N-protected-alpha-olefins as the derivatized difunctional cinchona or alkaloid catalyst compounds comprising a quinuclidine functional group as the base moiety and a squaramide functional group as the acid moiety. It may exhibit a bifunctional ability to simultaneously activate amidosulfone and dithiomalonate.
[Chemical Formula 1]
(2)
In the general formulas (1) and (2), R may include an ethyl group or a vinyl group, R 'may include hydrogen or a methoxy group, and Ar may have 6 to 16 carbon atoms Or a substituted or unsubstituted aryl group. And n can be 0 or 1.
In one embodiment, the formulas (1) and (trifluoromethyl) Ar in the formula (2) is benzene 3,5-bis (C 8 H 4 F 6) , ortho-toluene (C 7 H 8), meta-toluene (C 7 H 8), p-vinylbenzene (C 10 H 10), 1- naphthalene (C 10 H 8), 2- naphthalene (C 10 H 8), phenyl (C 6 H 5), pyrenyl (C 16 H 9 ), And the like.
In one embodiment, the compound of formula (I) may include at least one of the following compounds of the following general formulas 1-1 to 1-8.
[Formula 1-1]
[Formula 1-2]
[Formula 1-3]
[Formula 1-4]
[Formula 1-5]
[Chemical Formula 1-6]
[Chemical Formula 1-7]
[Chemical Formula 1-8]
In one embodiment, the compound of formula (2) may include at least one of the following compounds of the following formulas (2-1) to (2-5).
[Formula 2-1]
[Formula 2-2]
[Formula 2-3]
[Chemical Formula 2-4]
[Chemical Formula 2-5]
[Chemical Formula 2-6]
In the present specification, 'HQD', 'QD', 'CN' HQN ',' QN ',' CD ',' Py 'and' SQA 'refer to' hydroquinidine ',' quinidine Quot; cinchonine, hydroquinine, quinine, cinchonidine, pyreneyl and squaramide. ≪ RTI ID = 0.0 & .
In an embodiment of the present invention, the dithiomalonate, a reactant participating in the asymmetric Mannich reaction, may comprise a compound of the formula 3 and the N-protected-imine may comprise a compound of the formula And N-protected-alpha-amidosulfone may comprise a compound of formula (5).
(3)
[Chemical Formula 4]
[Chemical Formula 5]
In Formula 3, R 1 may be a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted benzyl group, and R 2 may be a hydrogen atom or a substituted or unsubstituted alkyl group. And in formulas 4 and 5, R 3 may be any of a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group, and R 4 is Amine protecting group.
In one embodiment, R 1 may be any one of an alkyl group having about 1 to 12 carbon atoms, an aryl group having about 6 to 16 carbon atoms, and a benzyl group having about 7 to 17 carbon atoms, , The aryl group and the benzyl group each may be substituted with an alkyl group having 1 to 12 carbon atoms, an alkoxy group having 1 to 12 carbon atoms, a halogen, a nitrile, or the like. In formula (3), R 2 may be hydrogen or an alkyl group having about 1 to 12 carbon atoms, and the alkyl group may be an alkyl group having about 1 to 12 carbon atoms, an alkoxy group having about 1 to 12 carbon atoms, a halogen, . In the above R 1 and R 2 , the alkyl group having 1 to 12 carbon atoms may include at least one group selected from methyl, ethyl, propyl, butyl, etc., and the alkoxy group having 1 to 12 carbon atoms may be methoxy, ethoxy, Propoxy, butoxy, and the like.
In one embodiment, in Formula 4 and 5, R 3 is an alkyl group having about 1 to 30 carbon atoms, a cycloalkyl group having about 3 to 6 carbon atoms, an aryl group having about 6 to 20 carbon atoms, Cycloalkyl, aryl, and heteroaryl groups, each of which may be optionally substituted with one or more substituents selected from an alkyl group having from about 1 to about 12 carbon atoms, an alkoxy group having from about 1 to about 12 carbon atoms, Nitrile, and the like. The alkyl group having 1 to 12 carbon atoms may include one selected from methyl, ethyl, propyl, butyl and the like, and the alkoxy group having 1 to 12 carbon atoms may include one selected from methoxy, ethoxy, propoxy, butoxy, can do.
The 'amine protecting group' refers to a functional group capable of protecting the nitrogen atom of the amine during the reaction, and is not particularly limited as long as it can protect the nitrogen atom of the amine during the reaction. For example, the amine protecting groups are described in Protecting Groups in Organic Synthesis, eds., Green and Wuts, Protecting Groups in Organic Synthesis, John Wiley and Sons, 1991, and Wuts, John Wiley and Sons, 2007 '. In one embodiment, the amine protecting group is a methyloxycarbonyl group, a benzyloxycarbonyl group, a p-methoxybenzyloxycarbonyl group, a t-butyloxycarbonyl group (Boc), a 9-fluorenylmethyloxycarbonyl group (FMOC) (Alloc), 2,2,2-trichloroethoxycarbonyl (Troc), benzoyl group (Bz), benzyl group (Bn), p-methoxybenzyl group (PMB), 3,4-dimethoxybenzyl group (DMPM), a p-methoxyphenyl group (PMP), a tosyl group (Ts), a trimethylsilylethyloxycarbonyl group (Teoc), benzhydryl, triphenylmethyl (Trityl), (4-methoxyphenyl) Mmt), dimethoxytrityl (DMT), diphenylphosphino group and the like.
In one embodiment, the dithiomalonate of formula (3) may comprise at least one of the following compounds of formula (3-1) to (3-6).
[Formula 3-1]
[Formula 3-2]
[Formula 3-3]
[Chemical Formula 3-4]
[Formula 3-5]
[Chemical Formula 3-6]
In one embodiment, the N-protected-imine of Formula 4 may comprise at least one of the compounds of Formulas 4-1 to 4-12 below.
[Formula 4-1]
[Formula 4-2]
[Formula 4-3]
[Formula 4-4]
[Formula 4-5]
[Formula 4-6]
[Formula 4-7]
[Formula 4-8]
[Chemical Formula 4-9]
[Formula 4-10]
[Formula 4-11]
[Formula 4-12]
In one embodiment, the N-protected-alpha-amidosulfone of formula (5) may comprise at least one of the following compounds of formulas (5-1) to (5-9).
[Formula 5-1]
[Formula 5-2]
[Formula 5-3]
[Formula 5-4]
[Formula 5-5]
[Formula 5-6]
[Formula 5-7]
[Formula 5-8]
[Formula 5-9]
, "Moc" represents a methyloxycarbonyl group, "Cbz" represents a benzyloxycarbonyl group, "Boc" represents a tert-butyloxycarbonyl group, , "Me" represents a methyl group, "Bn" represents a benzyl group, "Ph" represents a phenyl group, and "Et" represents an ethyl group.
On the other hand, the N-protected-beta-amino-dithioester produced by the asymmetric Mannich reaction between dithiomalonate and N-protected-imine or N-protected- 6 < / RTI >
[Chemical Formula 6]
In Formula 6, R 1 may be a substituted or unsubstituted alkyl group or a substituted or unsubstituted aryl group, and R 2 may be a hydrogen or a substituted or unsubstituted alkyl group. R 3 may be a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group, and R 4 may be an amine protecting group.
In one embodiment, the N-protected-beta-amino-dithioester of Formula 6 may comprise at least one of the compounds of Formulas 6-1 through 6-24.
[Formula 6-1]
[Formula 6-2]
[Formula 6-3]
[Formula 6-4]
[Formula 6-5]
[Formula 6-6]
[Formula 6-7]
[Formula 6-8]
[Formula 6-9]
[Chemical Formula 6-10]
[Chemical Formula 6-11]
[Chemical Formula 6-12]
[Formula 6-13]
[Chemical Formula 6-14]
[Chemical Formula 6-15]
[Chemical Formula 6-16]
[Chemical Formula 6-17]
[Chemical Formula 6-18]
[Chemical Formula 6-19]
[Chemical Formula 6-20]
[Chemical Formula 6-21]
[Chemical Formula 6-22]
[Chemical Formula 6-23]
[Chemical Formula 6-24]
In the formulas (6-1) to (6-24), "Boc" represents a tert-butyloxycarbonyl group, "Moc" represents a methyloxycarbonyl group, "Cbz" represents a benzyloxycarbonyl group, "Me" "Bn" represents a benzyl group, "Ph" represents a phenyl group, and "Et" represents an ethyl group.
In one embodiment of the present invention, the asymmetric Mannich reaction between the N-protected-imine of Formula 4 and the dithiomalonate of Formula 3 may be performed according to the following Reaction Scheme 1, Asymmetric Mannich reaction between the N-protected-alpha-amidosulfone of formula (III) and the dithiomalonate of formula (III) can be produced according to the following reaction formula (2). In the case of the reaction of Scheme 2, the asymmetry between the N-protected-imine and the dithiomalonate is substantially the same as in Scheme 1 after conversion of the N-protected-alpha-amidosulfone to the N-protected- Manihi reaction can occur. Meanwhile, sodium carbonate (Na 2 CO 3 ) may be added to the reaction of Scheme 2 in order to promote the conversion of N-protected-α-amidosulfone to N-protected-imine. In one embodiment, the sodium carbonate may be added in an amount of about 100 to 150 mol% based on the N-protected-alpha-amidosulfone.
[Reaction Scheme 1]
[Reaction Scheme 2]
In one embodiment, an N-protected-imine or N-protected-alpha-amidosulfone is dissolved in a solvent, followed by addition of a chiral catalyst and dithiomalonate, Beta] -amino-dithioester can be synthesized by inducing an asymmetric Mannich reaction between N-protected-imine-imine or N-protected-alpha-amidosulfone and dithiomalonate. When the asymmetric Mannich reaction is carried out in the presence of a chiral catalyst, a chiral N-protected-beta-amino-dithioester having a very high optical purity can be prepared and the reaction yield can be improved.
In one embodiment, in order to improve the yield and optical selectivity of the reaction, the asymmetric Mannich reaction of Scheme 1 or 2 can be carried out in a solvent in the temperature range of about -80 to 60 캜. For example, the asymmetric Mannich reaction of Scheme 1 or 2 can be carried out in a solvent at a temperature ranging from about -50 to 30 < 0 > C. As the solvent, an organic solvent, an aqueous solution, or a mixed solution of an organic solvent and an aqueous solution may be used. For example, as the organic solvent, dichloromethane, chloroform, toluene, tetrahydrofuran, acetone, ethyl acetate and the like can be used. As the aqueous solution, water, sodium chloride (NaCl) aqueous solution and the like can be used. In one embodiment, to improve the yield and optical selectivity of the reaction, dichloromethane may be used alone as the solvent or a mixed solution of dichloromethane and an aqueous solution of sodium chloride (NaCl) may be used.
In one embodiment, the chiral catalyst may be added in an amount of about 0.1 to 100 mol% based on N-protected-imine or N-protected-alpha-amidosulfone. For example, in order to induce an asymmetric aldol reaction, the chiral catalyst may be added in an amount of about 1 to 30 mol% based on N-protected-imine or N-protected-alpha-amidosulfone.
In one embodiment, for asymmetric Mannich reaction, about 1 to about 5 equivalents of dithiomalonate may be added based on the N-protected-imine or N-protected-alpha-amidosulfone. For example, the dithiomalonate may be added in an amount of about 1 to about 1.5 equivalents based on the N-protected-imine or N-protected-alpha-amidosulfone.
The chiral N-protected-beta-amino-dithioester prepared according to the embodiment of the present invention can provide an important structure for manufacturing various pharmaceuticals. For example, using the N-protected-beta-amino-dithioester prepared according to the present invention, various high-value-added optically active substances can be prepared through the substitution reaction of thioester groups.
Hereinafter, preferred embodiments of the present invention will be described in detail with reference to the accompanying drawings. However, the present invention is not limited by the scope of the present invention, And it is intended that the present invention cover the modifications and variations of this invention provided they come within the scope of the appended claims and their equivalents.
≪ Examples 1 to 41 >
[Example 1]
0.55 mmol of the dithiomalonate compound of Formula 3-1 wherein R 1 is benzyl and R 2 is hydrogen, 0.50 mmol of the N-protected-imine of Formula 4-1, and 1.0 mol% of the organic catalyst of Formula 1-1, Dissolved in 5.0 mL of chloromethane, and stirred at -50 ° C for 1 hour to synthesize an N-protected-β-amino-dithioester of formula (6-1). The solvent was then removed under reduced pressure and the product was isolated using silica-gel chromatography.
TLC (EtOAc / hexanes, 1: 4 v / v): Rf = 0.50; [ ? ] D 20 = +41.1 (c = 0.10 CHCl 3 ,> 99% ee); Mp 125 < 0 > C (> 99% ee); 1 H NMR (500 MHz, CDCl 3)? 7.29-7.18 (m, 11H), 7.12 (d, J = 6.4 Hz, 4H), 5.95 ), 4.14 (d, J = 13.9 Hz, 1H), 4.04 (t, J = 13.9 Hz, 2H), 1.39 (s, 9H); 13 C NMR (126 MHz, CDCl3 ) δ 192.69, 190.60, 154.91, 138.79, 136.31, 136.24, 128.86, 128.79, 128.67, 128.66, 128.46, 127.82, 127.48, 126.67, 125.84, 125.77, 79.92, 70.89, 55.62, 33.97, 33.91, 28.32; IR (KBr):? 3418, 2976, 2926, 1695, 1508, 1454, 1409, 1363, 1290, 1244, 1172, 1031, 978, 842, 759, 697 cm -1 ; LR-MS (ESI) Calcd for [C 29 H 31 NO 4 S 2 + Na] + : 544.16; Found: 544; HR-MS (ESI) Calcd for [C 29 H 31 NO 4 S 2 + Na] + : 544.1592; Found: 544.1593.
Isomers excess value (enantiomeric excess,%) was determined via HPLC analysis (Chiralcel OD-H; hexane: isopropyl alcohol = 95: 5; flow rate: 1.0 mL / min; 210 nm): t R = 15.9 min (major ), t R = 18.2 min; ≫ 99% ee ( S ).
[Example 2]
0.55 mmol of the dithiomalonate compound of Formula 3-1 wherein R 1 is benzyl and R 2 is hydrogen, 0.50 mmol of the N-protected-imine of Formula 4-1, 1.0 mol% of the organic catalyst of Formula 1-2, Dissolved in 5.0 mL of chloromethane, and stirred at -50 ° C for 1 hour to synthesize an N-protected-β-amino-dithioester of formula (6-1). The solvent was then removed under reduced pressure and the product was isolated using silica-gel chromatography.
Isomers excess value (enantiomeric excess,%) was determined via HPLC analysis (Chiralcel OD-H; hexane: isopropyl alcohol = 95: 5; flow rate: 1.0 mL / min; 210 nm): t R = 15.9 min (major ), t R = 18.2 min; ≫ 99% ee ( S ).
[Example 3]
0.5 mmol of the dithiomalonate compound of Formula 3-1 wherein R 1 is benzyl and R 2 is hydrogen, 0.50 mmol of the N-protected-imine of Formula 4-1, 1.0 mol% of the organic catalyst of Formula 1-3, Dissolved in 5.0 mL of chloromethane, and stirred at -50 ° C for 1 hour to synthesize an N-protected-β-amino-dithioester of formula (6-1). The solvent was then removed under reduced pressure and the product was isolated using silica-gel chromatography.
Isomers excess value (enantiomeric excess,%) was determined via HPLC analysis (Chiralcel OD-H; hexane: isopropyl alcohol = 95: 5; flow rate: 1.0 mL / min; 210 nm): t R = 15.9 min (major ), t R = 18.2 min; 83% ee ( S ).
[Example 4]
0.5 mmol of the dithiomalonate compound of Formula 3-1 wherein R 1 is benzyl and R 2 is hydrogen, 0.50 mmol of the N-protected-imine of Formula 4-1, 1.0 mol% of the organic catalyst of Formula 1-5, Dissolved in 5.0 mL of chloromethane, and stirred at -50 ° C for 1 hour to synthesize an N-protected-β-amino-dithioester of formula (6-1). The solvent was then removed under reduced pressure and the product was isolated using silica-gel chromatography.
Isomers excess value (enantiomeric excess,%) was determined via HPLC analysis (Chiralcel OD-H; hexane: isopropyl alcohol = 95: 5; flow rate: 1.0 mL / min; 210 nm): t R = 15.9 min (major ), t R = 18.2 min; 92% ee ( S ).
[Example 5]
0.5 mmol of the dithiomalonate compound of Formula 3-1 wherein R 1 is benzyl and R 2 is hydrogen, 0.50 mmol of the N-protected-imine of Formula 4-1, 1.0 mol% of the organic catalyst of Formula 1-8, Dissolved in 5.0 mL of chloromethane, and then stirred at -50 ° C for 1 hour to synthesize an N -protected-β-amino-dithioester of formula (6-1). The solvent was then removed under reduced pressure and the product was isolated using silica-gel chromatography.
Isomers excess value (enantiomeric excess,%) was determined via HPLC analysis (Chiralcel OD-H; hexane: isopropyl alcohol = 95: 5; flow rate: 1.0 mL / min; 210 nm): t S = 15.3 min (major ), t R = 16.8 min; ≫ 99% ee ( S ).
[Example 6]
0.55 mmol of the dithiomalonate compound of Formula 3-1 wherein R 1 is benzyl and R 2 is hydrogen, 0.50 mmol of the N-protected-imine of Formula 4-1, 1.0 mol% of the organic catalyst of Formula 2-1, Dissolved in 5.0 mL of chloromethane, and then stirred at -50 ° C for 1 hour to synthesize an N -protected-β-amino-dithioester of formula (6-1). The solvent was then removed under reduced pressure and the product was isolated using silica-gel chromatography.
Isomers excess value (enantiomeric excess,%) was determined via HPLC analysis (Chiralcel OD-H; hexane: isopropyl alcohol = 95: 5; flow rate: 1.0 mL / min; 210 nm): t R = 15.9 min, t R = 18.2 min (major); 95% ee ( R ).
[Example 7]
0.55 mmol of the dithiomalonate compound of Formula 3-1 wherein R 1 is benzyl and R 2 is hydrogen, 0.50 mmol of the N-protected-imine of Formula 4-1, 1.0 mol% of the organic catalyst of Formula 2-2, Dissolved in 5.0 mL of chloromethane, and then stirred at -50 ° C for 1 hour to synthesize an N -protected-β-amino-dithioester of formula (6-1). The solvent was then removed under reduced pressure and the product was isolated using silica-gel chromatography.
Isomers excess value (enantiomeric excess,%) was determined via HPLC analysis (Chiralcel OD-H; hexane: isopropyl alcohol = 95: 5; flow rate: 1.0 mL / min; 210 nm): t R = 15.9 min, t R = 18.2 min (major); 96% ee ( R ).
[Example 8]
0.5 mmol of the dithiomalonate compound of Formula 3-1 wherein R 1 is benzyl and R 2 is hydrogen, 0.50 mmol of the N-protected-imine of Formula 4-1, 1.0 mol% of the organic catalyst of Formula 2-3, Dissolved in 5.0 mL of chloromethane, and then stirred at -50 ° C for 1 hour to synthesize an N -protected-β-amino-dithioester of formula (6-1). The solvent was then removed under reduced pressure and the product was isolated using silica-gel chromatography.
Isomers excess value (enantiomeric excess,%) was determined via HPLC analysis (Chiralcel OD-H; hexane: isopropyl alcohol = 95: 5; flow rate: 1.0 mL / min; 210 nm): t R = 15.9 min, t R = 18.2 min (major); 84% ee ( R ).
[Example 9]
0.5 mmol of the dithiomalonate compound of Formula 3-1 wherein R 1 is benzyl and R 2 is hydrogen, 0.50 mmol of the N-protected-imine of Formula 4-1, 1.0 mol% of the organic catalyst of Formula 2-5, Dissolved in 5.0 mL of chloromethane, and then stirred at -50 ° C for 1 hour to synthesize an N -protected-β-amino-dithioester of formula (6-1). The solvent was then removed under reduced pressure and the product was isolated using silica-gel chromatography.
Isomers excess value (enantiomeric excess,%) was determined via HPLC analysis (Chiralcel OD-H; hexane: isopropyl alcohol = 95: 5; flow rate: 1.0 mL / min; 210 nm): t R = 15.9 min, t R = 18.2 min (major); 98% ee ( R ).
[Example 10]
0.55 mmol of the dithiomalonate compound of Formula 3-1 wherein R 1 is benzyl and R 2 is hydrogen, 0.50 mmol of the N-protected-imine of Formula 4-1, 1.0 mol% of the organic catalyst of Formula 2-6, Dissolved in 5.0 mL of chloromethane, and then stirred at -50 ° C for 1 hour to synthesize an N -protected-β-amino-dithioester of formula (6-1). The solvent was then removed under reduced pressure and the product was isolated using silica-gel chromatography.
Isomers excess value (enantiomeric excess,%) was determined via HPLC analysis (Chiralcel OD-H; hexane: isopropyl alcohol = 95: 5; flow rate: 1.0 mL / min; 210 nm): t R = 15.9 min, t R = 18.2 min (major); 94% ee ( R ).
[Example 11]
0.5 mmol of the dithiomalonate compound of Formula 3-1 wherein R 1 is benzyl and R 2 is hydrogen, 0.50 mmol of the N-protected-imine of Formula 4-1, 1.0 mol% of the organic catalyst of Formula 1-1, Dissolved in 5.0 mL of chloromethane, and then stirred at -15 DEG C for 0.5 hour to synthesize an N -protected-beta-amino-dithioester of formula (6-1). The solvent was then removed under reduced pressure and the product was isolated using silica-gel chromatography.
Isomers excess value (enantiomeric excess,%) was determined via HPLC analysis (Chiralcel OD-H; hexane: isopropyl alcohol = 95: 5; flow rate: 1.0 mL / min; 210 nm): t S = 15.3 min (major ), t R = 16.8 min; 99% ee ( S ).
[Example 12]
0.5 mmol of the dithiomalonate compound of Formula 3-1 wherein R 1 is benzyl and R 2 is hydrogen, 0.50 mmol of the N-protected-imine of Formula 4-1, 1.0 mol% of the organic catalyst of Formula 1-1, Dissolved in 5.0 mL of chloromethane, and stirred at 0 ° C for 0.2 hour to synthesize an N -protected-β-amino-dithioester of Chemical Formula 6-1. The solvent was then removed under reduced pressure and the product was isolated using silica-gel chromatography.
Isomers excess value (enantiomeric excess,%) was determined via HPLC analysis (Chiralcel OD-H; hexane: isopropyl alcohol = 95: 5; flow rate: 1.0 mL / min; 210 nm): t S = 15.3 min (major ), t R = 16.8 min; 95% ee ( S ).
[Example 13]
0.5 mmol of the dithiomalonate compound of Formula 3-1 wherein R 1 is benzyl and R 2 is hydrogen, 0.50 mmol of the N-protected-imine of Formula 4-1, 1.0 mol% of the organic catalyst of Formula 1-1 is dissolved in chloroform 5.0 mL and stirred at -50 ° C for 1 hour to synthesize the N -protected-beta-amino-dithioester of Chemical Formula 6-1. The solvent was then removed under reduced pressure and the product was isolated using silica-gel chromatography.
Isomers excess value (enantiomeric excess,%) was determined via HPLC analysis (Chiralcel OD-H; hexane: isopropyl alcohol = 95: 5; flow rate: 1.0 mL / min; 210 nm): t R = 15.9 min (major ), t R = 18.2 min; 99% ee ( S ).
[Example 14]
0.55 mmol of the dithiomalonate compound of Formula 3-1 wherein R 1 is benzyl and R 2 is hydrogen, 0.50 mmol of the N-protected-imine of Formula 4-1, 1.0 mol% of the organic catalyst of Formula 1-1, 5.0 mL and stirred at -50 ° C for 1 hour to synthesize the N -protected-beta-amino-dithioester of Chemical Formula 6-1. The solvent was then removed under reduced pressure and the product was isolated using silica-gel chromatography.
Isomers excess value (enantiomeric excess,%) was determined via HPLC analysis (Chiralcel OD-H; hexane: isopropyl alcohol = 95: 5; flow rate: 1.0 mL / min; 210 nm): t R = 15.9 min (major ), t R = 18.2 min; 99% ee ( S ).
[Example 15]
0.5 mmol of the dithiomalonate compound of Formula 3-1 wherein R 1 is benzyl and R 2 is hydrogen, 0.50 mmol of the N-protected-imine of Formula 4-1, 1.0 mol% of the organic catalyst of Formula 1-1, Dissolved in 5.0 mL of tetrahydrofuran and stirred at -50 ° C for 1 hour to synthesize the N -protected-β-amino-dithioester of formula (6-1). The solvent was then removed under reduced pressure and the product was isolated using silica-gel chromatography.
Isomers excess value (enantiomeric excess,%) was determined via HPLC analysis (Chiralcel OD-H; hexane: isopropyl alcohol = 95: 5; flow rate: 1.0 mL / min; 210 nm): t R = 15.9 min (major ), t R = 18.2 min; 58% ee ( S ).
[Example 16]
0.5 mmol of the dithiomalonate compound of Formula 3-1 wherein R 1 is benzyl and R 2 is hydrogen, 0.50 mmol of the N-protected-imine of Formula 4-1, 1.0 mol% of the organic catalyst of Formula 1-1, 5.0 mL and stirred at -50 ° C for 1 hour to synthesize the N -protected-beta-amino-dithioester of Chemical Formula 6-1. The solvent was then removed under reduced pressure and the product was isolated using silica-gel chromatography.
Isomers excess value (enantiomeric excess,%) was determined via HPLC analysis (Chiralcel OD-H; hexane: isopropyl alcohol = 95: 5; flow rate: 1.0 mL / min; 210 nm): t R = 15.9 min (major ), t R = 18.2 min; 41% ee ( S ).
[Example 17]
0.5 mmol of the dithiomalonate compound of Formula 3-1 wherein R 1 is benzyl and R 2 is hydrogen, 0.50 mmol of the N-protected-imine of Formula 4-2, 0.5 mol% of the organic catalyst of Formula 1-1, Dissolved in 5.0 mL of chloromethane, and stirred at -50 캜 for 24 hours to synthesize an N -protected-β-amino-dithioester of formula (6-2). The solvent was then removed under reduced pressure and the product was isolated using silica-gel chromatography.
TLC (EtOAc / hexanes, 1: 4 v / v): Rf = 0.26; [ ? ] D 20 = +30.2 (c = 0.10 CHCl 3 , 97% ee); Mp 79 [deg.] C (> 99% ee); 1 H NMR (500 MHz, CDCl 3 )? 7.30-7.19 (m, 11H), 7.19-7.11 (m, 4H), 6.10 (s, 4.15 (dd, J = 13.9, 2.9 Hz, 2H), 4.06 (t, J = 16.9 Hz, 2H), 3.62 (s, 3H). 13 C NMR (126 MHz, CDCl 3 ) δ 192.60, 190.43, 156.03, 138.42, 136.23, 136.16, 128.81, 128.76, 128.70, 128.63, 128.60, 127.94, 127.46, 126.55, 70.58, 55.90, 52.37, 33.96, 33.89; IR (KBr):? 3408, 1698, 1519, 1496, 1454, 1289, 1245, 1226, 1067, 1030, 981, 944, 847, 781, 754, 715, 699, 647 cm -1 ; LR-MS (ESI) Calcd for [C 26 H 25 NO 4 S 2 + Na] + : 502.11; Found: 502; HR-MS (ESI) Calcd for [C 26 H 25 NO 4 S 2 + Na] + : 502.1123; Found: 502.1117.
Isomers excess value (enantiomeric excess,%) was determined via HPLC analysis (Chiralpak IA; hexane: isopropyl alcohol = 90: 10; flow rate: 1.0 mL / min; 210 nm): t R = 11.0 min, t R = 14.9 min (major); 97% ee ( S ).
[Example 18]
0.55 mmol of the dithiomalonate compound of Formula 3-1 wherein R 1 is benzyl and R 2 is hydrogen, 0.50 mmol of N-protected-imine of Formula 4-3, 0.5 mol% of the organic catalyst of Formula 1-1, Dissolved in 5.0 mL of chloromethane, and stirred at -50 캜 for 24 hours to synthesize an N -protected-β-amino-dithioester of formula (6-3). The solvent was then removed under reduced pressure and the product was isolated using silica-gel chromatography.
TLC (EtOAc / hexanes, 1: 4 v / v): Rf = 0.35; [ ? ] D 20 = +28.0 (c = 0.10 CHCl 3 , 95% ee); Mp 115 [deg.] C (> 99% ee); 1 H NMR (500 MHz, CDCl 3) δ 7.33 (s, 5H), 7.23 (m, 11H), 7.13 (m, 6.7 Hz, 1H), 6.18 (s, 1H), 5.54 (s, 1H), 5.05 (s, 2H), 4.29 (s, 1H), 4.12 (dd, J = 13.8, 6.1 Hz, 2H), 4.04 (t, J = 15.7 Hz, 2H); 13 C NMR (126 MHz, CDCl 3) δ 192.64, 190.46, 155.50, 138.38, 136.34, 136.25, 136.16, 128.86, 128.80, 128.74, 128.67, 128.65, 128.50, 128.11, 128.00, 127.50, 126.65, 70.67, 67.00, 55.97 , 33.92; IR (KBr):? 3389, 2363, 1725, 1698, 1656, 1602, 1512, 1496, 1454, 1356, 1285, 1244, 1218, 1134, 1066, 1028, 985, 963, 910, 846, 750, 698, 637, 610 cm < -1 & gt ;; LR-MS (ESI) Calcd for [C 32 H 29 NO 4 S 2 + Na] +: 578.14; Found: 578; HR-MS (ESI) Calcd for [C 32 H 29 NO 4 S 2 + Na] + : 578.1436; Found: 578.1430.
Isomers excess value (enantiomeric excess,%) was determined via HPLC analysis (Chiralpak IA; hexanes / isopropyl alcohol = 90: 10; flow rate: 1.0 mL / min; 210 nm): t R = 29.8 min, t R = 36.5 min (major); 95% ee ( S ).
[Example 19]
0.55 mmol of a dithiomalonate compound of formula (3-2) wherein R 1 is ethyl and R 2 is hydrogen, 0.50 mmol of N-protected-imine of formula (4-1), 0.5 mol% of an organic catalyst of formula Dissolved in 5.0 mL of chloromethane, and stirred at -50 ° C for 24 hours to synthesize an N-protected-beta-amino-dithioester of Formula 6-4. The solvent was then removed under reduced pressure and the product was isolated using silica-gel chromatography.
TLC (EtOAc / hexanes, 1: 4 v / v): Rf = 0.50; [ ? ] D 20 = +29.7 (c = 0.50 CHCl 3 , 94% ee); 1 H NMR (300 MHz, CDCl 3) δ 7.40 - 7.19 (m, 5H), 5.96 (s, 1H), 5.43 (s, 1H), 4.23 (s, 1H), 3.04 - 2.73 (m, 4H), 1.39 (s, 9H), 1.18 (m, 6H); 13 C NMR (126 MHz, CDCl 3) δ 193.46, 191.33, 154.90, 139.06, 128.53, 127.71, 126.60, 79.73, 71.29, 55.58, 28.27, 24.14, 14.18; IR (KBr):? 3386, 2976, 2932, 1701, 1494, 1454, 1414, 1366, 1248, 1168, 1051, 1017, 989, 969, 885, 845 cm -1 ; LR-MS (ESI) Calcd for [C 19 H 27 NO 4 S 2 + Na] +: 420.12; Found: 420; HR-MS (ESI) Calcd for [C 19 H 27 NO 4 S 2 + Na] +: 420.1279; Found: 420.1276.
Isomers excess value (enantiomeric excess,%) was determined via HPLC analysis (Chiralpak IA; hexanes / isopropyl alcohol = 90: 10; flow rate: 1.0 mL / min; 210 nm): t R = 14.6 min (major), t R = 23.7 min; 78% ee ( S ).
[Example 20]
0.5 mmol of a dithiomalonate compound of Formula 3-3 wherein R 1 is phenyl and R 2 is hydrogen, 0.50 mmol of N-protected-imine of Formula 4-1, 0.5 mol% of an organic catalyst of Formula 1-1, Dissolved in 5.0 mL of chloromethane, and then stirred at -50 ° C for 24 hours to synthesize an N -protected-β-amino-dithioester of Formula 6-5. The solvent was then removed under reduced pressure and the product was isolated using silica-gel chromatography.
TLC (EtOAc / hexanes, 1: 4 v / v): Rf = 0.5; [ ? ] D 20 = +42.8 (c = 0.10 CHCl 3 , 94% ee); Mp 168 [deg.] C (> 99% ee); 1 H NMR (500 MHz, CDCl 3) δ 7.38 (m, 9H), 7.32 (d, J = 7.2 Hz, 3H), 7.26 (m, 3H), 6.03 (s, 1H), 5.59 (s, 1H) , 4.48 (s, 1 H), 1.39 (s, 1 H); 13 C NMR (126 MHz, CDCl 3 ) δ 191.97, 189.48, 154.97, 138.74, 134.60, 134.36, 130.01, 129.93, 129.35, 129.33, 128.72, 127.95, 126.65, 126.41, 126.38, 79.89, 70.26, 55.79, 28.27; IR (KBr):? 3366, 1707, 1687, 1512, 1478, 1440, 1365, 1328, 1310, 1279, 1242, 1167, 1061, 1039, 1017, 981, 963, 827, 787, 747, 702, 688, 627, 617 cm < -1 & gt ;; LR-MS (ESI) Calcd for [C 27 H 27 NO 4 S 2 + Na] + : 516.13; Found: 516; HR-MS (ESI) Calcd for [C 27 H 27 NO 4 S 2 + Na] + : 516.1279; Found: 516.1274.
Isomers excess value (enantiomeric excess,%) was determined via HPLC analysis (Chiralpak IA; hexanes / isopropyl alcohol = 90: 10; flow rate: 1.0 mL / min; 210 nm): t R = 15.2 min (major), t R = 16.9 min; 94% ee ( S ).
[Example 21]
0.55 mmol of a dithiomalonate compound of formula 3-4 wherein R 1 is 4-methylphenyl (4-CH 3 -C 6 H 4 ) and R 2 is hydrogen, 0.50 mmol of N-protected-imine of formula , 0.5 mol% of the organic catalyst of Formula 1-1 was dissolved in 5.0 mL of dichloromethane, and the mixture was stirred at -50 ° C for 24 hours to synthesize an N -protected-β-amino-dithioester of Formula 6-6 . The solvent was then removed under reduced pressure and the product was isolated using silica-gel chromatography.
1 H NMR (500 MHz, CDCl 3) δ 7.38 - 7.33 (m, 2H), 7.32 - 7.23 (m, 5H), 7.22 - 7.16 (m, 4H), 7.14 (m, 2H), 6.06 (s, 1H ), 5.56 (s, IH), 4.45 (s, IH), 2.36 (s, 3H), 2.35 (s, 3H), 1.38 (s, 9H); 13 C NMR (126 MHz, CDCl 3 ) δ 189.97, 155.00, 140.42, 140.30, 138.93, 134.56, 134.33, 130.18, 130.17, 128.69, 127.89, 126.68, 123.01, 122.98, 79.82, 70.07, 55.81, 28.31, 21.39.
Isomers excess value (enantiomeric excess,%) was determined via HPLC analysis (Chiralpak OD-H; hexanes / isopropyl alcohol = 98: 2; flow rate: 1.0 mL / min; 210 nm): t R = 24.0 min (major ), t R = 29.2 min; 66% ee ( S ).
[Example 22]
0.55 mmol of a dithiomalonate compound of formula (3-5) wherein R 1 is 3,5-dimethyl-phenyl (3,5- (CH 3 ) 2 -C 6 H 3 ) and R 2 is hydrogen, 0.5 mol of the N-protected-imine of Formula 1, 0.5 mol% of the organic catalyst of Formula 1-1 was dissolved in 5.0 mL of dichloromethane, and the mixture was stirred at -50 ° C for 24 hours to obtain N -protected- -Amino-dithioester was synthesized. The solvent was then removed under reduced pressure and the product was isolated using silica-gel chromatography.
1 H NMR (500 MHz, CDCl 3) δ 7.38 - 7.33 (m, 2H), 7.33 - 7.28 (m, 3H), 7.06 - 6.97 (m, 4H), 6.90 (d, J = 16.9 Hz, 2H), 6H), 2.29 (s, 6H), 1.39 (s, 9H); 13 C NMR (126 MHz, CDCl 3) δ 189.86, 155.00, 139.06, 139.01, 132.17, 132.04, 131.92, 131.86, 131.78, 131.49, 128.65, 127.84, 127.57, 126.68, 126.25, 125.75, 79.73, 69.96, 55.85, 28.30 , 21.12.
Isomers excess value (enantiomeric excess,%) was determined via HPLC analysis (Chiralpak OD-H; hexanes / isopropyl alcohol = 99: 1; flow rate: 1.0 mL / min; 210 nm): t R = 36.6 min, t R = 68.0 min (major); 68% ee ( S ).
[Example 23]
0.55 mmol of a dithiomalonate compound of Formula 3-6 wherein R 1 is benzyl and R 2 is methyl, 0.50 mmol of N-protected-imine 4-1, 5 mol% of an organic catalyst of Formula 1-1, Dissolved in 5.0 mL of chloromethane, and stirred at -50 캜 for 24 hours to synthesize an N -protected-β-amino-dithioester of Formula 6-8. The solvent was then removed under reduced pressure and the product was isolated using silica-gel chromatography.
TLC (EtOAc / hexanes, 1: 4 v / v): Rf = 0.44; [ ? ] D 20 = +48.4 (c = 0.50 CHCl 3 , 90% ee); 1 H NMR (300 MHz, CDCl 3) δ 7.36 - 7.21 (m, 10H), 7.22 - 7.07 (m, 5H), 6.51 (d, J = 7.3 Hz, 1H), 5.20 (d, J = 9.0 Hz, 1H), 4.28-4.01 (m, 4H), 1.51 (s, 3H), 1.37 (s, 9H); 13 C NMR (126 MHz, CDCl 3 ) 隆 200.63, 197.35, 154.72, 137.46,136.48,136.28,129.01,128.68,128.63,128.46,128.19,127.88,127.48,79.55,69.63,60.78,33.95,28.36,20.24,14.21 ; IR (KBr):? 3426, 3030, 2978, 2930, 1717, 1698, 1664, 1602, 1494, 1454, 1391, 1366, 1314, 1241, 1165, 1074, 1044, 1017, 961, 842 cm -1 ; LR-MS (ESI) Calcd for [C 30 H 33 NO 4 S 2 + Na] +: 558.17; Found: 558; HR-MS (ESI) Calcd for [C 30 H 33 NO 4 S 2 + Na] +: 558.1749; Found: 558.1744.
Isomers excess value (enantiomeric excess,%) was determined via HPLC analysis (Chiralpak IA; hexanes / isopropyl alcohol = 70: 30; flow rate: 1.0 mL / min; 210 nm): t R = 7.0 min, t R = 10.9 min (major); 95% ee ( S ).
[Example 24]
0.55 mmol of the dithiomalonate compound of Formula 3-1 wherein R 1 is benzyl and R 2 is hydrogen, 0.50 mmol of the N-protected-imine of Formula 4-4, 0.5 mol% of the organic catalyst of Formula 1-1, Dissolved in 5.0 mL of chloromethane, and then stirred at -50 캜 for 24 hours to synthesize an N -protected-β-amino-dithioester of Formula 6-9. The solvent was then removed under reduced pressure and the product was isolated using silica-gel chromatography.
TLC (EtOAc / hexanes, 1: 4 v / v): Rf = 0.47; [ ? ] D 20 = +54.1 (c = 0.10 CHCl 3 ,> 99% ee); Mp 55 < 0 > C (> 99% ee); 1 H NMR (500 MHz, CDCl 3) δ 8.13 (d, J = 8.5 Hz, 1H), 7.85 (d, J = 8.1 Hz, 1H), 7.74 (d, J = 7.9 Hz, 1H), 7.58 (t J = 7.7 Hz, 1H), 7.49 (t, J = 7.5 Hz, 1H), 7.35 (d, J = 7.1 Hz, 1H), 7.30 (m, 2H), 7.08 (s, 2H), 6.36 (d, J = 28.6 Hz, 2H), 4.45 2H), 1.41 (s, 9H); 13 C NMR (126 MHz, CDCl 3) δ 193.28, 190.70, 154.96, 136.22, 136.05, 134.21, 133.86, 129.94, 129.17, 128.89, 128.72, 128.67, 128.56, 127.50, 127.41, 126.96, 125.82, 125.12, 124.02, 122.14 , 69.02, 51.99, 33.95, 33.90, 28.30; IR (KBr):? 1698, 1495, 1454, 1391, 1366, 1245, 1165, 1058, 1018, 986, 851, 803, 777, 753, 732, 701, 665, 644, 611 cm -1 ; LR-MS (ESI) Calcd for [C 33 H 33 NO 4 S 2 + Na] +: 594.17; Found: 594; HR-MS (ESI) Calcd for [C 33 H 33 NO 4 S 2 + Na] +: 594.1749; Found: 594.1743.
Isomers excess value (enantiomeric excess,%) was determined via HPLC analysis (Chiralcel OD-H; hexanes / isopropyl alcohol = 90: 10; flow rate: 1.0 mL / min; 210 nm): t R = 11.8 min (major ), t R = 13.9 min; 98% ee ( S ).
[Example 25]
0.55 mmol of the dithiomalonate compound of Formula 3-1 wherein R 1 is benzyl and R 2 is hydrogen, 0.50 mmol of the N-protected-imine of Formula 4-5, 0.5 mol% of the organic catalyst of Formula 1-1, Dissolved in 5.0 mL of chloromethane, and then stirred at -50 ° C for 24 hours to synthesize the N -protected-beta-amino-dithioester of Formula 6-10. The solvent was then removed under reduced pressure and the product was isolated using silica-gel chromatography.
TLC (EtOAc / hexanes, 1: 4 v / v): Rf = 0.47; [ ? ] D 20 = + 50.7 (c = 0.10 CHCl 3 ,> 99% ee); Mp 161 [deg.] C (> 99% ee); 1 H NMR (500 MHz, CDCl 3) δ 7.22 (m, 6H), 7.12 (m, 6H), 7.04 (d, J = 7.9 Hz, 2H), 5.87 (s, 1H), 5.43 (s, 1H) , 4.29 (s, 1H), 4.14 (m, 2H), 4.10-3.95 (m, 2H), 2.29 (s, 3H), 1.38 (s, 9H); 13 C NMR (126 MHz, CDCl 3 ) δ 192.56, 190.58, 154.83, 137.37, 136.32, 136.26, 135.71, 129.27, 128.82, 128.76, 128.58, 127.39, 126.49, 79.77, 71.01, 55.38, 33.89, 33.83, 28.27, ; IR (KBr):? 1698, 1511, 1289, 1246, 1169, 1041, 1021, 991, 972, 846, 825, 761, 699 cm -1 ; LR-MS (ESI) Calcd for [C 30 H 33 NO 4 S 2 + Na] +: 558.17; Found: 558; HR-MS (ESI) Calcd for [C 30 H 33 NO 4 S 2 + Na] +: 558.1749; Found: 558.1757.
Isomers excess value (enantiomeric excess,%) was determined via HPLC analysis (Chiralpak IA; hexanes / isopropyl alcohol = 70: 30; flow rate: 1.0 mL / min; 210 nm): t R = 14.1 min (major), t R = 22.4 min; 95% ee ( S ).
[Example 26]
0.55 mmol of the dithiomalonate compound of Formula 3-1 wherein R 1 is benzyl and R 2 is hydrogen, 0.50 mmol of the N-protected-imine of Formula 4-6, 0.5 mol% of the organic catalyst of Formula 1-1, Dissolved in 5.0 mL of chloromethane, and then stirred at -50 캜 for 24 hours to synthesize an N -protected-β-amino-dithioester of formula (6-11). The solvent was then removed under reduced pressure and the product was isolated using silica-gel chromatography.
TLC (EtOAc / hexanes, 1: 4 v / v): Rf = 0.47; [ ? ] D 20 = +57.3 (c = 0.10 CHCl 3 ,> 99% ee); Mp 128 [deg.] C (> 99% ee); 1 H NMR (500 MHz, CDCl 3) δ 7.31 - 7.21 (m, 7H), 7.15 (m, 4H), 7.05 (m, 3H), 5.92 (s, 1H), 5.44 (s, 1H), 4.29 ( s, 1 H), 4.16 (m, 2H), 4.12-3.97 (m, 2H), 2.29 (s, 3H), 1.40 (s, 9H); 13 C NMR (126 MHz, CDCl 3) δ 192.71, 190.60, 154.93, 138.74, 138.28, 136.32, 136.24, 128.83, 128.75, 128.64, 128.59, 128.54, 127.45, 127.35, 123.60, 79.85, 70.92, 55.60, 33.94, 33.89 , 28.30, 21.49; IR (KBr): ν 1699, 1603, 1511, 1454, 1366, 1344, 1281, 1241, 1170, 1136, 1072, 1041, 1023, 987, 972, 759, 699, 627, 616 cm -1 ; LR-MS (ESI) Calcd for [C 30 H 33 NO 4 S 2 + Na] +: 558.17; Found: 558; HR-MS (ESI) Calcd for [C 30 H 33 NO 4 S 2 + Na] +: 558.1749; Found: 558.1757.
Isomers excess value (enantiomeric excess,%) was determined via HPLC analysis (Chiralpak IA; hexanes / isopropyl alcohol = 70: 30; flow rate: 1.0 mL / min; 210 nm): t R = 12.0 min (major), t R = 24.7 min; 95% ee ( S ).
[Example 27]
0.55 mmol of the dithiomalonate compound of Formula 3-1 wherein R 1 is benzyl and R 2 is hydrogen, 0.50 mmol of the N-protected-imine of Formula 4-7, 0.5 mol% of the organic catalyst of Formula 1-1, Dissolved in 5.0 mL of chloromethane, and stirred at -50 캜 for 24 hours to synthesize an N -protected-β-amino-dithioester of formula (6-12). The solvent was then removed under reduced pressure and the product was isolated using silica-gel chromatography.
TLC (EtOAc / hexanes, 1: 4 v / v): Rf = 0.47; [ ? ] D 20 = +52.6 (c = 0.10 CHCl 3 ,> 99% ee); Mp 197 [deg.] C (> 99% ee); 1 H NMR (500 MHz, CDCl 3) δ 7.47 (d, J = 8.1 Hz, 2H), 7.32 (d, J = 7.9 Hz, 2H), 7.25 (m, 6H), 7.18 - 7.11 (m, 4H) , 5.97 (s, 1H), 5.47 (s, IH), 4.28 (s, IH), 4.17 (d, J = 13.9 Hz, 2H), 4.04 (dd, J = 34.4, 13.8 Hz, 2H) s, 9H); 13 C NMR (126 MHz, CDCl 3) δ 192.44, 190.30, 154.83, 142.71, 136.10, 136.05, 130.25 (q, 2 J (CCF) = 32.3 Hz), 128.82, 128.72, 128.67, 128.65, 127.58, 127.38, 127.03 , 125.60, 125.57, 123.94 (q, 1 J (CF) = 272.0 Hz), 80.28, 70.12, 55.23, 34.03, 33.99, 28.25; IR (KBr):? 1695, 1681, 1507, 1329, 1291, 1245, 1159, 1123, 1070, 1042, 1019, 975, 842, 790, 761, 697, 610 cm -1 ; LR-MS (ESI) Calcd for [C 30 H 30 F 3 NO 4 S 2 + Na] +: 612.15; Found: 612; HR-MS (ESI) Calcd for [C 30 H 30 F 3 NO 4 S 2 + Na] +: 612.1466; Found: 612.1484.
Isomers excess value (enantiomeric excess,%) was determined via HPLC analysis (Chiralpak IA; hexanes / isopropyl alcohol = 70: 30; flow rate: 1.0 mL / min; 210 nm): t R = 19.3 min (major), t R = 31.2 min; 90% ee ( S ).
[Example 28]
0.55 mmol of the dithiomalonate compound of Formula 3-1 wherein R 1 is benzyl and R 2 is hydrogen, 0.50 mmol of the N-protected-imine of Formula 4-8, 0.5 mol% of the organic catalyst of Formula 1-1, Dissolved in 5.0 mL of chloromethane, and stirred at -50 ° C for 24 hours to synthesize an N -protected-β-amino-dithioester of formula (6-13). The solvent was then removed under reduced pressure and the product was isolated using silica-gel chromatography.
TLC (EtOAc / hexanes, 1: 4 v / v): Rf = 0.40; [ ? ] D 20 = +56.7 (c = 0.10 CHCl 3 ,> 99% ee); Mp 184 < 0 > C (> 99% ee)
1 H NMR (500 MHz, CDCl 3) δ 7.29 - 7.22 (m, 6H), 7.21 - 7.11 (m, 6H), 6.91 (t, J = 8.6 Hz, 2H), 5.87 (s, 1H), 5.41 ( s, 1H), 4.27 (s, 1H), 4.15 (dd, J = 13.8,9.4 Hz, 2H), 4.11-3.98 (m, 2H), 1.38 (s, 9H); 13 C NMR (126 MHz, CDCl 3) δ 192.53, 190.45, 162.19 (d, 1 J (CF) = 246.5 Hz), 154.81, 136.21 (d, 4 J (CCCCF) = 5.8 Hz), 134.57, 128.80 (d , 3 J (CCCF) = 6.5 Hz), 128.66, 128.45, 128.38, 127.54, 127.52, 115.51 (d, 2 J (CCF) = 21.6 Hz), 80.09, 70.77, 55.04, 34.01, 33.93, 28.28, 0.02; IR (KBr): ν 1697, 1683, 1511, 1366, 1290, 1247, 1222, 1168, 1161, 1075, 1041, 1022, 988, 973, 846, 833, 811, 771, 761, 698 cm -1 ; LR-MS (ESI) Calcd for [C 29 H 30 FNO 4 S 2 + Na] + : 562.15; Found: 562; HR-MS (ESI) Calcd for [C 29 H 30 FNO 4 S 2 + Na] + : 562.1498; Found: 562.1489.
Isomers excess value (enantiomeric excess,%) was determined via HPLC analysis (Chiralpak IA; hexanes / isopropyl alcohol = 70: 30; flow rate: 1.0 mL / min; 210 nm): t R = 18.2 min (major), t R = 27.4 min; 88% ee ( S ).
[Example 29]
0.55 mmol of a dithiomalonate compound of formula (3-1) wherein R 1 is benzyl and R 2 is hydrogen, 0.50 mmol of N-protected-imine of formula (4-9) and 0.5 mol% of an organic catalyst of formula Dissolved in 5.0 mL of chloromethane and stirred at -50 ° C for 24 hours to synthesize the N -protected-beta-amino-dithioester of formula (6-14). The solvent was then removed under reduced pressure and the product was isolated using silica-gel chromatography.
TLC (EtOAc / hexanes, 1: 4 v / v): Rf = 0.47; [ ? ] D 20 = +48.5 (c = 0.10 CHCl 3 ,> 99% ee); Mp 199 [deg.] C (> 99% ee); 1 H NMR (500 MHz, CDCl 3) δ 7.26 (m, 7H), 7.19 (d, J = 8.5 Hz, 2H), 7.18 - 7.11 (m, 5H), 5.87 (s, 1H), 5.40 (s, 1H), 4.26 (s, 1H), 4.16 (dd, J = 13.9, 5.6 Hz, 2H), 4.04 (t, J = 15.2 Hz, 2H), 1.38 13 C NMR (126 MHz, CDCl 3 ) δ 192.39, 190.36, 154.78, 137.26, 136.17, 136.11, 133.61, 128.81, 128.77,128.74,128.66,128.06,127.53,127.52,80.12,70.51,55.08,34.00,33.93,28.25 ; IR (KBr): ν 1697, 1513, 1494, 1365, 1284, 1245, 1167, 1073, 1039, 1015, 988, 972, 842, 828, 782, 772, 760, 697, 629 cm -1 ; LR-MS (ESI) Calcd for [C 29 H 30 ClNO 4 S 2 + Na] + : 578.12; Found: 578; HR-MS (ESI) Calcd for [C 29 H 30 ClNO 4 S 2 + Na] + : 578.1202; Found: 578.1197.
Isomers excess value (enantiomeric excess,%) was determined via HPLC analysis (Chiralpak IA; hexanes / isopropyl alcohol = 70: 30; flow rate: 1.0 mL / min; 210 nm): t R = 20.6 min (major), t R = 29.9 min; 95% ee ( S ).
[Example 30]
0.55 mmol of the dithiomalonate compound of Formula 3-1 wherein R 1 is benzyl and R 2 is hydrogen, 0.50 mmol of the N-protected-imine of Formula 4-10, 0.5 mol% of the organic catalyst of Formula 1-1, Dissolved in 5.0 mL of chloromethane, and then stirred at -50 캜 for 24 hours to synthesize the N -protected-β-amino-dithioester of formula (6-15). The solvent was then removed under reduced pressure and the product was isolated using silica-gel chromatography.
TLC (EtOAc / hexanes, 1: 4 v / v): Rf = 0.40; [ ? ] D 20 = +28.7 (c = 0.10 CHCl 3 ,> 99% ee); Mp 166 < 0 > C (> 99% ee); 1 H NMR (500 MHz, CDCl 3) δ 7.29 - 7.22 (m, 6H), 7.19 (m, 5H), 7.09 (s, 1H), 6.95 (d, J = 4.6 Hz, 1H), 5.80 (s, 1H), 5.53 (s, 1H), 4.40 (s, 1H), 4.17 (dd, J = 13.8,10.6 Hz, 2H), 4.12-4.00 (m, 1H), 1.40 (s, 9H); 13 C NMR (126 MHz, CDCl 3) δ 192.59, 190.53, 154.90, 139.82, 136.27, 136.25, 128.85, 128.75, 128.64, 128.44, 127.46, 126.27, 126.15, 122.24, 79.92, 70.28, 51.90, 33.93, 28.27; IR (KBr):? 1697, 1511, 1453, 1365, 1320, 1292, 1249, 1166, 1072, 1040, 1020, 988, 973, 809, 761, 697, 657, 650 cm -1 ; LR-MS (ESI) Calcd for [C 27 H 29 NO 4 S 3 + Na] + : 550.12; Found: 550; HR-MS (ESI) Calcd for [C 27 H 29 NO 4 S 3 + Na] + : 550.1156; Found: 550.1150.
Isomers excess value (enantiomeric excess,%) was determined via HPLC analysis (Chiralpak IA; hexanes / isopropyl alcohol = 70: 30; flow rate: 1.0 mL / min; 210 nm): t R = 17.3 min (major), t R = 36.4 min; 94% ee ( S ).
[Example 31]
0.55 mmol of the dithiomalonate compound of Formula 3-1 wherein R 1 is benzyl and R 2 is hydrogen, 0.50 mmol of the N-protected-imine of Formula 4-11, 0.5 mol% of the organic catalyst of Formula 1-1, Dissolved in 5.0 mL of chloromethane, and then stirred at -50 캜 for 24 hours to synthesize an N -protected-β-amino-dithioester of Chemical Formula 6-16. The solvent was then removed under reduced pressure and the product was isolated using silica-gel chromatography.
TLC (EtOAc / hexanes, 1: 4 v / v ): Rf = 0.60; [ ? ] D 20 = +88.5 (c = 0.10 CHCl 3 , 92% ee ); Mp 119 [deg.] C (> 99% ee ); 1 H NMR (500 MHz, CDCl 3) δ 7.27 (d, J = 4.9 Hz, 10H), 5.37 (d, J = 10.1 Hz, 1H), 4.22 (d, J = 13.9 Hz, 1H), 4.19 - 4.08 (m, 1H), 1.82 (s, 3H), 1.69 (m, 1H) 1.04-0.87 (m, 2H); 13 C NMR (126 MHz, CDCl 3) δ 193.21, 191.57, 155.57, 136.47, 136.43, 128.93, 128.77, 128.66, 128.62, 127.49, 127.40, 79.20, 67.19, 57.24, 41.30, 33.99, 33.86, 30.44, 29.04, 28.33 , 26.00, 25.87, 25.81; IR (KBr) :? 2926, 2853, 1703, 1690, 1507, 1452, 1364, 1297, 1248, 1168, 1072, 1060, 1044, 1003, 984, 956, 861, 846, 810, 771, 698, 639, 622 cm -1 ; LR-MS (ESI) Calcd for [C 29 H 37 NO 4 S 2 + Na] + : 550.21; Found: 550.
Isomers excess value (enantiomeric excess,%) was determined via HPLC analysis (Chiralpak IA; hexanes / isopropyl alcohol = 70: 30; flow rate: 1.0 mL / min; 210 nm): t R = 7.8 min (major), t R = 10.9 min; 92% ee ( R ).
[Example 32]
0.5 mmol of the dithiomalonate compound of Formula 3-1 wherein R 1 is benzyl and R 2 is hydrogen, 0.50 mmol of the N-protected-imine of Formula 4-12, 0.5 mol% of the organic catalyst of Formula 1-1, Dissolved in 5.0 mL of chloromethane, and then stirred at -50 캜 for 24 hours to synthesize an N -protected-β-amino-dithioester of Formula 6-17. The solvent was then removed under reduced pressure and the product was isolated using silica-gel chromatography.
TLC (EtOAc / hexanes, 1: 4 v / v): Rf = 0.50; [ ? ] D 20 = +56.0 (c = 0.050 CHCl 3 , 91% ee); Mp 100 [deg.] C (92% ee); 1 H NMR (500 MHz, CDCl 3) δ 7.31 - 7.21 (m, 11H), 7.18 (t, J = 7.3 Hz, 1H), 7.09 (d, J = 7.2 Hz, 2H), 5.19 (d, J = 1H, J = 8.1 Hz, 1H), 4.29-4.07 (m, 6H), 2.70 (m, 1H), 2.58 (m, 1H), 1.90 (m, 1H), 1.75 13 C NMR (126 MHz, CDCl 3) δ 192.73, 191.26, 155.22, 141.00, 136.46, 136.41, 128.88, 128.80, 128.69, 128.65, 128.43, 128.35, 127.49, 127.45, 126.01, 79.60, 69.47, 52.40, 34.63, 33.97 , 33.89, 32.59, 28.30; IR (KBr):? 3376, 2978, 1693, 1523, 1496, 1453, 1391, 1366, 1334, 1294, 1278, 1244, 1171, 1074, 1050, 1030, 1017, 989, 968, 855, 795, 768, 750, 702, 630, 613 cm < -1 & gt ;; LR-MS (ESI) Calcd for [C 31 H 35 NO 4 S 2 + Na] + : 572.19; Found: 572; HR-MS (ESI) Calcd for [C 31 H 35 NO 4 S 2 + Na] + : 572.1905; Found: 572.1907.
Isomers excess value (enantiomeric excess,%) was determined via HPLC analysis (Chiralpak IA; hexanes / isopropyl alcohol = 70: 30; flow rate: 1.0 mL / min; 210 nm): t R = 13.1 min (major), t R = 16.7 min; 92% ee ( R ).
[Example 33]
0.55 mmol of the dithiomalonate compound of Formula 3-1 wherein R 1 is benzyl and R 2 is hydrogen, 0.50 mmol of N-protected-alpha-amidosulfone of Formula 5-1, 1.0 mol% of Na 2 CO 3 and 0.75 mmol of Na 2 CO 3 were dissolved in a mixed solution of 1.0 mL of dichloromethane and 5.0 mL of a saturated aqueous solution of NaCl and stirred at 0 ° C for 24 hours to obtain N -protected-beta-amino-di Thioester was synthesized. Subsequently, the mixed solution is extracted with dichloromethane and distilled water, and the obtained organic layer is washed with MgSO 4 to remove water and the solvent is volatilized under reduced pressure. The product was isolated via silica-gel chromatography.
Isomers excess value (enantiomeric excess,%) was determined via HPLC analysis (Chiralcel OD-H; hexane: isopropyl alcohol = 95: 5; flow rate: 1.0 mL / min; 210 nm): t R = 15.9 min (major ), t R = 18.2 min; 95% ee ( S ).
[Example 34]
0.55 mmol of the dithiomalonate compound of Formula 3-1 wherein R 1 is benzyl and R 2 is hydrogen, 0.50 mmol of the N-protected-alpha-amidosulfone of Formula 5-2, 1.0 mol% of Na 2 CO 3 and 0.75 mmol of Na 2 CO 3 were dissolved in a mixed solution of 1.0 mL of dichloromethane and 5.0 mL of a saturated aqueous solution of NaCl and stirred at 0 ° C for 72 hours to obtain an N-protected-β-amino-di Thioester was synthesized. Subsequently, the mixed solution is extracted with dichloromethane and distilled water, and the obtained organic layer is washed with MgSO 4 to remove water and the solvent is volatilized under reduced pressure. The product was isolated via silica-gel chromatography.
TLC (EtOAc / hexanes, 1: 4 v / v): Rf = 0.17; [ ? ] D 20 = +52.7 (c = 0.10 CHCl 3 ,> 99% ee); Mp 130 [deg.] C (> 99% ee); 1 H NMR (500 MHz, CDCl 3) δ 7.27 (m, 10H), 5.18 (d, J = 8.5 Hz, 1H), 4.28 (d, J = 6.4 Hz, 1H), 4.25 - 4.09 (m, 5H) , 2.37 (m, 2H), 2.08-1.91 (m, 1H), 1.82 (m, 1H), 1.38 (s, 9H); 13 C NMR (126 MHz, CDCl 3) δ 192.27, 190.91, 155.25, 136.25, 136.13, 128.88, 128.83, 128.77, 127.65, 118.89, 80.31, 69.17, 51.59, 34.13, 34.07, 30.93, 28.24, 14.46; IR (KBr): ν 3357, 1696, 1519, 1453, 1368, 1320, 1286, 1244, 1169, 1071, 1053, 1031, 1017, 991, 969, 840, 779, 754, 706, 662, 631 cm -1 ; LR-MS (ESI) Calcd for [C 26 H 30 N 2 O 4 S 2 + Na] + : 521.15; Found: 521; HR-MS (ESI) Calcd for [C 26 H 30 N 2 O 4 S 2 + Na] + : 521.1545; Found: 521.1548.
Isomers excess value (enantiomeric excess,%) was determined via HPLC analysis (Chiralpak IA; hexanes / isopropyl alcohol = 70: 30; flow rate: 1.0 mL / min; 210 nm): t R = 16.0 min (major), t R = 17.0 min; 97% ee ( R ).
[Example 35]
0.55 mmol of the dithiomalonate compound of Formula 3-1 wherein R 1 is benzyl and R 2 is hydrogen, 0.50 mmol of N-protected-alpha-amidosulfone of Formula 5-3, 1.0 mol% of Na 2 CO 3 and 0.75 mmol of Na 2 CO 3 were dissolved in a mixed solution of 1.0 mL of dichloromethane and 5.0 mL of a saturated aqueous solution of NaCl and stirred at 0 ° C for 72 hours to obtain an N-protected-β-amino-di Thioester was synthesized. Subsequently, the mixed solution is extracted with dichloromethane and distilled water, and the obtained organic layer is washed with MgSO 4 to remove water and the solvent is volatilized under reduced pressure. The product was isolated via silica-gel chromatography.
TLC (EtOAc / hexanes, 1: 4 v / v): Rf = 0.50; [ ? ] D 20 = +56.0 (c = 0.050 CHCl 3 , 91% ee); Mp 100 [deg.] C (92% ee); 1 H NMR (500 MHz, CDCl 3) δ 7.31 - 7.21 (m, 11H), 7.18 (t, J = 7.3 Hz, 1H), 7.09 (d, J = 7.2 Hz, 2H), 5.19 (d, J = 1H, J = 8.1 Hz, 1H), 4.29-4.07 (m, 6H), 2.70 (m, 1H), 2.58 (m, 1H), 1.90 (m, 1H), 1.75 13 C NMR (126 MHz, CDCl 3) δ 192.73, 191.26, 155.22, 141.00, 136.46, 136.41, 128.88, 128.80, 128.69, 128.65, 128.43, 128.35, 127.49, 127.45, 126.01, 79.60, 69.47, 52.40, 34.63, 33.97 , 33.89, 32.59, 28.30; IR (KBr):? 3376, 2978, 1693, 1523, 1496, 1453, 1391, 1366, 1334, 1294, 1278, 1244, 1171, 1074, 1050, 1030, 1017, 989, 968, 855, 795, 768, 750, 702, 630, 613 cm < -1 & gt ;; LR-MS (ESI) Calcd for [C 31 H 35 NO 4 S 2 + Na] + : 572.19; Found: 572; HR-MS (ESI) Calcd for [C 31 H 35 NO 4 S 2 + Na] + : 572.1905; Found: 572.1907.
Isomers excess value (enantiomeric excess,%) was determined via HPLC analysis (Chiralpak IA; hexanes / isopropyl alcohol = 70: 30; flow rate: 1.0 mL / min; 210 nm): t R = 13.1 min (major), t R = 16.7 min; 92% ee ( R ).
[Example 36]
0.55 mmol of the dithiomalonate compound of Formula 3-1 wherein R 1 is benzyl and R 2 is hydrogen, 0.50 mmol of N-protected-alpha-amidosulfone of Formula 5-4, 1.0 mol% of Na 2 CO 3 and 0.75 mmol of Na 2 CO 3 were dissolved in a mixed solution of 1.0 mL of dichloromethane and 5.0 mL of a saturated aqueous solution of NaCl and stirred at 0 ° C for 72 hours to obtain an N-protected-β-amino-di Thioester was synthesized. Subsequently, the mixed solution is extracted with dichloromethane and distilled water, and the obtained organic layer is washed with MgSO 4 to remove water and the solvent is volatilized under reduced pressure. The product was isolated via silica-gel chromatography.
TLC (EtOAc / hexanes, 1: 4 v / v): Rf = 0.50; [ ? ] D 20 = +58.1 (c = 0.10 CHCl 3 , 94% ee); Mp 140 [deg.] C (94% ee); 1 H NMR (500 MHz, CDCl 3) δ 7.32 - 7.18 (m, 15H), 5.21 (d, J = 8.7 Hz, 1H), 4.43 - 4.32 (m, 1H), 4.24 (m, 2H), 4.22 - 4.09 (m, 4H), 3.02 (dd, J = 13.7, 8.1 Hz, 1H), 2.69 (dd, J = 13.7, 6.8 Hz, 1H), 1.36 (s, 9H); 13 C NMR (126 MHz, CDCl 3 ) δ 192.98, 191.66, 155.02, 137.34, 136.62, 136.36, 129.28, 128.88, 128.83, 128.69, 128.55, 127.51, 127.48, 126.76, 79.56, 68.04, 54.27, 38.45, 33.97, , 28.26; IR (KBr):? 1707, 1689, 1498, 1454, 1284, 1248, 1166, 1055, 993, 972, 860, 771, 758, 749, 702, 657, 641, 629, 615 cm -1 ; LR-MS (ESI) Calcd for [C 30 H 33 NO 4 S 2 + Na] +: 558.17; Found: 558; HR-MS (ESI) Calcd for [C 30 H 33 NO 4 S 2 + Na] +: 558.1749; Found: 558.1752.
Isomers excess value (enantiomeric excess,%) was determined via HPLC analysis (Chiralpak IA; hexanes / isopropyl alcohol = 90: 10; flow rate: 1.0 mL / min; 210 nm): t R = 24.2 min (major), t R = 30.2 min; 94% ee ( R ).
[Example 37]
0.55 mmol of the dithiomalonate compound of Formula 3-1 wherein R 1 is benzyl and R 2 is hydrogen, 0.50 mmol of N-protected-alpha-amidosulfone of Formula 5-5, 1.0 mol% of Na 2 CO 3 and 0.75 mmol of Na 2 CO 3 were dissolved in a mixed solution of 1.0 mL of dichloromethane and 5.0 mL of a saturated aqueous solution of NaCl and stirred at 0 ° C for 72 hours to obtain an N-protected-β-amino-di Thioester was synthesized. Subsequently, the mixed solution is extracted with dichloromethane and distilled water, and the obtained organic layer is washed with MgSO 4 to remove water and the solvent is volatilized under reduced pressure. The product was isolated via silica-gel chromatography.
TLC (EtOAc / hexanes, 1: 4 v / v): Rf = 0.37; [ ? ] D 20 = +17.4 (c = 0.10 CHCl 3 , 94% ee); Mp 85 [deg.] C (94% ee); 1 H NMR (300 MHz, CDCl 3 , Me 4 Si):? 1 H NMR (500 MHz, CDCl 3 )? 7.34-7.19 (m, 10H), 5.53 (d, J = 8.7 Hz, 1H) 2H), 4.16 (m, 3H), 1.41 (s, 2H), 4.84 (d, J = , ≪ / RTI > 9H), 1.16 (t, J = 7.1 Hz, 3H); 13 C NMR (126 MHz, CDCl 3 ) δ 192.48, 190.89, 169.19, 155.28, 136.41, 136.26, 128.93, 128.85, 128.69, 127.55, 127.51, 80.42, 66.52, 62.20, 54.15, 34.06, 33.91, 30.96, 28.21, , 1.05; IR (KBr):? 3375, 1741, 1692, 1517, 1496, 1454, 1369, 1336, 1281, 1253, 1208, 1166, 1080, 1008, 873, 817, 805, 770, 758, 729, -1 ; LR-MS (ESI) Calcd for [C 26 H 31 NO 6 S 2 + Na] + : 540.15; Found: 540; HR-MS (ESI) Calcd for [C 26 H 31 NO 6 S 2 + Na] + : 540.1490; Found: 540.1493.
Isomers excess value (enantiomeric excess,%) was determined via HPLC analysis (Chiralcel OD-H; hexanes / isopropyl alcohol = 70: 30; flow rate: 1.0 mL / min; 210 nm): t R = 9.0 min, t R = 15.3 min (major); 92% ee ( S ).
[Example 38]
0.55 mmol of the dithiomalonate compound of Formula 3-1 wherein R 1 is benzyl and R 2 is hydrogen, 0.50 mmol of N-protected-alpha-amidosulfone of Formula 5-6, 1.0 mol% of Na 2 CO 3 and 0.75 mmol of Na 2 CO 3 were dissolved in a mixed solution of 1.0 mL of dichloromethane and 5.0 mL of a saturated aqueous solution of NaCl and the mixture was stirred at 0 ° C for 72 hours to obtain an N-protected-β-amino-di Thioester was synthesized. Subsequently, the mixed solution is extracted with dichloromethane and distilled water, and the obtained organic layer is washed with MgSO 4 to remove water and the solvent is volatilized under reduced pressure. The product was isolated via silica-gel chromatography.
TLC (EtOAc / hexanes, 1: 4 v / v): Rf = 0.46; [ ? ] D 20 = -32.7 (c = 0.10 CHCl 3 , 91% ee); Mp 113 [deg.] C (92% ee); 1 H NMR (500 MHz, CDCl 3) δ 7.30 - 7.21 (m, 8H), 7.16 (m, 5H), 6.96 - 6.86 (m, 2H), 6.52 - 6.42 (m, 1H), 6.04 (d, J = 10.6 Hz, 1H), 4.97 (dd, J = 13.7, 7.7 Hz, 1H), 4.25 (m, 3H), 4.04 (dd, J = , ≪ / RTI > 1H), 1.43 (s, 9H); 13 C NMR (126 MHz, CDCl 3) δ 190.43, 189.94, 151.27, 138.78, 135.83, 135.41, 127.88, 127.69, 127.59, 127.57, 127.44, 126.82, 126.32, 126.15, 126.07, 125.24, 106.79, 79.46, 72.27, 47.10 , 32.88, 32.53, 27.28, 27.22; IR (KBr):? 3396, 1705, 1686, 1503, 1454, 1368, 1329, 1313, 1250, 1235, 1167, 1072, 1019, 985, 960, 864, 811, 768, 749, 698, 654, -1 ; LR-MS (ESI) Calcd for [C 31 H 33 NO 4 S 2 + Na] + : 570.17; Found: 570; HR-MS (ESI) Calcd for [C 31 H 33 NO 4 S 2 + Na] + : 570.1749; Found: 570.1752.
Isomers excess value (enantiomeric excess,%) was determined via HPLC analysis (Chiralpak IA; hexanes / isopropyl alcohol = 70: 30; flow rate: 1.0 mL / min; 210 nm): t R = 11.5 min, t R = 12.8 min (major); 92% ee ( R ).
[Example 39]
0.55 mmol of the dithiomalonate compound of Formula 3-1 wherein R 1 is benzyl and R 2 is hydrogen, 0.50 mmol of N-protected-alpha-amidosulfone of Formula 5-7, 1.0 mol% of Na 2 CO 3 and 0.75 mmol of Na 2 CO 3 were dissolved in a mixed solution of 1.0 mL of dichloromethane and 5.0 mL of a saturated aqueous NaCl solution and stirred at 0 ° C for 72 hours to obtain an N-protected-β-amino-di Thioester was synthesized. Subsequently, the mixed solution is extracted with dichloromethane and distilled water, and the obtained organic layer is washed with MgSO 4 to remove water and the solvent is volatilized under reduced pressure. The product was isolated via silica-gel chromatography.
TLC (EtOAc / hexanes, 1: 4 v / v): Rf = 0.56; [ ? ] D 20 = +48.3 (c = 0.10 CHCl 3 ,> 99% ee); Mp 153 [deg.] C (> 99% ee); 1 H NMR (500 MHz, CDCl 3) δ 7.31 - 7.22 (m, 10H), 6.94 (dd, J = 16.8, 8.9 Hz, 1H), 6.86 (td, J = 9.5, 6.8 Hz, 1H), 5.09 ( (dd, J = 8.3 Hz, 1H), 4.35 (m, 2H), 4.27-4.09 (m, 4H), 2.94 , ≪ / RTI > 1H), 1.32 (s, 9H); 13 C NMR (126 MHz, CDCl 3 ) δ 192.49, 191.26, 156.19, 154.89, 148.98, 146.56, 136.48, 136.27, 128.87, 128.81, 128.71, 127.55, 120.93, 119.06, 105.36, 79.84, 68.83, 52.63, 34.03, , 31.16, 28.13; IR (KBr):? 3352, 1691, 1521, 1281, 1240, 1168, 1152, 1047, 1027, 988, 974, 850, 794, 755, 697, 654, 639, 625 cm -1 ; LR-MS (ESI) Calcd for [C 30 H 30 F 3 NO 4 S 2 + Na] +: 612.15; Found: 612. HR-MS (ESI ) Calcd for [C 30 H 30 F 3 NO 4 S 2 + Na] +: 612.1466; Found: 612.1463.
Isomers excess value (enantiomeric excess,%) was determined via HPLC analysis (Chiralcel OD-H; hexanes / isopropyl alcohol = 90: 10; flow rate: 1.0 mL / min; 210 nm): t R = 10.3 min, t R = 13.6 min (major); 95% ee ( R ).
[Example 40]
0.55 mmol of the dithiomalonate compound of Formula 3-1 wherein R 1 is benzyl and R 2 is hydrogen, 0.50 mmol of N-protected-alpha-amidosulfone of Formula 5-8, 1.0 mol% of Na 2 CO 3 and 0.75 mmol of Na 2 CO 3 were dissolved in a mixed solution of 1.0 mL of dichloromethane and 5.0 mL of a saturated aqueous solution of NaCl and stirred at 0 ° C for 72 hours to obtain an N-protected-β-amino-di Thioester was synthesized. Subsequently, the mixed solution is extracted with dichloromethane and distilled water, and the obtained organic layer is washed with MgSO 4 to remove water and the solvent is volatilized under reduced pressure. The product was isolated via silica-gel chromatography.
TLC (EtOAc / hexanes, 1: 10 v / v): Rf = 0.23; [ ? ] D 20 = +65 (c = 0.10 CHCl 3 , 88.79% ee); Mp 149 [deg.] C (88.97% ee); 1 H NMR (500 MHz, CDCl 3) δ 7.34 - 7.18 (m, 10H), 6.97 - 6.81 (m, 2H), 5.39 (d, J = 9.0 Hz, 1H), 4.43 (tt, J = 9.3, 5.7 J = 13.8, 9.7 Hz, 1 H), 2.76 (dd, J = 8 Hz, 1H), 4.27-4.21 (m, 1H), 4.21-4.12 14.1, 5.0 Hz, 1 H); 13 C NMR (126 MHz, CDCl 3 ) δ 192.50, 191.13, 156.16, 156.11, 149.05, 146.60, 136.34, 136.22, 128.87, 128.81, 128.71, 127.59, 127.57, 120.58, 118.95, 105.46, 68.59, 52.88, 52.26, 34.05 , 33.99, 31.45; IR (KBr):? 3340, 1698, 1519, 1264, 1244, 1208, 1153, 1098, 1050, 982, 936, 886, 788, 766, 699, 674, 666, 657 cm -1 ; HR-MS (FAB) Calcd for [C 27 H 24 F 3 NO 4 S 2 + H] + : 548.1177; Found: 548.1174.
The enantiomeric excess (%) was determined by HPLC analysis (Chiralcel AD-H, hexanes / isopropyl alcohol = 70: 30; flow rate: 1.0 mL / min; 210 nm): t R = 12.32 min, t R = 16.23 min (major); 88% ee ( R ).
[Example 41]
0.55 mmol of the dithiomalonate compound of Formula 3-1 wherein R 1 is benzyl and R 2 is hydrogen, 0.50 mmol of N-protected-alpha-amidosulfone of Formula 5-9, 1.0 mol% of Na 2 CO 3 and 0.75 mmol of Na 2 CO 3 were dissolved in a mixed solution of 1.0 mL of dichloromethane and 5.0 mL of a saturated aqueous solution of NaCl and stirred at 0 ° C for 72 hours to obtain an N-protected-β-amino-di Thioester was synthesized. Subsequently, the mixed solution is extracted with dichloromethane and distilled water, and the obtained organic layer is washed with MgSO 4 to remove water and the solvent is volatilized under reduced pressure. The product was isolated via silica-gel chromatography.
TLC (EtOAc / hexanes, 1: 4 v / v): Rf = 0.40; [ ? ] D 20 = +54 (c = 0.10 CHCl 3 , 75.03% ee); Mp 143 [deg.] C (75.03% ee); 1 H NMR (500 MHz, CDCl 3) δ 7.34 - 7.20 (m, 15H), 6.89 (dd, J = 16.6, 8.9 Hz, 1H), 6.81 (dd, J = 16.1, 9.5 Hz, 1H), 5.45 ( d, J = 9.0 Hz, 1H ), 4.96 (q, J = 12.3 Hz, 2H), 4.51 - 4.41 (m, 1H), 4.25 (d, J = 6.3 Hz, 1H), 4.19 - 4.10 (m, 4H ), 2.89 (dd, J = 13.8, 10.0 Hz, 1H), 2.76 (dd, J = 14.0, 4.8 Hz, 1H); 13 C NMR (126 MHz, CDCl 3) 192.54, 191.14, 156.20, 155.52, 149.08, 146.62, 136.33, 136.26, 128.93, 128.87, 128.77, 128.76, 128.51, 128.18, 128.01, 127.64, 127.62, 120.58, 119.01, 105.49, 68.76, 66.81, 52.91, 34.09, 34.07, 31.56; IR (KBr):? 3337, 1696, 1520, 1297, 1241, 1210, 1152, 1072, 1043, 982, 906, 885, 793, 772, 736, 697, 681 cm -1 ; HR-MS (FAB) Calcd for [C 26 H 23 F 3 NO 4 S 2 + H] + : 624.1490; Found: 624.1493.
Isomers excess value (enantiomeric excess,%) was determined via HPLC analysis (Chiralcel AD-H; hexanes / isopropyl alcohol = 70: 30; flow rate: 1.0 mL / min; 210 nm): t R = 22.05 min, t R = 34.91 min (major); 75% ee ( R ).
Experimental Examples The yield and enantiomer ratio of Examples 1 to 41
Table 1 shows the results obtained by measuring the yields and enantiomer ratios of the reactants participating in Examples 1 to 41, the products produced by the reaction, and the reaction conditions (catalyst, solvent, temperature and stirring time).
(mol%)
Temperature
(%)
(enantiomeric excess,%)
3-1
4-1
6-1
(1.0 mol%)
-50
3-1
4-1
6-1
(1.0 mol%)
-50
3-1
4-1
6-1
(1.0 mol%)
-50
3-1
4-1
6-1
-50
3-1
4-1
6-1
-50
3-1
4-1
6-1
-50
3-1
4-1
6-1
-50
3-1
4-1
6-1
-50
3-1
4-1
6-1
-50
3-1
4-1
6-1
-50
3-1
4-1
6-1
-15
3-1
4-1
6-1
0
3-1
4-1
6-1
3-1
4-1
6-1
3-1
4-1
6-1
3-1
4-1
6-1
3-1
4-2
6-2
3-1
4-3
6-3
3-2
4-1
6-4
-50
3-3
4-1
6-5
-50
3-4
4-1
6-6
-50
3-5
4-1
6-7
-50
3-6
4-1
6-8
-50
3-1
4-4
6-9
-50
3-1
4-5
6-10
-50
3-1
4-6
6-11
-50
3-1
4-7
6-12
-50
3-1
4-8
6-13
-50
3-1
4-9
6-14
-50
3-1
4-10
6-15
-50
3-1
4-11
6-16
-50
3-1
4-12
6-17
-50
3-1
5-1
6-1
0 C
3-1
5-2
6-18
0
3-1
5-3
6-17
0 C
3-1
5-4
6-19
0
3-1
5-5
6-20
0
3-1
5-6
6-21
0
3-1
5-7
6-22
0
3-1
5-8
6-23
0
3-1
5-9
6-24
0
Referring to Table 1, in accordance with an embodiment of the present invention, in the presence of a catalyst of Formula 1 or 2, a mixture of dithiomalonate of Formula 3 and N-protected-imine of Formula 4 or N- It was confirmed that the N-protected-beta-amino-dithioester of the formula (6) can be synthesized with a high yield and a high stereoselectivity.
On the other hand, in the case of reacting the dithiomalonate of Formula 3 with the N-protected-imine of Formula 4, when the reaction is performed in the presence of the chiral catalyst of Formula 1, the optically active N-protected- It is possible to synthesize the S-isomer of the isomer and, when the reaction is carried out in the presence of the chiral catalyst of the formula (2), the R-isomer can be synthesized.
≪ Comparative Examples 1 to 5 and Examples 42 and 43 >
In order to compare the reactivity according to the reactants, experiments were conducted in which malonate, monothiomalonate and dithiomalonate were respectively reacted with the N-protected-imine of formula (4-1).
[Comparative Example 1]
0.5 mmol of the dibenzylmalonate compound of formula (7), 0.50 mmol of N-protected-imine of formula (4-1) and 10 mol% of the organic catalyst of formula (1-1) were dissolved in 5.0 mL of dichloromethane, Time-agitated to synthesize the N -protected-beta-amino-diester of formula 8. The solvent was then removed under reduced pressure and the reaction conversion was determined using 1 H NMR integration.
(7)
[Chemical Formula 8]
1 H NMR (500 MHz, CDCl 3) δ 7.37 - 7.29 (m, 5H), 7.28 - 7.21 (m, 8H), 7.10 (m, 2H), 6.19 (s, 1H), 5.55 (s, 1H), 5.15 (m, 2H), 5.04 (s, 2H), 4.01 (s, 1H), 1.41 (s, 9H).
The enantiomeric excess (%) was determined by HPLC analysis (Regis Pirkle Covalent ( R , R ) Whelk-O 1; hexanes / isopropyl alcohol = 95: 5; flow rate: 1.0 mL / min; : t R = 16.0 min (major ), t R = 19.1 min; 94% ee ( S ).
[Comparative Example 2]
0.5 mmol of the dibenzylmalonate compound of the formula (7), 0.50 mmol of the N-protected-imine of the formula (4-1) and 0.5 mol% of the organic catalyst of the formula (1-1) were dissolved in 5.0 mL of dichloromethane, Time-agitated to synthesize the N -protected-beta-amino-diester of formula 8-1. The solvent was then removed under reduced pressure and the reaction conversion was determined using 1 H NMR integration.
1 H NMR (500 MHz, CDCl 3) δ 7.37 - 7.29 (m, 5H), 7.28 - 7.21 (m, 8H), 7.10 (m, 2H), 6.19 (s, 1H), 5.55 (s, 1H), 5.15 (m, 2H), 5.04 (s, 2H), 4.01 (s, 1H), 1.41 (s, 9H).
The enantiomeric excess (%) was determined by HPLC analysis (Regis Pirkle Covalent ( R , R ) Whelk-O 1; hexanes / isopropyl alcohol = 95: 5; flow rate: 1.0 mL / min; : t R = 16.0 min (major ), t R = 19.1 min; 79% ee ( S ).
[Comparative Example 3]
0.5 mmol of the dibenzylmalonate compound of Formula 7, 0.50 mmol of N-protected-imine of Formula 4-1, 0.5 mol% of the organic catalyst of Formula 1-1 was dissolved in 5.0 mL of dichloromethane, Time-agitated to synthesize the N -protected-beta-amino-diester of formula 8-1. The solvent was then removed under reduced pressure and the reaction conversion was determined using 1 H NMR integration.
1 H NMR (500 MHz, CDCl 3) δ 7.37 - 7.29 (m, 5H), 7.28 - 7.21 (m, 8H), 7.10 (m, 2H), 6.19 (s, 1H), 5.55 (s, 1H), 5.15 (m, 2H), 5.04 (s, 2H), 4.01 (s, 1H), 1.41 (s, 9H).
[Comparative Example 4]
0.5 mmol of the monothiomalonate compound of Formula 9, 0.50 mmol of N-protected-imine of Formula 4-1, 0.5 mol% of the organic catalyst of Formula 1-1 was dissolved in 5.0 mL of dichloromethane, Followed by stirring for 24 hours to synthesize a product of formula (10). The solvent was then removed under reduced pressure and the reaction conversion was determined using 1 H NMR integration.
[Chemical Formula 9]
[Chemical formula 10]
TLC (EtOAc / hexanes, 1: 4 v / v ): Rf = 0.33; = +33.1 (c = 0.10 CHCl 3 , 99% ee, 99% ee); Mp 89 ㅀ C (99% ee , 99% ee ); 1 H NMR (300 MHz, CDCl 3 , diastereomeric mixture) 1 H NMR (500 MHz, CDCl 3 )? 7.32-7.21 (m, 13H), 7.11 mixture of -NH protons), 5.52 (s, 1H), 5.12-5.02 (m, 2H), 4.17-4.02 (m, 3H), 1.40 (s, 9H); 13 C NMR (126 MHz, CDCl 3, diastereomeric mixture) δ 193.62, 191.64, 167.21, 166.13, 155.04, 154.88, 139.12, 138.91, 136.40, 136.33, 134.93, 134.80, 128.85, 128.68, 128.64, 128.58, 128.57, 128.50, 128.38, 128.33, 128.21, 128.03, 127.70, 127.67, 127.44, 127.38, 126.40, 126.38, 79.80, 67.70, 67.46, 64.08, 63.32, 54.71, 54.39, 33.76, 33.71, 28.28; IR (KBr) :? 3382, 1737, 1694, 1551, 1455, 1365, 1310, 1292, 1163, 960, 752, 727, 661, 623 cm -1 ; LR-MS (ESI) Calcd for [C 29 H 31 NO 5 S + Na] + : 505.19 (100%); Found: 505 (100%); HR-MS (ESI) Calcd for [C 29 H 31 NO 5 S + Na] + : 505.1923 (100%); Found: 505.1920 (100%).
Isomers excess value (enantiomeric excess,%) was determined via HPLC analysis (Chiralpak IA; hexanes / isopropyl alcohol = 70: 30; flow rate: 1.0 mL / min; 210 nm): t R = 28.1 min (major), t R = 43.7 min; 99% ee / t R = 33.2 min (major), t R = 35.2 min; 99% ee.
[Comparative Example 5]
0.5 mmol of the monothiomalonate compound of Formula 9, 0.50 mmol of N-protected-imine of Formula 4-1, 0.1 mol% of the organic catalyst of Formula 1-1 was dissolved in 5.0 mL of dichloromethane, And the mixture was stirred for 60 hours to synthesize the product of formula (10). The solvent was then removed under reduced pressure and the reaction conversion was determined using 1 H NMR integration.
Isomers excess value (enantiomeric excess,%) was determined via HPLC analysis (Chiralpak IA; hexanes / isopropyl alcohol = 70: 30; flow rate: 1.0 mL / min; 210 nm): t R = 28.1 min (major), t R = 43.7 min; 75% ee / t R = 33.2 min (major), t R = 35.2 min; 71% ee.
[Example 42]
0.5 mmol of the dithiomalonate compound of Formula 3-1 wherein R 1 is benzyl and R 2 is hydrogen, 0.50 mmol of the N-protected-imine of Formula 4-1, 0.1 mol% of the organic catalyst of Formula 1-1, Dissolved in 5.0 mL of chloromethane, and stirred at -50 ° C for 1 hour to synthesize an N-protected-β-amino-dithioester of formula (6-1). The solvent was then removed under reduced pressure and the product was isolated using silica-gel chromatography.
Isomers excess value (enantiomeric excess,%) was determined via HPLC analysis (Chiralcel OD-H; hexane: isopropyl alcohol = 95: 5; flow rate: 1.0 mL / min; 210 nm): t R = 15.9 min (major ), t R = 18.2 min; ≫ 99% ee ( S ).
[Example 43]
0.5 mmol of the dithiomalonate compound of Formula 3-1 wherein R 1 is benzyl and R 2 is hydrogen, 0.50 mmol of the N-protected-imine of Formula 4-1, 0.1 mol% of the organic catalyst of Formula 1-1, Dissolved in 5.0 mL of chloromethane, and then stirred at -50 ° C for 1 hour to synthesize an N -protected-β-amino-dithioester of formula (6-1). The solvent was then removed under reduced pressure and the product was isolated using silica-gel chromatography.
Isomers excess value (enantiomeric excess,%) was determined via HPLC analysis (Chiralcel OD-H; hexane: isopropyl alcohol = 95: 5; flow rate: 1.0 mL / min; 210 nm): t R = 15.9 min (major ), t R = 18.2 min; 99% ee ( S ).
<Experimental Example>
Table 2 shows the reaction conversion ratios and enantiomer ratios of Comparative Examples 1 to 5 and Examples 40 and 41 according to reactants, products and reaction conditions (catalyst, solvent, temperature and stirring time).
(mol%)
Temperature
Conversion Rate
( 1 H NMR,%)
(enantiomeric excess,%)
1-1
(10 mol%)
1-1
(0.5 mol%)
1-1
(0.1 mol%)
1-1
(0.5 mol%)
(1: 1 dr)
1-1
(0.1 mol%)
(1: 1 dr)
3-1
1-1
(0.5 mol%)
3-1
Referring to Table 2, when malonate, monothiomalonate and dithiomalonate are reacted with the electrophile of Formula 4, dithiomalonate is reacted with dibenzyl malonate and monothiomalonate It can be confirmed that a high reaction conversion ratio and an isomer excess value can be achieved even when a small amount of catalyst is used.
Specifically, in the case of using dibenzyl malonate as the reactant as shown in the results of Comparative Examples 1 to 3, even when the catalyst was used in an amount of 0.5 mol% and 10 mol%, reaction conversion of 17% and 39% , And when the catalyst was used in an amount of 0.1 mol%, the reaction did not proceed at all. In the case of using monothiomalonate as the reactant as shown in the results of Comparative Examples 4 and 5, the reaction conversion ratio (1: 1 dr) of 88% and 99%, 99% (1: 1 dr) and 75% and 79% isomer excess, respectively, at the catalyst usage of 0.1 mol%.
On the contrary, when dithiomalonate was used as the reactant as shown in the results of Examples 42 and 43, both the reaction conversion rate of> 99% and the 99% isomerization rate in both 0.5 mol% and 0.1 mol% An excess value could be obtained.
Therefore, when dithiomalonate is used as the reactant for the N-protected-imine contained in the general formula (4) as in the present invention, compared with the case of using malonate or monothiomalonate as the reactant A remarkably high reaction conversion ratio and high stereoselectivity can be achieved.
≪ Comparative Examples 6 to 10 and Examples 44 to 46 >
In order to compare the reactivity with the reactants, experiments were conducted in which malonate, monothiomalonate and dithiomalonate were reacted with N-protected-alpha-amidosulfone of formula (5), respectively.
[Comparative Example 6]
0.55 mmol of the dibenzylmalonate compound of Formula 7, 0.50 mmol of N-protected-alpha-amidosulfone of Formula 5-4, 10 mol% of the organic catalyst of Formula 1-1 and 0.75 mmol of Na 2 CO 3 were dissolved in dichloromethane 1.0 mL and a saturated aqueous solution of NaCl (5.0 mL), and the mixture was stirred at 0 ° C for 24 hours to synthesize a product of the formula (11). Subsequently, the mixed solution was extracted with dichloromethane and distilled water. The obtained organic layer was washed with water using MgSO 4 and filtered. The solvent was removed under reduced pressure, and 1 H NMR integration was used to measure the conversion of the product to the formula (11) .
(11)
[Comparative Example 7]
0.55 mmol of the dibenzylmalonate compound of Formula 7, 0.50 mmol of N-protected-alpha-amidosulfone of Formula 5-5, 10 mol% of the organic catalyst of Formula 1-1 and 0.75 mmol of Na 2 CO 3 were dissolved in dichloromethane 1.0 mL and a saturated aqueous solution of NaCl (5.0 mL), and the mixture was stirred at 0 ° C for 24 hours to synthesize a product of the formula (11). Subsequently, the mixed solution was extracted with dichloromethane and distilled water. The obtained organic layer was dehydrated using MgSO 4 and filtered. The solvent was removed under reduced pressure, and the conversion of the product to the formula (12) was measured using 1 H NMR integration.
TLC (EtOAc / hexanes, 1: 2 v / v ): Rf = 0.51; 1 H NMR (500 MHz, CDCl 3) δ 7.32 (m, 10H), 5.62 (d, J = 9.1 Hz, 1H), 5.17 (m, 4H), 4.99 (dd, J = 9.1, 4.2 Hz, 1H) , 4.25 (d, J = 4.2 Hz, 1H), 4.10 (m, 2H), 1.43 (s, 9H), 1.15 (t, J = 7.1 Hz, 3H); 13 C NMR (126 MHz, CDCl 3) δ 169.63, 167.45, 166.81, 155.40, 134.97, 128.58, 128.48, 128.45, 128.36, 128.34, 80.29, 67.78, 67.61, 62.12, 53.61, 52.85, 29.71, 28.24, 13.90; LR-MS (ESI) Calcd for [C 26 H 31 NO 8 + Na] + : 509.20 (100%); Found: 509 (100%); IR (KBr) :? 2919, 2849, 2580, 1735, 1498, 1457, 1368, 1346, 1261, 1098, 1082, 1054, 1046, 1025, 751, 741, 697 cm -1 .
Isomers excess value (enantiomeric excess,%) was determined via HPLC analysis (Chiralcel AD-H; hexanes / isopropyl alcohol = 90: 10; flow rate: 1.0 mL / min; 210 nm): t R = 24.4 min (major ), t R = 26.8 min; 62% ee ( S ).
[Chemical Formula 12]
[Comparative Example 8]
0.55 mmol of the dibenzylmalonate compound of Formula 7, 0.50 mmol of N-protected-alpha-amidosulfone of Formula 5-7, 10 mol% of the organic catalyst of Formula 1-1 and 0.75 mmol of Na 2 CO 3 were dissolved in dichloromethane 1.0 mL and a saturated aqueous solution of NaCl (5.0 mL), and the mixture was stirred at 0 ° C for 24 hours to synthesize a product of the formula (11). Subsequently, the mixed solution was extracted with dichloromethane and distilled water, and the obtained organic layer was filtered using MgSO 4 to remove moisture, and the solvent was removed under reduced pressure. The reaction conversion to the product, Formula 13, was measured using 1 H NMR integration .
[Chemical Formula 13]
[Comparative Example 9]
0.50 mmol of the monothiomalonate compound of Formula 9, 0.50 mmol of N-protected-alpha-amidosulfone of Formula 5-4, 1 mol% of the organic catalyst of Formula 1-1 and 0.75 mmol of Na 2 CO 3 were dissolved in dichloromethane 1.0 mL of methane and 5.0 mL of a saturated aqueous solution of NaCl, and the mixture was stirred at 0 ° C for 24 hours to synthesize a product of formula (11). Subsequently, the mixed solution was extracted with dichloromethane and distilled water. The obtained organic layer was filtered using MgSO 4 to remove water, and the solvent was removed under reduced pressure, and the conversion of the resulting product to the formula (14) was measured using 1 H NMR integration.
[Chemical Formula 14]
[Comparative Example 10]
0.50 mmol of the monothiomalonate compound of Formula 9, 0.50 mmol of N-protected-alpha-amidosulfone of Formula 5-7, 1 mol% of the organic catalyst of Formula 1-1 and 0.75 mmol of Na 2 CO 3 were dissolved in dichloromethane 1.0 mL of methane and 5.0 mL of a saturated aqueous solution of NaCl, and the mixture was stirred at 0 ° C for 24 hours to synthesize a product of formula (11). Subsequently, the mixed solution was extracted with dichloromethane and distilled water. The obtained organic layer was removed with water using MgSO 4 , the solvent was removed under reduced pressure, and the reaction conversion to the product, Formula 15, was measured using 1 H NMR integration.
[Chemical Formula 15]
[Example 44]
0.55 mmol of the dithiomalonate compound of Formula 3-1 wherein R 1 is benzyl and R 2 is hydrogen, 0.50 mmol of N-protected-alpha-amidosulfone of Formula 5-4, 1.0 mol% of Na 2 CO 3 and 0.75 mmol of Na 2 CO 3 were dissolved in a mixed solution of 1.0 mL of dichloromethane and 5.0 mL of a saturated aqueous solution of NaCl and stirred at 0 ° C for 72 hours to obtain N -protected-beta-amino-di Thioester was synthesized.
Isomers excess value (enantiomeric excess,%) was determined via HPLC analysis (Chiralpak IA; hexanes / isopropyl alcohol = 90: 10; flow rate: 1.0 mL / min; 210 nm): t R = 24.2 min (major), t R = 30.2 min; 94% ee ( R ).
[Example 45]
0.55 mmol of the dithiomalonate compound of Formula 3-1 wherein R 1 is benzyl and R 2 is hydrogen, 0.50 mmol of N-protected-alpha-amidosulfone of Formula 5-5, 1.0 mol% and 0.75 mmol of Na 2 CO 3 were dissolved in a mixed solution of 1.0 mL of dichloromethane and 5.0 mL of a saturated aqueous solution of NaCl, and the mixture was stirred at 0 ° C for 72 hours to obtain N -protected-beta-amino-di Thioester was synthesized.
Isomers excess value (enantiomeric excess,%) was determined via HPLC analysis (Chiralcel OD-H; hexanes / isopropyl alcohol = 70: 30; flow rate: 1.0 mL / min; 210 nm): t R = 9.0 min, t R = 15.3 min (major); 92% ee ( S ).
[Example 46]
0.55 mmol of the dithiomalonate compound of Formula 3-1 wherein R 1 is benzyl and R 2 is hydrogen, 0.50 mmol of N-protected-alpha-amidosulfone of Formula 5-7, 1.0 mol% of Na 2 CO 3 and 0.75 mmol of Na 2 CO 3 were dissolved in 1.0 mL of dichloromethane and 5.0 mL of a saturated aqueous solution of NaCl and the mixture was stirred at 0 ° C for 72 hours to obtain an N -protected-β-amino-dithioester Were synthesized.
Isomers excess value (enantiomeric excess,%) was determined via HPLC analysis (Chiralcel OD-H; hexanes / isopropyl alcohol = 90: 10; flow rate: 1.0 mL / min; 210 nm): t R = 10.3 min, t R = 13.6 min (major); 95% ee ( R ).
<Experimental Example>
Table 3 shows the results of measuring the reaction conversion ratio and enantiomer ratio according to the reactants, products and reaction conditions (catalyst, solvent, temperature and stirring time) of Comparative Examples 1 to 5 and Examples 40 and 41.
(mol%)
( 1 H NMR,%)
(enantiomeric excess,%)
3-1
3-1
3-1
Referring to Table 3, when reacting malonate, monothiomalonate and dithiomalonate with an alkyl substituted electrophile in Formula 5, a high reaction conversion and high isomer excess can be achieved can confirm.
Specifically, when the dibenzylmalonate compound represented by the formula (7) and the N-protected-α-amidosulfone contained in the formula (5) were reacted, the reaction did not occur in Comparative Examples 6 and 8, and 16% The reaction conversion rate was shown. When the monothiomalonate compound represented by the formula (9) and the N-protected-alpha-amidosulfone contained in the formula (5) were reacted, the reaction conversion rate was <1% as shown in Comparative Examples 9 and 10 .
On the other hand, in the case of reacting the dithiomalonate contained in the formula 3 with the N-protected-α-amidosulfone contained in the formula 5 as in the present invention, the yields of 81% and 95% % And 71%, and an isomer excess of 94%, 92% and 95%, respectively.
Therefore, when dithiomalonate is used as the reactant for the N-protected-alpha-amidosulfone contained in the general formula (5) as in the present invention, malonate or monothiomalonate is used as the reactant It can be confirmed that a remarkably high reaction conversion ratio and high stereoselectivity can be achieved.
According to the present invention described above, it is possible to produce dithiomalonate, an N-protected-imine or an N-protected-alpha-dicarboxylic acid in the presence of an organic solvent or a chiral catalyst which can be easily synthesized from a natural product in a mixed solution of an organic solvent and an aqueous solution. The chiral N-protected beta-amino dithioesters of various structures can be synthesized with very high enantiomeric selectivity by reacting asymmetrically with amidosulfone. Meanwhile, various chiral N-protected beta-aminodithioesters prepared through the present invention can be used to synthesize stereochemically or pharmaceutically useful chiral compounds according to conventional processes.
It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the spirit or scope of the present invention as defined by the following claims. It can be understood that it is possible.
Claims (24)
[Chemical Formula 1]
(2)
(3)
[Chemical Formula 4]
[Chemical Formula 6]
In the above Chemical Formulas 1 and 2, R includes an ethyl group or a vinyl group, R 'includes hydrogen or a methoxy group, n is 0 or 1, Ar is a carbon number An aryl group having 6 to 16 carbon atoms,
Wherein R 1 is one of an alkyl group having 1 to 12 carbon atoms, an aryl group having 6 to 16 carbon atoms, and a benzyl group having 7 to 17 carbon atoms, and R 2 is selected from the group consisting of hydrogen and an alkyl group having 1 to 12 carbon atoms And R 3 is one of an alkyl group having 1 to 30 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, an aryl group having 6 to 20 carbon atoms, and a heteroaryl group having 4 to 10 carbon atoms, and R 4 is an amine protecting group.
[Chemical Formula 1]
(2)
(3)
[Chemical Formula 5]
[Chemical Formula 6]
In the above Chemical Formulas 1 and 2, R includes an ethyl group or a vinyl group, R 'includes hydrogen or a methoxy group, n is 0 or 1, Ar is a carbon number An aryl group having 6 to 16 carbon atoms,
Wherein R 1 is one of an alkyl group having 1 to 12 carbon atoms, an aryl group having 6 to 16 carbon atoms, and a benzyl group having 7 to 17 carbon atoms, and R 2 is selected from the group consisting of hydrogen and an alkyl group having 1 to 12 carbon atoms And R 3 is one of an alkyl group having 1 to 30 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, an aryl group having 6 to 20 carbon atoms, and a heteroaryl group having 4 to 10 carbon atoms, and R 4 is an amine protecting group.
Wherein Ar is 3,5-bis (trifluoromethyl) benzene (C 8 H 4 F 6) , ortho-toluene (C 7 H 8), meta-toluene (C 7 H 8), p-vinyl benzene (C 10 H 10), comprising one selected from the group consisting of 1-naphthalene (C 10 H 8), 2- naphthalene (C 10 H 8), phenyl (C 6 H 5), and pyrenyl (C 16 H 9) ≪ / RTI >
Wherein the bifunctional chiral catalyst compound of Formula 1 comprises at least one member selected from the group consisting of compounds represented by the following Formulas 1-1 to 1-8:
[Formula 1-1]
[Formula 1-2]
[Formula 1-3]
[Formula 1-4]
[Formula 1-5]
[Chemical Formula 1-6]
[Chemical Formula 1-7]
[Chemical Formula 1-8]
Wherein the bifunctional chiral catalyst compound of Formula 2 comprises at least one member selected from the group consisting of compounds represented by the following Formulas 2-1 to 2-6:
[Formula 2-1]
[Formula 2-2]
[Formula 2-3]
[Chemical Formula 2-4]
[Chemical Formula 2-5]
[Chemical Formula 2-6]
In Formula 3, R 1 is an alkyl group having 1 to 12 carbon atoms which is substituted or unsubstituted with at least one functional group selected from the group consisting of an alkyl group having 1 to 12 carbon atoms, an alkoxy group having 1 to 12 carbon atoms, a halogen and a nitrile, An aryl group having 1 to 16 carbon atoms and a benzyl group having 7 to 17 carbon atoms, and R 2 is at least one selected from the group consisting of an alkyl group having 1 to 12 carbon atoms, an alkoxy group having 1 to 12 carbon atoms, a halogen atom and a nitrile group Or a substituted or unsubstituted alkyl group having 1 to 12 carbon atoms or hydrogen. A process for producing an aminodithioester compound.
Wherein the dithiomalonate compound of formula (3) comprises at least one compound selected from the group consisting of compounds represented by the following formulas (3-1) to (3-6).
[Formula 3-1]
[Formula 3-2]
[Formula 3-3]
[Chemical Formula 3-4]
[Formula 3-5]
[Chemical Formula 3-6]
In Formula 4, R 3 is an alkyl group having 1 to 30 carbon atoms which is unsubstituted or substituted with at least one functional group selected from the group consisting of an alkyl group having 1 to 12 carbon atoms, an alkoxy group having 1 to 12 carbon atoms, a halogen and a nitrile, A cycloalkyl group having 3 to 6 carbon atoms, an aryl group having 6 to 20 carbon atoms, and a heteroaryl group having 4 to 10 carbon atoms. The method for producing an aminodithioester compound according to claim 1,
Wherein the imine compound of formula (4) comprises at least one compound selected from the group consisting of compounds represented by the following formulas (4-1) to (4-12): < EMI ID =
[Formula 4-1]
[Formula 4-2]
[Formula 4-3]
[Formula 4-4]
[Formula 4-5]
[Formula 4-6]
[Formula 4-7]
[Formula 4-8]
[Chemical Formula 4-9]
[Formula 4-10]
[Formula 4-11]
[Formula 4-12]
In Formula 5, R 3 is a substituted or unsubstituted alkyl group having 1 to 12 carbon atoms, an alkoxy group having 1 to 12 carbon atoms, a halogen and a nitrile group, An alkyl group having 1 to 30 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, an aryl group having 6 to 20 carbon atoms, and a heteroaryl group having 4 to 10 carbon atoms. The amino dithioester ≪ / RTI >
Wherein the alpha-amidosulfone compound of formula (5) comprises at least one compound selected from the group consisting of compounds represented by the following formulas (5-1) to (5-9):
[Formula 5-1]
[Formula 5-2]
[Formula 5-3]
[Formula 5-4]
[Formula 5-5]
[Formula 5-6]
[Formula 5-7]
[Formula 5-8]
[Formula 5-9]
The reaction of the dithiomalonate compound of Formula 3 with the imine compound of Formula 4 or the alpha-amidosulfone compound of Formula 5 occurs in a solvent,
Wherein the solvent is an organic solvent, an aqueous solution, or a mixed solution thereof.
Wherein the organic solvent comprises at least one selected from the group consisting of dichloromethane, chloroform, toluene, tetrahydrofuran, acetone and ethyl acetate,
Wherein the aqueous solution comprises water or an aqueous solution of sodium chloride (NaCl).
Wherein the solvent is dichloromethane alone or a mixed solution of dichloromethane and an aqueous sodium chloride solution is used as the solvent.
Reacting the dithiomalonate compound of Formula 3 with the imine compound of Formula 4 or the alpha-amidosulfone compound of Formula 5 in the solvent in the temperature range of -80 to 60 ° C. A method for preparing a dithioester compound.
The bifunctional chiral catalyst compound of Formula 1 or Formula 2 is added in an amount of 0.1 to 100 mol% based on the imine compound of Formula 4 or the alpha-amidosulfone compound of Formula 5. [ ≪ / RTI >
The dithiomalonate compound of Formula 3 is used in an amount of 1 to 3 equivalents based on the imine compound of Formula 4 or the alpha-amidosulfone compound of Formula 5, ≪ / RTI >
[Chemical Formula 6]
Wherein R 1 is one of an alkyl group having 1 to 12 carbon atoms, an aryl group having 6 to 16 carbon atoms, and a benzyl group having 7 to 17 carbon atoms, R 2 is hydrogen or an alkyl group having 1 to 12 carbon atoms, An alkyl group having 1 to 30 carbon atoms or a cycloalkyl group having 3 to 6 carbon atoms, and R4 is an amine protecting group.
[Formula 6-1]
[Formula 6-2]
[Formula 6-3]
[Formula 6-4]
[Formula 6-5]
[Formula 6-6]
[Formula 6-7]
[Formula 6-8]
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| Title |
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| Angewandte Chemie International Edition, Vol.49, pp.3823-3826, 2010 |
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| RSC Advances, Vol. 3, pp.16349-16358, 2013 |
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