Catalytic asymmetric synthesis of chiral aziridines

Details Catalytic asymmetric synthesis of chiral aziridines Catalytic asymmetric synthesis of chiral aziridines

2000-03-17

2001-07-10

Powers, Fiona T. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S966000, C568S006000

Reexamination Certificate

active

06258960

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to the synthesis of chiral cis-aziridines (III) by reacting an imine (I) with a diazo compound (II) in the presence of a chiral vaulted biaryl-Lewis Acid complex.
Aziridines are versatile intermediates that have great value in organic synthesis.
1
A recent review on the asymmetric synthesis of aziridines reveals that nearly all non-racemic aziridines are made from other chiral materials.
2
Therefore, there is a need for the development of new methods for the asymmetric catalytic synthesis of aziridines.
Previous reports have focused on three different strategies to this problem. Most past effort has involved the transfer of a nitrene from [N-(p-toluenesulfonyl)imino]phenyl iodinane to an alkene mediated by a chiral metal catalyst which can result in the production of N-tosyl aziridines in good asymmetric inductions with certain alkene substrates.
3
An alternate method involves the transfer of a carbene to an imine which has been reported with a chiral copper catalyst
4a
and more successfully with a rhodium catalyst that was mediated by a chiral sulfur ylide.
4b
A third strategy arises from the recent observation that simple Lewis acids can catalyze formation of aziridines from ethyl diazoacetate and imines.
5,6
However, a screen of this reaction with a variety of chiral Lewis acids failed to produce aziridines with significant asymmetric induction.
5c
Despite these advances, there remains a need for a process for producing chiral aziridines.
BRIEF SUMMARY OF THE INVENTION
Accordingly, one aspect of the present invention is a process for producing chiral cis-aziridines.
These and other aspects of this invention, which will become apparent during the course of the following detailed description of the invention, have been discovered by the inventors. That is, the present inventors have discovered that a chiral vaulted biaryl-Lewis Acid complex can give very high asymmetric inductions in the formation of aziridines from the reaction of an imine (I) with a diazo compound (II).
DETAILED DESCRIPTION OF THE INVENTION
I. Definitions
“Alkyl” (or alkyl- or alk-) refers to a substituted or unsubstituted, straight, branched or cyclic hydrocarbon chain containing of from 1 to 20 carbon atoms. Preferred alkyl groups are lower alkyl groups, i.e., alkyl groups containing from 1 to 6 carbon atoms. Preferred cycloalkyls have from 3 to 10, preferably 3-6, carbon atoms in their ring structure. Suitable examples of unsubstituted alkyl groups include methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, iso-butyl, tert-butyl, sec-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl, and the like.
“Alkenyl” refers to a substituted or unsubstituted, straight, branched or cyclic, unsaturated hydrocarbon chain that contains at least one double bond and 2 to 20, preferably 2 to 6, carbon atoms. Exemplary unsubstituted alkenyl groups include ethenyl (or vinyl)(—CH═CH
2
), 1-propenyl, 2-propenyl (or allyl)(—CH
2
—CH═CH
2
), 1,3-butadienyl (—CH═CHCH═CH
2
), 1-butenyl(—CH═CHCH
2
CH
3
), hexenyl, pentenyl, 1,3,5-hexatrienyl, and the like. Preferred cycloalkenyl groups contain five to eight carbon atoms and at least one double bond. Examples of cycloalkenyl groups include cyclohexadienyl, cyclohexenyl, cyclopentenyl, cycloheptenyl, cyclooctenyl, cyclohexadienyl, cycloheptadienyl, cyclooctatrienyl and the like.
“Alkoxy” refers to a substituted or unsubstituted, —O-alkyl group. Exemplary unsubstituted alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, and the like.
“Alkynyl” refers to a substituted or unsubstituted, straight, branched or cyclic unsaturated hydrocarbon chain containing at least one triple bond and 2 to 20, preferably 2 to 6, carbon atoms.
“Aryl” refers to any monovalent aromatic carbocyclic group of 5 to 10 carbon atoms. The aryl group can be bicyclic (i.e. phenyl (or Ph)) or polycyclic (i.e. naphthyl) and can be unsubstituted or substituted.
“Amine” refers to an unsubstituted or substituted amino group. The amine can be primary (—NH
2
), secondary (—NHR) or tertiary (—NR
2
), where R is a substituent. Examples of substituted amino groups include methylamino, dimethylamino, ethylamino, diethylamino, 2-propylamino, 1-propylamino, di(n-propyl)amino, di(iso-propyl)amino, methyl-n-propylamino, t-butylamino, and the like.
“Halogen” (or halo-) refers to fluorine, chlorine, iodine or bromine. The preferred halogen is fluorine or chlorine.
“Heterocyclic” (Het or heterocyclyl) refers to a stable, saturated, partially unsaturated, or aromatic group containing 5 to 10, preferably 5 or 6, ring atoms. The ring can be substituted 1 or more times with a substituent. The ring can be mono-, bi- or polycyclic. The heterocyclyl group consists of carbon atoms and from 1 to 3 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. Examplary heterocyclyl groups include acridine, benzathiazoline, benzimidazole, benzofuran, benzothiapene, benzthiazole, benzothiophenyl, carbazole, cinnoline, furan, imidazole, 1H-indazole, indole, isoindole, isoquinoline, isothiazole, morpholine, oxazole (i.e. 1,2,3-oxadiazole), phenazine, phenothiazine, phenoxazine, phthalazine, piperazine, pteridine, purine, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, quinazoline, quinoline, quinoxaline, thiazole, 1,3,4-thiadiazole, thiophene, 1,3,5-triazines, triazole (i.e. 1,2,3-triazole), and the like.
“Inert atmosphere” refers to reaction conditions in which the mixture is covered with a layer of inert gas such as nitrogen or argon.
“Protecting group” refers to a group used to protect a heteroatom such as oxygen, nitrogen, sulfur or phosphorus from chemical reaction. For example, a O-protecting group is used to protect an oxygen heteroatom, such as in a hydroxy group, from reaction. Examples of O-protecting groups include t-butoxycarbonyl (Boc), t-butyl ether, benzyl ethers, and the like. Examples of N-protecting groups include carbobenzoyl (Cbz), fluorenylmethyloxycarbonyl (FMOC), nitropiperonyl, pyrenylethoxycarbonyl, nitroveratryl (NV), nitrobenzyl, and the like. Protecting groups are well known in the art, see for example, Protective Groups in Organic Synthesis, Peter G. M. Wuts (Editor), Theodora W. Greene, 3rd ed. (April 1999), Vch Pub.; Protective Groups in Organic Synthesis, Theodora W. Greene, Peter G. Wuts (Contributor), 2nd ed., (May 1991) John Wiley & Sons. Preferred protecting groups include, but are not limited to, the “Boc” protecting group, trialkyl silyl groups such as TBS (tert-butyldimethylsilyl, Si(CH
3
)
2
C(CH
3
)
3
), MEM, MOM, SEM, and THP.
“Substituted” means that the moiety contains at least one, preferably 1-3 substituent(s). Suitable substituents include hydrogen and hydroxyl, amino, oxy (—O—), thio (—S—), thiol, alkyl, alkenyl, alkynyl, halo, nitrile, nitro, silyl, aryl and heterocyclyl groups. These substituents can optionally be further substituted with 1-3 substituents. For example, substituted substituents include alkoxy, carbonyl, esters, ketones, carboxylic esters, sulfonyl, thionyl, carboxamide, alkylmercapto, alkylsulphonyl, alkylamino, dialkylamino, carboxylate, alkoxycarbonyl, alkylaryl, aralkyl, alkylheterocyclyl, and the like.
All other acronyms and abbreviations have the corresponding meaning as published in journals relative to the art of chemistry.
II. Process of the Present Invention
The process of the present invention comprises reacting an imine (I) with an diazo compound (II) in the presence of a catalyst to form a cis-aziridine product (III).
Imine (I) can be commercially obtained. Alternatively, such imines can be formed via a variety of known chemical reactions (See e.g. March, Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 3
rd
ed., John Wiley & Sons: New York, p. 1165, 1985).
In imine (I):
R
1
is hydrogen, substituted carbonyl, halo, secondary amino, tertiary amino, nitrile, nitro, alkyl, alkenyl, alkynyl, alkoxy, aryl or heterocyclyl groups. R
1
is preferably hydrogen, alkyl, alken

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