Asymmetric synthesis of 4 H -1,3-dioxins and investigations in the metal catalyzed aziridination: aziridination versus insertion and stereoselective course

The asymmetric synthesis of highly enantiomerically enriched 5-methyl-4 H -1,3-dioxins by DIOP-and DuPHOS-modified nickel complexes via double-bond isomerization and metal catalyzed nitrogen transfer reactions to the resulting dioxins are reported. While Rh catalysis in the reaction of dioxins with nitrenes generated from PhI=NTs afforded insertion products 5 , the Cu(I) catalyzed reactions led to 4-methyl-1,3-oxazolidine-4-carbaldehydes 4 in an aziridination-rearrangement process with diastereoselectivities up to 73% de. Enantiomerically pure aldehydes 4 were obtained by crystallization of the diastereomeric mixture from TBME. A method for the determination of the diastereomeric excess in the intermediate aziridination step is described, and the absolute configurations of the ( S , S )- and ( R , R )-isomer, respectively, were established by X-ray crystallography.


Introduction
Aziridines, nitrogen analogues of epoxides, 1 have attracted great interest to chemists for years because of their easy transformation into pharmacological and biological active compounds, 2 their appearance as structural subunits in naturally occurring substances, 3 their antitumor and antibiotic activity, 4 or their use as precursors for chiral ligands, building blocks etc. 5 A variety of methods have been developed for the synthesis of aziridines. 6Among them, metal catalyzed nitrogen transfer processes to alkenes, 7,8 particularly metal catalyzed aziridinations using [N-(arenesulfonyl)imino]phenyliodinanes as nitrogen sources, 9 have intensively been studied. 10To obtain optimal yields, these reactions are often performed with a large excess of alkenes, and they are also often accompanied by insertion of a nitrene into activated C-H bonds.8q,11 More recently, the in situ generation of PhI=NTs and [N-(alkenesulfonyl)imino]phenyliodinanes have been reported, which avoid the tedious preparation of PhI=NTs 12 and extend the scope of this type of aziridination. 13n contrast to the aziridination of substituted alkenes, less is known about metal catalyzed nitrogen transfer processes to functionalized alkenes, e.g.enol ethers, glucals, silylketene acetals and others. 14In this case, the substrates are usually the limiting components of the reactions, and aziridines are often formed as intermediates, which directly rearrange to give aminated products.Only a few reports detail the isolation of aziridines derived from functionalized alkenes. 15e have previously reported the copper catalyzed aziridination of rac-5-methyl-4H-1,3dioxin 1a (R = isopropyl) with [N-(4-methylbenzenesulfonyl)imino]phenyliodinane, which leads to a diastereomeric mixture of N,O-protected α-methylserinal derivatives 4a in a single step. 16e assume, that the aziridination of 2 intermediately affords an aziridine 3, which immediately rearranges via ring opening / ring contraction to give diastereomeric oxazolidinecarbaldehydes 4 (Scheme 1).

Scheme 1
Since serinal derivatives 4 are useful precursors for the synthesis of α-alkylated α-amino acids bearing a quarternary chiral center attached to nitrogen, we investigated the stereochemical course of the aziridination of 2 starting with enantiomerically enriched compounds.In this context we also studied the asymmetric double bond isomerization of 1 using DIOP-and DuPHOS-modified nickel complexes.

Scheme 2
For the stereoselective synthesis of oxazolidinecarbaldehydes 4 starting with optically active dioxins 2, however, only the tert-butyl derivative 2b was available so far with high enantiomeric excess (92% ee). 17Therefore, we first studied the aziridination of the tert-butyl derivative 2b.
In contrast to the aziridination of 2a, the reaction of 2b proceeded very sluggishly.Diastereomers 4bA and 4bB were formed in < 10% yield, and only small amounts of insertion product 5b could be isolated as a single diastereomer from the crude reaction mixture.(Scheme To get more information about the product formation, we also investigated the aziridination of both 2a and 2b using rhodium catalysts. 18These reactions proceeded very smoothly, but only insertion products 5a,b were formed in good yields (79 -83%) as single diastereomers (Table 1, entries 3, 4). 19The reason for the high selectivity is still unclear. 19hen we turned our attention back again to the copper catalyzed aziridination and the asymmetric synthesis of the isopropyl derivative 2a.First, we investigated the asymmetric double-bond isomerization of 1a with DIOP-modified nickel complexes (Scheme 3). 20Under optimized conditions, the DIOP-modified nickeldibromo complex proved to be superior to the dichloro complex.[NiI 2 DIOP] exhibited no catalytic activity after activation with lithium triethylborohydride, probably due to the insolubility of the catalyst precursor in diethyl ether at -70°C.However, the [NiBr 2 (-)-DIOP]/LiBHEt 3 catalyzed isomerization of 1a in diethyl ether at -70°C afforded (S)-(-)-2a only with 30% ee (Table 2, entry 1).

Scheme 3
On the other hand, our findings in the asymmetric double bond isomerizations of dioxepins revealed, that improved enantioselectivities can be obtained using [NiI 2 (MeDuPHOS)] 21,22 instead of [NiBr 2 DIOP] as catalyst precursor. 23In fact, a significant improvement of the enantiomeric excess was achieved for the isomerization of 1a with [NiI 2 (MeDuPHOS)] in toluene at -20°C (Table 2, entry 2), and a slight enhancement of the enantiomeric excess was also observed for the isomerization of 1b under the same reaction conditions (Table 2, entry 5 and 6).

Table 2. Nickel catalyzed double-bond isomerization of 1a and 1b
Entry Product Catalyst a Solvent Temperature The copper(I) catalyzed aziridination of (S)-(-)-2a with (PhI=NTs) in acetonitrile at room temperature again afforded a 90:10 mixture of diastereomers 4aA and 4aB, but with respect to the diastereostereoselectivity of the intermediate nitrogen transfer step, the reaction proved to be unselective (Scheme 4; Table 3, entry 1).
We also investigated the aziridination of (S)-(-)-2a with PhI=NTs in different solvents (Table 3, entries 2-11).In dichloromethane, increasing amounts of insertion product 5a are formed, particularly at lower temperatures and low catalyst concentrations (Table 3, entry 3).With higher catalyst concentration at ambient temperatures the formation of 5a can be completely suppressed (Table 3, entry 11).With respect to the stereoselectivity of the aziridination step, no selectivity was observed.The reaction in acetone afforded nearly the same result as in acetonitrile (Table 3, entry 12).THF, which proved to be superior to other solvents in the epoxidation of dioxins 2, 24 is excluded because of preferred insertion of PhI=NTs into an activated C-H bond and formation of 7 (Scheme 5).8q However, we found that tert-butylmethyl ether (TBME) is a suitable substitute for THF.The Cu(I) catalyzed reaction of (S)-(-)-2a (92.7% ee) with PhI=NTs in TBME proceeded slower than in dichloromethane or acetonitrile, and increasing amounts of the minor diastereomer 4B were found, but for the first time we observed a moderate diastereoselectivity for the intermediate step (Table 3, entry 13).
On the other hand, recrystallization of diastereomer 4bB from TBME led to a crystalline material exhibiting a higher optical rotation than the starting material.After conversion of the crystalline solid into 6, only one diastereomer could be detected in the NMR spectra.The same crystalline material was also obtained by recrystallization of the amorphous solid of 4b from TBME.Obviously, (2S,4S)-4bB crystallizes from the diastereomeric mixture in an enantiomerically pure form.The enantiomeric purity was confirmed by X-ray crystallography, and the absolute configuration was established as the (2S,4S)-configuration (Figure 1A).The enantiomer (2R,4R)-(+)-4bB was readily prepared by isomerization of 1b using [NiI 2 (S,S)-(+)-MeDuPHOS)] as a precatalyst, Cu(I) catalyzed aziridination of (R)-(+)-2b with PhI=NTs in TBME and crystallization from TBME after separation of the catalyst, iodobenzene and byproducts by flash chromatography (Scheme 6).The absolute configuration of (2R,4R)-4bB was also confirmed by X-ray crystallography (Figure 1B). 25 The optical purity again emerged from transformation of (2R,4R)-(+)-4bB into (2R,4'R,5'R)-6, which in the NMR-spectra only showed signals of a single diastereomer.

Scheme 6
From the results described above we conclude, that attack of a nitrene or nitrenoid species derived from PhI=NTs preferentially attacks dioxin (S)-2b in TBME trans to the tert-butyl group in the 2-position (Scheme 7).The enhanced diastereoselectivity of the aziridination of tert-butyl substituted dioxin 2b may be reasoned by a more rigid conformation in comparison to isopropyl substituted dioxin 2a.We also assume, that the reversed A/B diastereomeric ratio results from the fact, that aziridination reactions of dioxins 2 in TBME occure at a slower rate than in acetonitrile or the other described solvents giving rise for prolonged times for rotation of the intermediate carboxonium ion.
In summary, diastereomers of oxazolidinecarbaldehydes 4b are prepared from readily available 5-methylene-1,3-dioxanes 1 in two simple steps: asymmetric double-bond isomerization and Cu(I) catalyzed aziridination in TBME.Enantiomerically pure compounds 4bB are obtained by recrystallization of the diastereomeric mixture from TBME.The diastereomeric excess of the intermediately formed aziridine (up to 73% de) can be determined by transformation of aldehydes 4b into the ring-opened acetals 6.Further investigations in the stereoselective course of the formation of insertion products 5 are in progress.

Experimental Section
General Procedures.Solvents were purified according to standard procedures.Analytical TLC was performed using silica gel 60 F254 plates.Column chromatography was performed using silica gel 60 (0.063-0.200 mm).Melting points are uncorrected and were measured in open glassware. 1H and 13 C NMR spectra were recorded on a Varian Unity INOVA 500 spectrometer.Chemical shifts are reported in ppm, coupling constants in Hz.Optical rotations were measured on a Perkin-Elmer 241 polarimeter in 1 cm or 10 cm cells.Microanalyses were carried out on a Vario El analyzer and were in good agreement with the calculated values.IR spectra were recorded on a Bio-Rad FTS 40a spectrometer.Mass spectra and high-resolution mass spectra were measured on a Finnigan LCQ Deca (ThermoQuest, San José, USA) and a micrOTOF (Bruker Daltonics, Bremen, D) with an Apollo TM "Ion Funnel" ESI-ion source, respectively.GC analysis for reaction control: Star 3400C (Varian), column 25 m x 0,25 mm, ID FS-OV-1-CB; GC analysis of the enantiomeric excess of 2a and 2b: GC 8000 Top Serie (CE Instruments), column 30 m x 0.32 mm ID, Rt-βDEXcst TM (Restek GmbH).

General procedure for [NiI 2 MeDuPHOS] catalyzed double bond isomerization of dioxanes (1)
[NiI 2 MeDuPHOS] (1.98 g, 3.2 mmol) was dissolved in anhydrous solvent at room temperature and activated with LiBHEt 3 (3.2mmol, 3.2 mL, 1M in THF).After cooling (reaction temperature is given in Table 2), a solution of 1 (32 mmol) in anhydrous solvent (25 mL) was added, and the mixture was left at this temperature in a deep freezer.The conversion of 1 was monitored by GC.After complete conversion, the mixture was allowed to warm up to room temperature and quenched with saturated NH 4 Cl solution (50 mL).The organic layer was separated and the aqueous layer was extracted 3 times with diethyl ether.The combined organic layers were dried (MgSO 4 ).After removal of the solvent, the residue was distilled in vacuo.Absolute configuration of the precatalyst, yields, sign of the optical rotation and enantiomeric excess of 2 are given in Table 2.  2, entry 6).The isomerization of 1a was performed according to the procedure for the [NiBr 2 (-)-DIOP] catalyzed isomerization of 1b (Table 2, entry 2). 17Yields and enantiomeric excess are given in Table 2 (entry 1).