Preparation of β -amino-alcohol analogs by the addition of N, O-and S-containing substituents to ferrocenyl-camphorsulfonamide – ligands for enantioselective addition of diethylzinc to benzaldehyde

The synthesis of 2-exo -hydroxy-3-ferrocenemethylidene-10-sulfonamido-camphane derivatives with 2-endo - positioned heterocyclic substituents was realized through addition reactions of N, O, and S-containing organolithium reagents. These chiral β -heteroatom- containing alcohols were found to catalyze effectively the addition Et 2 Zn to benzaldehyde with up to 76% degree of enantioselectivity.


Introduction
The synthesis of chiral amino-alcohols, first reported by Oguni and Omi, 1 to catalyze enantioselectively the addition of diorganozinc compounds to aldehydes, still attracts considerable interest due to the utility of the secondary alcohols formed by this reaction. 1,2][3] One of the most potent amino-alcohols used as a catalyst is the dimethylamino-isoborneol investigated by Noyori. 4Therefore the large number of efforts for synthesis of ligands containing the bicyclic camphene core is highly justified.In recent years, a large variety of amino-alcohols starting from camphor, 5 fenchone, 5d-i, 6 camphor-10-sulfonamides 7 and similar chiral compounds 8 have been prepared and used as catalysts.
It is important to point out that chiral amino-alcohols have been applied as chiral catalysts in several different type of chemical reactions, e.g., hydride reductions, nucleophile additions to carbonyl compounds, aldol reactions, Diels-Alder reactions, and also as auxiliaries for synthesis

Scheme 1
The ferrocene-substituted camphor derivative 4a was used as starting compound for addition reactions of heteroatom-substituted organolithiums (Scheme 2).The organolithium compounds 5 and 7-9 were generated in situ by known procedures, 11 and the ketone 4a was added at appropriate temperature.The desired hydroxy derivatives 10 and 12-14 were isolated in moderate to very good yields after column chromatography.Compound 11 was synthesized by a published procedure. 12This procedure (addition of n-BuLi to a mixture of 4a and 2-bromopyridine at -80°C) is expected to give better yields than that in which 2-lithiopyridine is generated in situ prior to the addition reaction.5d In the present case we could obtain 11 in 47% yield (after column chromatography) together with unchanged 4a (18%) and 5% of the addition product of n-BuLi to 4a. 13

Scheme 2
The endo-position of the substituents was proved by NOESY spectra through the observed proximities of H-atoms from the heterocyclic moiety in compounds 10-14 with the endopositioned protons of the bicyclic core (Figure 1).Besides, the observed proximity of the other protons indicates the rigid structure of the compounds.The position of the unsubstituted Cp-ring is arbitrary, since there are no Cp-proton proximities observed.
The 13 C-signals of compounds 2, 4 and 10-14 are listed in Table 2.The assignments for quaternary C-atoms C(2)-C(13), C(3)-C(2') and for C(14)-C(17) are tentative, due to a significant overlap of signals in the latter case.
The compounds 10-14 were applied as ligands (3 mol.%) for the enantioselective addition of Et 2 Zn to benzaldehyde (Table 1) according to the published procedure. 5,6igure 1   The yields of the isolated 1-phenyl-1-propanol were in all cases excellent.The observed enantioselectivities were low to moderate.Comparison of 11 with the published results for 2endo-pyridyl-isoborneol (observed 41% ee R) 5d shows, however, that there is a lowering of the enantioselectivity with formation of the S-enantiomer.In all cases, the use of toluene as solvent In conclusion, a practical synthesis of new chiral β-heteroatom-containing hydroxy camphene derivatives has been realized.These compounds used as ligands catalyzed the addition of Et 2 Zn to benzaldehyde with moderate enantioselectivity.

Experimental Section
General.Reactions were carried out in flame-dried Schlenk flasks under an argon atmosphere.THF and Et 2 O were distilled over sodium-benzophenone.Hexane and toluene were distilled over Na(Et 4 Al).Thin layer chromatography (TLC) used aluminum sheets pre-coated with silica gel 60 F 254 (Merck).Column chromatography was carried out at normal pressure, using silica gel 60 (0.040-0.063 mm, 230-400 mesh ASTM, Merck).Melting points were determined in capillary tubes on an Electrothermal MEL-TEMP 1102D-230 VAC apparatus without corrections.Optical rotation [α] 20 D measurements were obtained using a Perkin-Elmer 241 polarimeter.Enantiomeric excesses were measured on a Shimadzu GC-17A gas chromatograph equipped with a chiral capillary column Cyclodex-β-I/P (L = 30 m, Ø = 0.38 mm, film thickness 0.25 µm) and flame ionization detector (FID).Mass spectra (MS) were recorded on a Hewlett Packard Mass Selective Detector 5973, and are reported as fragmentation in m/z with relative intensities (%).NMR spectra were recorded on Bruker Avance DRX-250 ( 1 H at 250.13 MHz; 13 C at 62.90 MHz) and Bruker Avance II+ 600 ( 1 H at 600.13 MHz; 13 C at 150.92 MHz) instruments with TMS as internal standard; samples for NOE difference experiments were prepared by blowing argon through the CDCl 3 solution of the corresponding compound.Elemental analyses were performed by the Microanalytical Laboratory for Elemental Analysis of the Institute of Organic Chemistry, Bulgarian Academy of Sciences.The following starting materials were commercially available: thiophene, furan, (+)-camphor-10-sulfonyl chloride, n-BuLi, benzofuran, diethylzinc (1 M solution in hexane), and gaseous Me 2 NH (from 40% aqueous solution) were obtained from Fluka probably; 1-ethylimidazole was from Merck and ferrocenecarboxaldehyde from Acros.

Enantioselective addition of dialkylzinc to aldehyde in presence of ligands 11-14. General procedure
To a solution of 6 ml hexane or toluene and ligand 11-14 (3 mol.%) Et 2 Zn (5.67 mmol of 1 M solution in hexane) was added dropwise at -10°C.The mixture was stirred for 30 min at -10°C and then PhCHO (2.83 mmol) was added at -20°C.The reaction was stirred at R.T. and monitored by TLC (petroleum: Et 2 O = 4:1) until the PhCHO was consumed.The mixture was quenched (aq.NH 4 Cl), extracted with Et 2 O (3×20 ml) and dried.After evaporation of the solvent the crude 1-phenyl-1-propanol was purified by column chromatography (petroleum/Et 2 O = 5:1).

Table
, owing to the higher solubility of the catalyst formed in situ by reaction of Et 2 Zn and the corresponding ligand.The best enantioselectivities were realized with ligands 12 and 13 possessing the furan heterocyclic moiety (Entry 3 and 4).

Table 2 .
13C NMR chemical shifts of compounds 2, 4 and 10-14 (CDCl 3 , 300 K, δ in ppm from TMS); assignments marked with asterisks are tentative a For the numbering of the bicyclic moiety see Scheme 2 and the following fragments: a