Synthesis , Resolution and Absolute Configuration of 2 , 3-Dihydro-2-Tert-Butyl-3N-Benzylquinazolin-4-One : A Possible Chiral Auxiliary for Synthesis of β-Amino Cyclohexancarboxylic Acid

3-Benzyl-2-(tert-butyl)-2,3-dihydroquinazolin-4(1H)-one rac-11 was resolved via the preparation of diastereomers with N-phthalyl-L-alanine chloride and its absolute configuration was determined by X-ray crystallographic analysis. This heterocycle has potential as a substrate chiral in asymmetric induction due to the steric effects of its tert-butyl group.

The present paper describes the synthesis and resolution of 2,3-dihydro-2-tert-butyl-3-N-benzylquinazolin-4-one rac-11 as a possible precursor of cis-and trans-2-aminocyclohexanecarboxylic acids.In this compound, it is important to mention that the tert-butyl group at C(2) adopts a pseudoaxial position, as shown by analysis of X-ray diffraction [10]- [12], and we would expect higher induction in asymmetric hydrogenation reaction: the ad-dition of the hydrogen on the syn face, leading to the exclusive formation of the only one diastereomer.
Our research was focused in the preparation of starting material following the methodology previously reported by our group [11]- [13] in which a reaction between isatoic anhydride and benzylamine in ethyl acetate at 40˚C results in the corresponding aminobenzamide 10 with 90% yield.Next, cyclocondensation of 10 with pivalaldehyde in dichloromethane and p-toluenesulfonic acid monohydrate gives (±)-2,3,dihydro-4(1H)-quinazolinone rac-11 at 86% yield (Scheme 3).
It is noteworthy that was necessary to protect the reaction from light source since this would suffer photoinduced elimination and hence reduces the yield of compound 11 [11].
The resolution was achieved by the preparation of the diastereomers 13a and 13b via condensation between the quinazolinone anion, formed with NaHMDS at −78˚C, and N-phthalyl-L-alanine chloride (S)-12 as the resoluting agent [14].Separation of the diastereomers was accomplished by flash chromatography from hexane/ AcOEt (Scheme 4).
The assignment of the absolute configuration of the main products was achieved by X-ray diffraction analysis with the diastereomer 13a (Figure 1).In this way, we were able to determine the relative configuration S at C(2) in the quinazolinone system for diastereomer 13a, and consequently the opposite configuration for diastereomer 13b.
It is important to mention that X-ray crystal-structure determinations used to elucidate the stereochemical outcome of 13a revealed a pseudoaxial disposition of the tert-butyl group at C(2) (consequence of a powerful A 1,3 effect) [15]- [21], which could directs higher induction in addition toward the face opposite to this group in the hydrogenation reaction, leading to the exclusive formation of a single diastereomer.
Finally, as shown in Scheme 5, conversion of diastereoisomers 13a and 13b to the enantiomerically pure quinazolinones (R)-11 and (S)-11, was completed by hydrolysis with Bu 4 N +− OH in 75 and 67% yield respectively.

Conclusion
In conclusion, we present a new method for the preparation of enantiomerically pure quinazolinones (R)-11 and (S)-11.The interest for these quinazolinones as intermediaries is given by their potential use in the formation of Scheme 1. Synthesis of octahydroquinazolinone diastereoisomers.β-amino cyclohexancarboxylic acids.Further studies to explore these quinazolinones as new chiral auxiliaries in the synthesis of β-amino acids are in progress.

Experimental
TLC: Merck-DC-F254 plates; detection by UV light.Flash column chromatography [22]: Merck silica gel (0.040 -0.063 mm).Mp: Mel-Temp apparatus; not corrected.Optical rotations were determined in a Perkin-Elmer 241 polarimeter at the sodium D-line. 1 H NMR spectra: Varian Oxford 400 MHz, 13 C NMR spectra: Varian Oxford 100 MHz.Chemical shifts (δ) in ppm downfield from the integral TMS reference; the coupling constants (J) in Hz.X-Ray: APEX-Bruker diffractometer.The structures were solved by direct methods using the program SHELXS [23].Flasks, stirring bars and hypodermic needles used for the generation and reactions of organolithiums were dried for 12 h at 120˚C and al-lowed to cool in a desiccator over anhydrous CaSO 4 .Anhydrous solvents were obtained by distillation from benzophenone ketyl.

Procedure for the Quinazolinone-11 Resolution
A solution of rac-11 in THF was cooled to −78˚C before slowly adding 1.1 mol equiv. of NaHMDS in hexane (1.0 M).The resulting solution was stirred at −78˚C for 10 min and treated successively with the resolution agent (N-phthalyl-L-alanine chloride) [12] [24].The mixture was stirred at the same temperature for 1 h and treated with saturated ammonium chloride solution and then with water.The aqueous phase was extracted with CH 2 Cl 2 .The combined extracts were dried (Na 2 SO 4 ), filtered and evaporated to give the crude product.Purification of the crude product was accomplished by flash chromatography (hexane/AcOEt) and then by recrystallization from hexane/AcOEt yielding the corresponding diastereomer.

Procedure for Remotion of the Resolution Agent
To the appropriate diastereomer in THF was added at 0˚C an excess of Bu 4 NOH solution under stirring for 12 h.The resulting mixture was concentrated at reduced pressure and purified by column chromatography (hex/AcOEt 50:50_0:10) to give the product as a white solid.