Fourth International Electronic Conference on Synthetic Organic Chemistry (ECSOC-4), www.mdpi.org/ecsoc-4.htm, September 1-30, 2000

[A0007]

Received: 24 July 2000 / Uploaded: 29 July 2000

INTRODUCTION
RESULTS
REFERENCES
COMMENTS
 

Oxazolidine moieties are widely recognized as very useful chiral auxiliaries in asymmetric reactions,¹ and chiral epoxides have been frequently involved in the design of strategies for the achievement of stereocontrol.²  However, only few examples reported in literature,³ combine the  influence in the same substrate of both epoxide and oxazolidine moieties, although in any case related with intramolecular reactions.
As a part of our ongoing research  program aimed at the synthesis of biologically relevant hydroxylated amino acids,⁴ we wish to report an easy strategy which allows the stereoselective preparation of 4,5-disubstituted oxazolidinones 5, based on the use of the homochiral epoxy oxazolidines derived from L-Serine, which could be precursors of b,g-dihydroxy-a-amino acids (Scheme 1).
 
 
 

RESULTS AND DISCUSSIONS

Alkenyl oxazolidines 2a-d were obtained starting from Garner´s protected aldehyde 1a  (R = tert-Bu) and its N-Cbz analogue 1b (R = Bn)⁵ by using the Wittig olefination standard procedure.⁶ Next, epoxidation of each olefin by treatment with MCPBA in dichloromethane, gave the corresponding threo 3a-d and erythro 4a-c, N-protected a-amino epoxides, with excellent stereoselectivities.⁷ The threo diastereomer was always favoured⁸ (in the epoxidation of 2d, the erythro isomer 4d, was not detected) and the resulting mixtures were conveniently separated by conventional column chromatography       (Scheme 2).
 
 

Addition of p-TSA to a solution of the threo amino epoxides 3a-d in anhydrous methanol at room temperature, afforded the corresponding cyclic carbamates 5a (R´ = H) and 5b (R´ = Me). According to the literature,⁹ tert-butyl carbamates 3a, 3c reacted faster and with higher yields than their benzyl analogues 3b, 3d  and in these cases, the oxazolidinones 5 were isolated with good to excellent yields (Scheme 3).
 
 
 

                                                                               Scheme 3
 

The key-step in the asymmetric synthesis of the oxazolidinones 5 is a fully regio- and stereoselective cyclocarbamation process through an intramolecular nucleophilic attack of the carbamate moiety on the C-a of the protonated epoxide under acidic conditions (Scheme 4). Such participation of a carbamate moiety had been observed in intramolecular epoxide opening under acidic conditions.^9,10 To the best of our knowledge this is the first example of an intramolecular nucleophilic epoxide opening reaction in 4-oxiranyl-oxazolidines.
 
 

                                                                               Scheme 4
 
 

The good results obtained in the case of compounds 3a-d, suggested a similar study with the erythro N,O-protected epoxide 4c. However, when compound 4c was submitted under the same conditions, failed to give the expected cyclic product 5, and compound 6 (Figure 1) was isolated, as a result of an intermolecular reaction with the methanol used as solvent .
 
 

                                                                                       Figure 1
 

Moreover, theoretical calculations have been performed in order to explain the faster intramolecular rearrangement towards the intermolecular displacement in the case of the threo compounds 3. Calculations were carried out using Gaussian94.¹¹ Geometries were fully optimized by ab initio calculations using restricted Hartree-Fock level of theory with  6-31G* basis sets. The structures were characterized as a minimun by a frecuency calculation and the RHF/6-31G* energies were corrected for unscaled zero point energies. The optimized structures are shown in Figure 2.
The different behaviour between 4c and 3c could be explained by the larger stability of the protonated epoxide 4c  in comparison with the protonated epoxide 3c ( relative stability of 14.59 Kcal/mol). Apparently, one reason for the intermolecular nucleophilic attack of the methanol in the case of the erythro compound 4c is the formation of an intramolecular hydrogen bonding between the carbonylic oxygen atom of tert-butoxy carbonyl group and the hydrogen of the protonated oxygen atom of the epoxide group (interatomic distance C=O^.......H-O , 1.498 Aº ). This hydrogen bonding unables the carbonyl group to act as a nucleophile.
The outcome of the reaction in the case of the threo epoxide 3c could be explained by the model  shown in Figure 2. In this case the absence of an intramolecular hydrogen bond places the N-Boc group in a such conformation that the nucleophilic attack by the carbonyl oxygen atom is highly favoured.
The natural bond population (NBO) analysis on the protonated epoxide 3c allows us to understand the total regioselection affording oxazolidinones 5a,b through a 5-exo mode cyclization. This calculations are in agreement with larger positive charge in C-a position ( C-a is 0.17 and C-b is 0.16) leading to the 5-exo closure pathway. Similar calculations performed on the protonated epoxide 4c revealed that the positive charge is larger on the C-b position ( C-a 0.12 and C-b 0.15) and the intermolecular nucleophilic attack occurs on the distal oxiranyl carbon atom (C-b) according to the literature.^{1a, 2}
 
 
 
 

            Protonated epoxide 3c                                                                                               Protonated epoxide 4c

                                                                                 Figure 2
 
 

CONCLUSIONS

In summary, treatment of threo amino epoxides 3a-d, with catalytic p-TSA in anhydrous methanol led to a highly regio- and stereoselective intramolecular epoxide opening reaction, affording cis-oxazolidinones 5 via a 5-exo-tet process. Theoretical calculations confirm the preference of intramolecular versus intermolecular nucleophilic attack in threo isomers 3a-d.
 

REFERENCES and NOTES

1.  a) Agami, C.; Couty, F.; Hamon, L.; Venier, O. J. Org. Chem. 1997, 62, 2106-2112. b) García-Valverde, M.; Pedrosa, R.; Vicente, M; García-Granda, S.; Gutierrez-Rodriguez, A. Tetrahedron,1996, 52, 10761-10770.

2. Nicolau, K. C.; Sorensen, E. J. Clasics in Total Synthesis; VCH: New-York, 1996

3. Azuma H.; Tamagaki, S.; Ogino, K.  J. Org. Chem. 2000, 65, 3538-3541. Moore, J.  W. Luzzio, F.A. . TetrahedronLett. 1995, 36, 6599-6602. Bernardi, A.; Cardani, S.; Scolastico, C.; Villa, R. Tetrahedron, 1990, 46, 1987-1998. Cardani, S.; Genari, C.; Scolastico, C.; Villa, R. Tetrahedron, 1989, 45, 7397-7404.

4. Jordá-Gregori, J.M.; González-Rosende, M.E.; Sepúlveda-Arques, J.; Galeazzi, R.; Orena, M. Tetrahedron: Asymmetry 1999,10, 1135-1143. Sepúlveda-Arques, J.; Armero-Alarte, T.; Acero-Alarcón, A.; Zaballos-García, E.; Yruretagoyena, Solesio, B.; Ezquerra-Carrera, J. Tetrahedron, 1996, 52, 2097-2102.

5 Garner, P.; Park, J. M. Org. Synth. Coll. Vol. IX  1998, 300. Dondoni, A.; Perrone, D. Synthesis 1997, 527-529.  McKillop, A.; Taylor, R. J. K. Watson, R. J.; Lewis, N. Synthesis1994, 31-33. Garner, P.; Park, J. M. J. Org. Chem. 1987, 52, 2361-2364.

6 Beaulieu, P.L.; Duceppe, J.-S.; Johnson, C. J. Org. Chem. 1991, 56, 4196-4204.

7 Moore, J. W. Luzzio, F.A. Tetrahedron Lett. 1995, 36, 6599-6602. Chiral oxiranyl derivative 3a by means of dimethyl sulfinium methylide epoxidation has been obtained in 55 % yield. Protected as the benzyloxy carbamate led only to 20 % of the desired oxirane.

8 Berkowitz, D. B.; Pedersen, M. L. J. Org. Chem. 1995, 60, 5368-5369. Diastereoselective peracid-mediated epoxidations have been reported. It is worthy of note that the most commly accepted model for hydroxyl- or carbamate –directed epoxidations attributes the threo diastereoselectivity usually observed to A(1,3) interactions present in the erythro transition state.

9 Vanucci, C.; Brusson, X.; Verdel, V.; Zana, F.; Dhimane, H.; Lhommet, G. Tetrahedron Lett.  1995,  36, 2971-2974

10 Urabe, H.; Aoyama, Y.; Sato, F. Tetrahedron 1992, 48, 5639-5646. Farr, R. A.; Holland, A. M.; Huber, E. W.; Peet, N. P. Weintraub, P. M., Tetrahedron 1994, 50, 1033-1040. Romeo, S.; Rich, D.H. Tetrahedron Lett. 1993, 34, 7187-7190.

11 Frisch, M.J.; Schelegel, H.B.; Gill, P.M.W.; Johnson, B.G.; Robb, M.A.; Cheeseman, J.R.; Keith, T.; Peterson, G.A.; Montgomery, J.A.; Raghavachari, K.; Al-Laham, M.A.; Zakrzewski, V.G.; Ortiz, J.V.; Foresman, J.B.; Cioloswki, B.B.; Stefanov, B.B.; Nanayakkara, A.; Challacombe, N.; Peng, C.Y.; Ayala, P.Y.; Chen, W.; Wong, M.W.; Andrés, J.L.; Replogle, E.S.; Gomperts, R.; Martín, R.L.; Fox, D.J.; Binkley, J.S.; Defrees, D.J.; Stewart, J.J.P.; Head-Gordon, M.; González, C.; Pople, J.A. GAUSSIAN 94, Revisión C.: Gaussian Inc.: Pittsburg, PA, 1995

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