1,3-Dipolar Cycloaddition of Diazomethane with a Chiral Azalactone: A Semiempirical Study

C. Cativiela, M. D. Díaz de Villegas, J. I. García and A. I. Jiménez

Departamento de Química Orgánica. Instituto de Ciencia de Materiales de Aragón. C.S.I.C.-Universidad de Zaragoza. E-50009 Zaragoza (España)

INTRODUCTION

alpha,beta-Didehydroamino acid derivatives are useful prochiral building blocks in synthetic organic chemistry. In particular, azlactones unsaturated in C4 have proved to be versatile intermediates in the synthesis of amino acids [1], cycloaliphatic [2] and cyclopropylamino acids [3]. Moreover, these compounds are easily transformed into N-acyl-alpha,beta-didehydroamino acid derivatives, which are powerful synthetic tools [4]. Our interest in the asymmetric synthesis of cyclopropylamino acids has prompted us to use a chiral azlactone as a synthetic precursor of these compounds and we have tested 1,3-dipolar cycloadditions of diazomethane with the chiral azlactone 1Z derived from glyceraldehyde in solvents of low polarity:

EXPERIMENTAL FACTS

The 2c / 2t ( cis/trans ) selectivity observed is about 80/20 in all cases, i.e. the 1,3-dipolar cycloaddition occurs with partial isomerization.
The diastereofacial selectivity obtained is about 90/10 for both 2c and 2t .
The absolute stereochemistry of the major compound (determined by X-ray analysis) indicates that the addition of diazomethane takes place to the C1-Re face of the double bond [5] .

THEORETICAL CALCULATIONS

Procedures

All the semiempirical calculations were carried out by means of the MOPAC 6.0 package [6]. Transition structures (TS) were located by using the Eigenvector Following algorithm (TS keyword). All the stationary points were fully characterized by testing the sign of the Hessian matrix eigenvalues, and the normal mode vibration corresponding to the only negative eigenvalue of the Hessian, in the case of TS.

Preliminary results. Conformational Analysis of 1Z

In a first approach, given that the 1,3-dipolar cycloadditions are known to have reagent-like transition states, it can be thought that the conformational preference of the dipolarophile is important in order to determine the stereochemical course of the reaction. This hypothesis has already been invoked in the case of the Diels-Alder reaction of 1Z with cyclopentadiene [7].

As can be seen in the above Figure , there is only a deep minimum in the rotation of the chiral auxiliary around the C1-C2 bond. This minimum corresponds to a conformation in which the chiral auxiliary shields the C1-Si face of the double bond, which is in agreement with the diastereofacial selectivity observed. However, this is a rather crude approach, since selectivity actually depends on the energy differences of the TS leading to the different products.

Theoretical Study of the Addition of Diazomethane to 1Z

It is generally accepted that ¹ pyrazolines are intermediates in the reactions of diazomethane with dipolarophiles to give cyclopropanes. Is some cases (but not in the present case) these pyrazolines can be isolated and characterized [8]. So, in an initial stage we examine the potential energy surfaces (PES) of the addition of diazomethane to 1Z to give the corresponding pyrazolines, by considering both the C1-Re and C1-Si approaches. The resulting PES indicated very asynchronous, but concerted, transition structures (TS_C1-Re and TS_C1-Si), which were further located using the TS keyword of the MOPAC program. The concertedness of this reaction path was confirmed by means of IRC calculations starting from both TS. The energy difference between both TS (9.91 kcal/mol, Table ) indicates an almost total diastereofacial selectivity, the attack of diazomethane proceeding through the C1-Re face of 1Z, in agreement with the observed stereochemistry of the reaction.

Given that in TS1 the C-N bond is very little formed, we examined a second, not concerted, reaction path, and we foud two more possible TS (TS2_C1- Re and TS2_C1- Si ), as well as two reaction intermediates (Int_C1-Re and Int_C1-Si ). The energy difference between both TS (8.52 kcal/mol, Table ) is also consistent with a high diastereofacial selectivity. However, the existence of non-cyclic intermediates allows the easy interconversion between Z and E isomers of the oxazolone, each isomer leading to different cyclopropanes (cis and trans, respectively). A rotational barrier of 5.20 kcal/mol from Int_C1-Re to IntE_C1-Re has been estimated by locating the corresponding rotational TS (TS_ct ).

The calculated reaction profile is summarized in this Scheme:

CONCLUSIONS

Two reaction paths can operate in the cycloaddition of diazomethane to 1Z. The first one is the classical concerted addition to give a pyrazoline intermediate. The second one is non-concerted and leads to non-cyclic intermediates.
For both reaction paths, the preferred addition of diazomethane takes place to the C1-Re face of the exocyclic double bond of 1Z. The energy differences between the corresponding TS indicates a high diastereofacial selectivity, in agreement with the experimental results. Also, the stereochemistry of the major compound is in agreement with the experimental observation.
The possibility of cis/trans isomerization exists through the non-cyclic intermediates Int_C1-Re and IntE_C1-Re, which explain the partial isomerization experimentally observed, leading to the appearance of 2t .

REFERENCES

[1]

J. Org. Chem.

J. Mol. Catal.

[2] (a) C. Cativiela, M. D. Diaz de Villegas, J. A. Mayoral, A. Avenoza, J. M. Peregrina, Tetrahedron, 49, 677 (1993). (b) C. Cativiela, M. D. Diaz de Villegas, A. Avenoza, J. M. Peregrina, Tetrahedron, 49, 10987 (1992).

[3] See for example: (a) S. W. King, J. M. Riordan, E. M. Holt, C. H. Stammer, J. Org. Chem., 47, 3270 (1982). (b) I. Arenal, M. Bernabe, H.. Fernandez-Alvarez, S. Penades-Ullate, Synthesis, 773 (1985). (c) J. Bland, A. Shah, A. Bortolusi, C. H. Stammer, J. Org. Chem., 53, 992 (1988).

[4] For a review see: U. Schmidt, A. Lieberknecht, J. Wild, Synthesis, 159 (1988).

[5] C. Cativiela, M. D. Diaz de Villegas, A. I. Jimenez, F. Lahoz, Tetrahedron Lett., 35, 617 (1994).,

[6] J. J. P. Stewart, MOPAC 6.0, QCPE 455.

[7] E. Buñuel, C. Cativiela, M. D. Diaz de Villegas, J. I. Garcia, Tetrahedron:Asymmetry, 5, 759 (1994).

[8] C. Cativiela, M. D. Diaz de Villegas, J. A. Mayoral, E. Melendez, J. Org. Chem., 50, 3167 (1985).

**Table.** Geometries (in pdb format) and energies of the calculated reaction intermediates and transition structures for the reaction between 1Z and diazomethane.
Geometry (.pdb file)	Heat of Formation (Kcal/mol)
TS_C1-Re	-8.96
TS_C1-Si	0.95
TS2_C1-Re	-8.36
TS2_C1-Si	-0.16
Int_C1-Re	-14.32
Int_C1-Si	-11.90
IntE_C1-Re	-13.85
TS_ct	-9.12