Diastereoselective Synthesis of γ-Amino Acids and Their Derivatives from Nitroethane via Intermediacy of 5,6-Dihydro-4H-1,2-oxazines Bearing the CH₂CH(CO₂Me)₂ Substituent at C3

 

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Abstract

Stereoselective two-step reduction of available 2-[(5,6-dihydro-4H-1,2-oxazin-3-yl)methyl]malonates provides an efficient route to derivatives of different γ-amino acids. The mechanism and stereochemistry of the first step, reduction of the C=N bond with sodium cyanoborohydride, is discussed.

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Our attempts to reduce the N-O bond [H₂ (75 bar), Raney nickel, 100 ˚C; H₂ (60 bar), 5% Pd/C, 100 ˚C; SmI₂, THF; COCl₂, NaBH₄, MeOH] in products 10 failed, therefore they could not be used in route c (Scheme  [³] ).

We were unable to obtain derivatives of 6 with carbamate-type protecting groups (Boc, Cbz), which are more easily cleaved, because under the applied reduction conditions tetrahydrooxazines 6 reacted neither with Boc₂O nor with CbzCl.

Attempts to reduce this substrate with Et₃SiH in TFA or TfOH; NaBH₄/AcOH; and Zn/AcOH were also unsuccessful: either no conversion of the starting material was observed or protonation of oxazine leading to the corresponding salt occurred (for details see the discussion of process 4, NaBH₃CN, AcOH, Scheme  [9] ).

Successful transformation 6h to 10h can be realized only by heating 6h in AcOH (see experimental part).

For similar processes in the hydrogenation of other 6-phenyl-substituted 5,6-dihydro-4H-1,2-oxazines see ref. 3.

Reduction of iminium salt 15c to tetrahydrooxazine 6c is accompanied by the partial formation of oxime ether 4c (yield: 25%).

It is noteworthy, that according to NMR cation 15c and its precursor, dihydrooxazine 4c, have the same dominant conformation.

In the studies^²³ the stereochemistry of C-C coupling with six-membered cyclic nitronates possessing substitution at C5 was not examined. The stereochemical course the reduction of some 5-substituted dihydrooxazines with NaBH₃CN^¹0 can be also rationalized in terms of proximal approach of the reducing agent to the cation intermediate.

An example of such a process is discussed in ref. 23a.