Stereoselective Synthesis and Catalytical Application of Perillaldehyde-Based 3-Amino-1,2-diol Regioisomers

Abstract

A library of regioisomeric monoterpene-based aminodiols was synthesised and applied as chiral catalysts in the addition of diethylzinc to benzaldehyde. The synthesis of the first type of aminodiols was achieved starting from (-)-8,9-dihydroperillaldehyde via reductive amination, followed by Boc protection and dihydroxylation with the OsO₄/NMO system. Separation of formed stereoisomers resulted in a library of aminodiol diastereoisomers. The library of regioisomeric analogues was obtained starting from (-)-8,9-dihydroperillic alcohol, which was transformed into a mixture of allylic trichloroacetamides via Overman rearrangement. Changing the protecting group to a Boc function, the protected enamines were subjected to dihydroxylation with the OsO₄/NMO system, leading to a 71:16:13 mixture of diastereoisomers, which were separated, affording the three isomers in isolated form. The obtained primary aminodiols were transformed into secondary derivatives. The regioselectivity of the ring closure of the N-benzyl-substituted aminodiols with formaldehyde was also investigated, resulting in 1,3-oxazines in an exclusive manner. To explain the stability difference between diastereoisomeric 1,3-oxazines, a series of comparative theoretical modelling studies was carried out. The obtained potential catalysts were applied in the reaction of aromatic aldehydes and diethylzinc with moderate to good enantioselectivities (up to 94% ee), whereas the opposite chiral selectivity was observed between secondary aminodiols and their ring-closed 1,3-oxazine analogues.

Keywords: aminodiol; catalyst; chiral; diethylzinc; enantioselective; monoterpene; regioselective.

Scheme 1

Synthesis of BOC-protected aminodiols. (i) (1) 1.05 eq. R-NH₂ (R = a: CH₂Ph, b: CH(Me)Ph (S), c: CH(Me)(R)), dry EtOH, rt, 2 h; (2) 3 eq. NaBH₄, dry EtOH, rt, 2 h, 66–86%; (ii) Boc₂O, TEA, DMAP, THF; rt, 90–95%; (iii) 50% NMO/H₂O, cat. 2% OsO₄ in tert-BuOH, acetone/H₂O, rt, 2 h, 25–48%, 5:6 = 1:1.

Scheme 2

Preparation of aminodiol derivatives starting from 5a–c: (i) Et₂O, 18% HCl, overnight,, 82–88%; (ii) 10% Pd/C, n-hexane/EtOAc 1:2 mixture, 1 atm, H₂, rt, 5 h, 35%; (iii) R = Bn, 3 eq. LiAlH₄, THF, reflux, 6 h, 60%; (iv) 35% aq. CH₂O, Et₂O, rt, 3 h 70–96%.

Scheme 3

Preparation of aminodiol derivatives starting from 6a–c: (i) TFA, DCM, rt, 2 h, 78–97%; (ii) 10 % Pd/C, n-hexane/EtOAc 1:1 mixture, 1 atm, H₂, rt, 5 h, 45%; (iii) R = Bn, 3 eq. LiAlH₄, THF, reflux, 6 h, 58%; (iv) 35% aq. CH₂O, Et₂O, rt, 3 h—product could not be isolated.

Figure 1

Structural determination of aminodiol 7a by X-ray crystallography and NOESY experiments.

Figure 2

Calculated thermodynamic data of formaldehyde-mediated cyclisation reactions of diastereomeric aminodiols 7a and 14a.

Figure 3

Calculated thermodynamics of acid-promoted iminium-generating ring opening of O-protonated diastereomeric cyclohexane-fused 1,3-oxazines 10a/OH⁺ and 14a/OH⁺, as assumed to be effected during chromatographic workup on silica. The highly exothermic energetics disclosed for both ring-opening reactions analysed here clearly indicate that formaldehyde-mediated annulations cannot proceed via iminium intermediates.

Figure 4

Calculated kinetics and thermodynamics of the cyclisation of the ring-inverted N-hydroxymethyl derivative 11a taking place with the S_N2 reaction promoted by a cascade of proton shifts along the H-bond-connected cluster chain of four water molecules.

Scheme 4

Synthesis of the regioisomer allylamines via Overman rearrangement: (i) NaBH₄, MeOH, 0 °C to rt, 1 h, 95%; (ii) (1) CCl₃CN, dry DCM, DBU, Ar atm, 0 °C to rt, 2 h; (2) toluene, Ar atm, 130 °C, 24 h, 72%, de = 70% for 16a; (iii) (1) 5M NaOH/H₂O, EtOH/DCM 2/1, 50 °C, 15 h; (iv) Boc₂O, cat. DMAP, THF, TEA, rt, 12 h, 59%.

Figure 5

Structural determination of the diastereoisomers 18a and 18b by NOESY experiments.

Scheme 5

Dihydroxylation of the protected allylamine mixture (i) 50% NMO/H₂O, cat. 2% OsO₄ in tert-BuOH, rt, 72 h, 19a: 48%, 19b and 19c: 33%.

Scheme 6

Separation of 19b and 19c via formation of acetonides. Reactions and conditions: (i) (a) dry acetone, cat. PTSA, Ar atm, rt; (b) flash chromatography, 20b: 56%, 20c: 18%; (ii) 10% HCl, Et₂O, rt, 24 h, 21b: 86%, 21c: 80%.

Figure 6

Structural determination of diastereoisomers 21a–c by NOESY experiments.

Scheme 7

Preparation of aminodiol library. Reactions and conditions: (i) 3 eq. LiAlH₄, THF, rt, 2 h, 65%; (ii) 40% CH₂O, Et₂O, rt, 1 h, 66%; (iii) 10% HCl, Et₂O, rt, 24 h, 86%; (iv) (1) benzaldehyde, dry EtOH, rt, 2 h; (2) NaBH₄, EtOH, rt, 6 h, 54%; (v) 40% CH₂O sol., Et₂O, rt, 1 h, 89%.

Scheme 8

Synthesis of aminodiol library. Reaction conditions: (i) (1) PhCHO, dry EtOH, rt, 2 h; (2) NaBH₄, dry EtOH, rt, 6 h, 89% overall; (ii) 40% CH₂O, Et₂O, rt, 1 h, 80%.

Scheme 9

Model reaction of diethylzinc with benzaldehyde 26a. Reactions and conditions: (i) Et₂Zn, 10 mol% catalyst, n-hexane, Ar atm., rt, 20 h, 51–92%.

Scheme 10

Model reaction of diethylzinc with aromatic aldehydes. Reactions and conditions: Et₂Zn, 10 mol% catalyst, n-hexane, Ar atm., rt, 20 h, b: 4-MeC₆H₄, c: (4-MeO)C₆H₄, d: (3-MeO)C₆H₄, 80–90%.