Resolution and Absolute Configuration of Some -Aminoacetals: En Route to Enantiopure

Resolution and absolute configuration of some -aminoacetals: en route to enantiopure N-protected -aminoaldehydes.

Amino Acids

Muriel Albalat-Serradeil,[a] Géraldine Primazot,[a] Didier Wilhelm,[a] Jean-Claude Vallejos,[b] Nicolas Vanthuyne,[b] and Christian Roussel*[b]

[a] CLARIANT France, Usine de Lamotte, L.R.A., F-60350 Trosly Breuil, France

[b] ISM2, Chirosciences, UMR 6263, 13397 Marseille CEDEX 20, France

*Corresponding author e-mail:

SupportingInformation

Resolution of racemic -aminoacetals 3

1.1.Screening of acidic resolving agent

For the resolution of compounds rac-3a and rac-3b, the most used and typical acidic resolving agents (Kozma 2002) such as (L)-(+)-tartaric acid (A), (D)-(+)-dibenzoyltartaric acid (B), (D)-(+)-camphor-10-sulfonic acid (C), (L)-(-)-di-p-toluyltartaric acid (D), (S)-(+)-mandelic acid (E) and (L)-(-)-N-tosylproline (F), were screened with rac-3a and rac-3b in various solvents, without success: no salt formation or no selectivity (Table 1).

Table 1: Resolution of rac-3a and rac-3b with various resolving agents

entry / resolving agent (mol.eq.) / rac-3 (mol.eq.) / solvent / operating conditions / yield (%)(a) / ee (%)(b)
1 / A (0.25) / 3a (1) / iPrOH (10%) / r.t. (24 h)
or reflux (1 h) / no salt
2 / A (0.25) / 3b (1) / iPrOH (10%) / reflux (1 h) / r.t. / 20 / 0
3 / B (0.25) / 3a (1) / MeOH (9.5%) / r.t. (24 h) / n.d. / 0
4 / C (1) / 3a (1) / CH3CN (25%) / r.t. (24 h) / no salt
5 / C (1) / 3b (1) / MeOH (9%) / r.t. (24 h) / no salt
6 / D (0.25) / 3a (1) / MeOH (13%) / r.t. (24 h) / no salt
7 / D (0.5) / 3a (1) / MeOH (16%) / r.t. (24 h) / n.d. / 0
8 / E (1) / 3a (1) / MeOH (9.6%) / r.t. (24h) / no salt
9 / E (0.5) / 3b (1) / cyclohexane (9.5%) / reflux / 6% / 0
10 / F (0.5) / 3b (1) / THF (17%) / reflux / 14% / 0

(a)Yield with respect to engaged rac-3. Determined after salt decomposition.

(b)Chiral HPLC analyses were led after salt decomposition on N-free compound for 3a, or on N-Cbz derivative for 3b.

1.2.Resolution and enantiomeric enrichment of racemic -aminoacetals 3

Some resolution and enrichment results for rac-3a-e with (L)- or (D)-5 (Huffman and Ingersoll 1951; Synge 1939; Fones 1952; Holland et al. 1953) are detailed in Table 2 (Scheme 1) (Albalat et al. 2009).

Scheme 1: Resolution of rac-3a-e with(L)- or (D)-5

Table 2: Resolution of rac-3a-d with(L)- or (D)-5

entry / resolving agent(a) / rac-3(a) / solvent / Operating conditions / Recrystallization R
Washing W / Yield(b)
(%) / ee(c)
(%) / Absolute configuration(d)
1 / (L)-5 / 3a / iPrOH (6%) / 50°C(3 h)/23°C / - / 74 / 78 / (R)
2 / (L)-5 / 3a / iPrOH (6%) / 50°C(3 h)/23°C / R 5.5%iPrOH / 38 / 95 / (R)
3 / (L)-5 / 3a / iPrOH (6%) / 50°C(3 h)/40°C(2 h)/23°C / R 5.5%iPrOH / 41 / 97 / (R)
4 / (L)-5 / 3a / iPrOH (6%) / 23°C(4 h)/50°C(3 h)/40°C(2 h 30)/23°C / R 5.5%iPrOH / 43 / 97 / (R)
5 / (L)-5 / 3a / iPrOH (9%) / 23°C / - / 76 / 27 / (R)
6 / (L)-5 / 3a / iPrOH (9%) / 50°C(3 h)/23°C / - / 60 / 89 / (R)
7 / (L)-5 / 3a / iPrOH (9%) / 50°C(3 h)/40°C(2 h)/23°C / L 5.5%iPrOH / 45 / 95 / (R)
8 / (D)-5 / 3a / iPrOH (6%) / 23°C(4 h 30)/50°C/23°C / - / 76 / 65 / (S)
9 / (D)-5 / 3a / iPrOH (6%) / 20°C(4 h)/50°C/40°C(2 h)/19°C / L 5.5%iPrOH / 48 / 91 / (S)
10 / (D)-5 / 3a / iPrOH (6%) / 50°C(3 h)/40°C(2 h)/19°C / R 5.5%iPrOH / 44 / 99 / (S)
11 / (L)-5 / 3b / acetone (6%) / 50°C(3 h)/19°C / R 7%iPrOH / 59 / 88 / (R)
12 / (L)-5 / 3b / iPrOH (6%) / 50°C(3 h)/18°C / R 5.5%iPrOH
R 5.5%iPrOH / 46
32 / 91 / (R)
13 / (L)-5 / 3b / acetone/iPrOH (87/13) (6%) / 50°C(3 h)/19°C / - / 85 / 61 / (R)
14 / (L)-5 / 3b / acetone/iPrOH (87/13) (6%) / 50°C(3 h)/19°C / R 7%iPrOH / 66 / 90 / (R)
15 / (L)-5 / 3b / acetone/iPrOH (87/13) (6%) / 50°C(3 h)/19°C / R 9%iPrOH
R 9%iPrOH / 66
57 / 96 / (R)
16 / (D)-5 / 3b / acetone/iPrOH (50/50) (6%) / 50°C(3 h)/19°C / R 7%iPrOH / 47 / 81 / (S)
17 / (D)-5 / 3b / acetone/iPrOH (87/13) (6%) / 50°C(3 h)/19°C / R 5%iPrOH / 58 / 82 / (S)
18 / (D)-5 / 3b / acetone/iPrOH (87/13) (9%) / 50°C(3 h)/19°C / R 5%iPrOH / 70 / 81 / (S)
19 / (D)-5 / 3b / acetone/iPrOH (87/13) (9%) / 50°C(3 h)/23°C / -
R 7%iPrOH
R 7%iPrOH / 91
61
51 / 96 / (S)
20 / (D)-5 / 3b / acetone/iPrOH (87/13) (9%) / 50°C(3 h)/22°C / -
R 9%iPrOH
R 9%iPrOH / 95
67
56 / 95 / (S)
21 / (L)-5 / 3c / iPrOH (9%) / 50°C(3 h)/24°C / - / 87 / 11 / (S)
22 / (L)-5 / 3c / iPrOH (9%) / 25°C(2 h)/50°C/35°C / -
R 5.5%iPrOH / 59
38 / 51
79 / (S)
(S)
23 / (L)-5 / 3c / iPrOH (6%) / 22°C(2 h)/50°C/30°C / -
R 5.5%iPrOH
R 5.5%iPrOH / 41
32
16 / 60
-
94 / (S)
(S)
24 / (L)-5 / 3c / iPrOH (6%) / 19°C(2 h)/50°C/30°C / -
R 3%iPrOH
R 3%iPrOH / 75
27
19 / -
85
96 / (S)
(S)
25 / (L)-5 / 3c / iPrOH (6%) / 28°C(2 h)/50°C/30°C / -
R 3%iPrOH
R 3%iPrOH / 44
18
9 / -
-
98 / (S)
26 / (D)-5 / 3c / iPrOH (6%) / 19°C(2 h)/50°C/30°C / -
R 3%iPrOH
R 3%iPrOH / 60
35
23 / -
-
96 / (R)
27 / (D)-5 / 3c / iPrOH (6%) / 28°C(2 h)/50°C/29°C / -
R 3%iPrOH
R 3%iPrOH / 48
18
11 / -
-
97 / (R)
28 / (L)-5 / 3d / iPrOH (9%) / 50°C(3 h)/26°C / - / 89 / 63 / (S)
29 / (L)-5 / 3d / iPrOH (6%) / 50°C(3 h)/25°C / -
R 5.5%iPrOH
R 5.5%iPrOH / 93
82
60 / -
91
97 / (S)
(S)
30 / (L)-5 / 3d / iPrOH (6%) / 50°C(3 h)/25°C / -
R 3%iPrOH
R 3%iPrOH / 94
62
56 / 56
94
98 / (S)
(S)
31 / (D)-5 / 3d / iPrOH (6%) / 50°C(3 h )/25°C / -
R 5.5%iPrOH
R 5.5%iPrOH / 94
78
70 / 65
92
97 / (R)
(R)
(R)

(a)Resolving agent/rac-3=0.5/1 (molar ratio)

(b)Yield with respect to limiting reactant (resolving agent). Determination after salt decomposition.

(c)Chiral HPLC analyses were led after salt decomposition on N-free compound for 3a, 3c and 3d or on N-Cbz derivative for 3b.

(d)For the assignment of the absolute configuration, see paragraph 2. in Supplementary Material.

Resolution of rac-3e with (L)-4 was also studied and some attempts led were detailed in Table 3 (Scheme 2).

Scheme 2: Resolution of rac-3e with(L)-4

Table 3: Resolution of rac-3e with(L)-4 (0,5mol.eq.)

entry / solvent / Operating conditions / Recrystallization R
Washing W / Yield(a)
(%) / ee(b)
(%) / Absolute configuration(c)
1 / acetone (3.6%) / 27°C(4 h)/reflux(1 h 30)/filtration(30°C) / - / n.d. / 30 / (R)
2 / acetone (3.6%) / 19°C(2 h)/reflux(1 h)/filtration(30°C) / - / 96 / 30 / (S)
3 / THF (3.6%) / 21°C(2 h)/56°C(1 h)/filtration(21°C) / - / 72 / 29 / (R)
4 / THF (3.6%) / 19°C(2 h)/reflux/filtration(30°C) / - / 88 / 45 / (S)
5 / THF/CH3CN (50/50) (3.5%) / 19°C(2 h)/reflux/filtration(30°C) / - / 64 / 27 / (R)
6 / THF/AcOEt (50/50) (3.5%) / 19°C(2 h)/reflux/filtration(30°C) / - / 88 / 32 / (S)
7 / THF/acetone (90/10) (3.5%) / 19°C(2 h)/reflux/filtration(19°C) / - / 95 / 39 / (S)
8 / THF/acetone (25/75) (3.5%) / 19°C(2 h)/reflux/filtration(25°C) / - / 95 / 31 / (S)
9 / THF/acetone (50/50) (3.5%) / 19°C(2 h)/reflux/filtration(25°C) / - / 96 / 43 / (S)
10 / THF/acetone (75/25) (3.5%) / 19°C(2 h)/reflux/filtration(25°C) / -
R 4%THF (66°C20°C)
R 4%acetone (66°C20°C) / 93
76
62 / 47
55
68 / (S)
(S)
(S)
11 / THF/acetone (75/25) (3.5%) / 19°C(2 h)/reflux/filtration(22°C) / -
R 4%THF/acetone (75/25)
2R 4% THF/acetone (75/25) / 93
-
32 / 50
78
91 / (S)
(S)
(S)
12 / THF/acetone (75/25) (3.5%) / 19°C(2 h)/  (62°C40°C / seeding /filtration(22°C) / W THF/acetone (75/25)
R 4%THF/acetone (75/25) + W 4% THF/acetone (75/25)
W 4% THF/acetone (75/25) / 70
21
6 / 23
84
94 / (S)
(S)
(S)

(a)Yield with respect to limiting reagent, (L)-4 (0.5mol.eq.), determined after salt decomposition.

(b)Chiral HPLC analyses were led after salt decomposition on N-Cbz carbamate derivative of 3e.

(c)For absolute configuration assignment, see paragraph 2. in Supplementary Material section.

Absolute Configuration Assignment

Optically pure chlorhydrate salt of α-aminoesters 10, were available in one absolute configuration at least (Fig. 1).

Fig. 1: Optically pure α-aminoesters chlorhydrate salt 10

The absolute configuration assignment process is reported in Scheme 3.

To assign the absolute configuration of the two enantiomers of 3a-e, the associated N-protected β-aminoalcohol 9a-e were synthesized on the one hand from optically pure α-aminoesters 10a-e (after N-Cbz protection step and metal hydride reduction), and on the other hand fromα-aminoacetals 3a-e as racemates and as optically enriched ones thanks to optical resolution step (see main text, Fig. 1) (after N-Cbz protection step, acetal function hydrolysis and metal hydride reduction).

Chiral HPLC was used as analytical support to check optically pure, optically enriched and racemic 9a-e (Table 4) (Zemlicka and Murata 1976; Guindon et al. 1992; Ito et al. 1975; Maeda et al. 1992; Nakamura et al. 2003; Herranz et al. 1978; Reddy and Sharpless 1998; O’Brien et al. 1998; Horwell et al. 1991; Li et al. 1996; Sharpless and Li 1997).

Scheme 3: General process for the absolute configuration assignment for aminoacetals 3a-e

Table 4: Chiral HPLC analysis conditions for compounds 9a-e

entry / product / R / Chiral HPLC analysis
1 / 9a / CH2Ph / Chiralpak AD hexane/iPrOH 90/10
(S)-(-) tR=12,9min (R)-(+) tR=15,6min
2 / 9b / iBu / Chiralpak AD hexane/iPrOH 90/10
(S)-(-) tR=7min (R)-(+) tR=9,9min
3 / 9c / CH2CH2Ph / Chiralcel OD-H hexane/iPrOH 90/10
(R)-(+) tR=22min (S)-(-) tR=26,3min
4 / 9d / Ph / Chiralcel OD-H hexane/iPrOH 90/10
(-) tR=15,8min (+) tR=17,6min
5 / 9e / cyclohexyl / Chiralcel OD-H hexane/iPrOH 90/10
(R)-(+) tR=8,3min (S)-(-) tR=9min

With this general process, the absolute configuration of each recovered enantiomer of aminoacetals 3a-c and 3e was determined. For compound 3d, special investigations were led because full racemization was observed during metal hydride reduction of optically pure N-benzyloxycarbonyl-(L)-phenylglycine methyl ester.

1-Cyclohexyl-2,2-dimethoxyethylamine 3ewas obtained from 3dby hydrogenation of the phenyl without significative racemization (Table 5). Since the absolute configuration for each enantiomer of 3e was known, it was possible to assign the absolute configuration of each enantiomer of 3d (Scheme 4).

Scheme 4: Process to assign the absolute configurations of each enantiomer of 3d

Table 5: Aromatic ring hydrogenation of 3d

entry / optical purity 3d(a) (%) / catalyst (%mass.) / solvent / PH2 (bars) / T (°C) / t (h) / conv.(b) (%) / optical purity 3e(c) (%)
1 / rac / 5%Rh/Al2O3
(50) / MeOH/AcOH (96/4) (9%) / 50b / 70-110°C / 11 h / 100
2 / 75%ee / 5%Rh/Al2O3
(24) / MeOH/AcOH (96/4) (18%) / 5b / rt
50°C / 84 h
26 h / 100 / 75%ee
3 / rac / 5%Rh/Al2O3
(10) / MeOH/AcOH (96/4) (17%) / 50b / 70-110°C / 19 h / 100
4 / rac / 5%Rh/C
(10) / MeOH/AcOH (96/4) (17%) / 50b / 70-110°C / 19 h / 100
5 / rac / 5%Ru/Al2O3
(10) / MeOH/AcOH (96/4) (17%) / 50b / 70-110°C / 17 h / 100
6 / rac / 5%Ru/C
(10) / MeOH/AcOH (96/4) (17%) / 50b / 70-110°C / 19 h / 100
7 / ee≥98% / 5%Ru/C
(3) / MeOH/AcOH (96/4) (20%) / 35b / 70-110°C / 14 h / 100(d) / ee97%
8 / ee≥98% / 5%Ru/C
(3) / MeOH/AcOH (96/4) (22%) / 35b / 70-110°C / 11 h / 100(d) / ee97%

(a)Determined by chiral HPLC analyses.

(b)Determined by 1H RMN analyses.

(c)Determined by chiral HPLC analyses after a N-Cbz protection step (compound 7e).

(d)Purification by distillation (Bp=106°C/5mmHg): yield3e=65% (with respect to 3d).

Table 6 gathered for all compounds 3a-e and 7a-e the chiral HPLC analysis conditions, the absolute configuration assignment of each enantiomer and optical rotation.

Table 6: Chiral HPLC analysis conditions for compounds 3a-e and 7a-e

entry / product / Chiral HPLC conditions / optical rotation
1 / 3a / Chiralcel OD-H hexane/iPrOH 90/10 v/v
(S)-(-) tR=5.6min (R)-(+) tR=6.5min / (S)-(-) [α]D25=-27.7 (c=1 in MeOH)
(R)-(+) [α]D25=+27.6 (c=1 in MeOH)
2 / 7a / Chiralcel OD-H hexane/iPrOH 90/10 v/v
(S)-(-) tR=7.5min (R)-(+) tR=10.7min / (S)-(-) [α]D25=-45.0 (c= 1 in MeOH)
(R)-(+) [α]D25=+44.9 (c= 1 in MeOH)
3 / 3b / (a) / (S)-(-) [α]D25=-20.4 (c= 1 in MeOH)
(R)-(+) [α]D25=+20.9 (c= 1 in MeOH)
4 / 7b / Chiralcel OD-H hexane/iPrOH 90/10 v/v
(S)-(-) tR=4.8min (R)-(+) tR=7.9min / (S)-(-) [α]D25=-34.9 (c= 1 in MeOH)
(R)-(+) [α]D25=+35.1 (c= 1 in MeOH)
5 / 3c / Chiralcel OD-H hexane/iPrOH 90/10 v/v
(S)-(-) tR=6.9min (R)-(+) tR=9.9min / (S)-(-) [α]D25 = -18.0 (c= 1 in MeOH)
(R)-(+) [α]D25 = +17.8 (c= 1 in MeOH)
6 / 7c / Chiralcel OD-H hexane/iPrOH 90/10 v/v
(S)-(-) tR=9.3min (R)-(+) tR=12.2min / (S)-(-) [α]D25 = -25.5 (c=0.4 in MeOH)
(R)-(+) [α]D25 = +26.0 (c=0.4 in MeOH)
7 / 3d / Chiralcel OD-H hexane/iPrOH 90/10 v/v
(S)-(+) tR=6.7min (R)-(-) tR=8.2min / (S)-(+) [α]D25=+9.1 (c= 1 in MeOH)
(R)-(-) [α]D25=-8.9 (c= 1 in MeOH)
8 / 7d / Chiralcel OD-H hexane/iPrOH 90/10 v/v
(S)-(+) tR=10.9min (R)-(-) tR=12min / (S)-(+) [α]D25=+6.7 (c= 1 in MeOH)
(R)-(-) [α]D25=-6.6 (c= 1 in MeOH)
9 / 3e / (a) / (S)-(+) 0[α]D251 (c=15 in MeOH)
(R)-(-) -1[α]D250 (c=15 in MeOH)
10 / 7e / Chiralcel OD-H hexane/iPrOH 90/10 v/v
(S)-(-) tR=5min (R)-(+) tR=6.8min / (S)-(-) [α]D25=-5.3 (c=1 in MeOH)
(R)-(+) [α]D25=+5.2 (c=1 in MeOH)

(a)Chiral HPLC analyses on the compounds 3b and 3e were led on the compounds 7b and 7e after a N-Cbz protection step.

Recycling of undesired enantiomer

Treatment of -aminoacetals 3a-b with aqueous hydrogen peroxide and catalytic sodium tungstate (Na2WO4.2H2O) at room temperature in a mixture of methanol and water, afforded the corresponding oximes 6a-b in good yields (70-90%) (Scheme5) (Kahr and Berther 1960; Kahr 1956; Synthese-Chemie G.m.b.H. 1956). The reduction of the oximes 6a-b was successfully accomplished using catalytic hydrogenation (20-50bar H2) with Raney nickel as catalyst in ethanol at room temperature (crude yield=75-90%) (Nielsen and Lies 1990; Paul 1937; Shivers and Hauser 1947; Ikeda et al. 1977).

Scheme5: Tandem oxidation and reduction to recycle the unresolved -aminoacetal 3 (Albalat et al. 2008)

Experimental

1H NMR and 13C NMR spectra were recorded on a Brücker AC200 or AC300 spectrometers in deuteriochloroform (CDCl3) or deuteriodimethylsulfoxide ([D6]DMSO). Coupling constants (J) are quoted in Hertz.

Gas chromatographic (GC) analyses were run on a Varian 3900 Gas Chromatograph (FID detector) (Chrompack, CP-SIL 8 CB-low bleed MS, 30 m*0,25 mm, 1 m): Tinjector=250 °C, Tdetector=300 °C, oven program: 80°C for 1 min, 80°C300°C (15°C/ min) and 300°C for 30 min.

GC-MS analyses were performed on a GC Varian 3500 gas chromatograph with an Automass 150 Unicam mass detector.

[]D were measured on a 241 MC Perkin-Elmer polarimeter with a sodium lamp and a double-jacked cell thermostated at 25°C.

Melting points were determined on a Kofler apparatus, and are uncorrected.

Chiral HPLC analyses were performed in the Dynamic Stereochemistry and Chirality Laboratory at PaulCezanneAix-MarseilleIIIUniversity. Experiments were run on a unit composed of a Merck D-7000 system manager, a Merck Hitachi L-6000 pump, a Merck Hitachi L-4000 UV-detector and a Jasco OR-1590 polarimeter.

Exact mass measurements were performed using ESI-MS premium LCP (Waters) device in the Mass Spectroscopy department of Clariant Analyses Central Service (Lamotte, France).

Solvents were from SDS (Peypin, France) or Riedel de Hahn, of anhydrous grade, pure for syntheses and analyses and used without further purification. Chemicals for reactions were used as purchased from commercial sources. Dimethoxyethanal (60% in water) was provided by Clariant France.

4.1.Benzyl-(2,2-dimethoxy-ethylidene)-amine 2 (Terinek and Vasella 2004)

A solution of dimethoxyethanal 1 (60% in water, 112.65 g, 0.65 mol) was dissolved in 200 mL toluene. One molar equivalent of benzylamine (69.65 g, 0.65 mol) was added at room temperature. The mixture was then strirred at ambient temperature for 4 h. After decantation, the organic phase was evaporated to dryness; yellow oil (128.8 g, quantitative yield); GC tR=13.2 min; 1H NMR (200MHz, CDCl3,25°C, TMS): 3.46 (s, 6H), 4.70 (s, 2H), 4.78 (d, J=4.4 Hz, 1H), 7.28-7.37 (m, 5H), 7.65 ppm (d, J=4.4 Hz, 1 H); 13C NMR (75 MHz, CDCl3,25°C, TMS): 54.06, 64.6, 103.2, 127.2, 128.5, 128.56, 138.2, 161.4 ppm.

4.2.General procedure for the reaction of benzyl-(2,2-dimethoxy-ethylidene)-amine 2 with Grignard reagent and for the synthesis of -aminoacetals 3

Benzyl-(2,2-dimethoxy-ethylidene)-amine 2 (1 equiv) was dissolved in toluene (0,7-1,3 mL /mmol) under N2 atmosphere and cooled to T[-20, 0]°C. At this temperatue, a Grignard reagent solution in Et2O or THF (3 equiv) was added dropwise at a rate of 250 mL /h. The reaction mixture was then stirred for 4 h at T[-20, 0]°C. A saturated aqueous ammonium chloride solution was slowly added and the resulting emulsion was extracted with toluene. The organic extracts were evaporated to dryness.

The crude residue was hydrogenated with 5%Pd-C (50%wet, 0.05 weight equiv) in MeOH (40-50% weight) under 15 to 40 b H2 at T[20, 80] °C for 4 to 24 h. After filtration over a celite pad, the filtrate was evaporated to dryness.

The crude residue was purified by a H+/OH- treatment and distillation.

4.2.1. 1-Benzyl-2,2-dimethoxyethylamine 3a (Gacek and Undheim 1974; Grobelny and Galardy 1986; Guillaumie et al. 2000)

rac-3a: Colorless oil (58.2g, 45%);b.p. 115-120°C /5mmHg; GC tR=13.65 min; 1H NMR (300MHz, CDCl3,25°C, TMS1.3 (s, 2H), 2.5 (m, 1H), 3 (m, 1H), 3.15 (m, 1H), 3.49 (s, 6H), 4.14 (d, J=5.6Hz, 1H), 7.19-7.4 ppm (m, 5H); 13C NMR (75MHz, CDCl3,25°C, TMS): 38.7, 54.2, 55.05, 55.19, 107.9, 126.3, 128.3, 128.56, 129.1, 129.4, 139.1 ppm; EI MS: m/z (%): 164 (M-31, 11), 120 (M-75, 96), 104 (M-91, 39), 91 (62), 75 (100).

(S)-(-)-3a: chiral HPLC (Chiralcel OD-H, hexane/ iPrOH 90/10 v/v): tR=5.6 min; Optical rotation: D=-27.7 (c= 1 in MeOH).

(R)-(+)-3a:chiral HPLC (Chiralcel OD-H, hexane/ iPrOH 90/10 v/v): tR=6.5 min; Optical rotation: D25=+27.6 (c= 1 in MeOH).

4.2.2. 1-Dimethoxymethyl-3-methyl-butylamine 3b

rac-3b: Colorless oil (32.2g, 30%);b.p.75°C /10mmHg; GC tR=8.65 min; 1H NMR (300MHz, CDCl3,25°C, TMS): 0.85 (dd, 6H, J=6.4 Hz, J= 6.6 Hz), 1.2 (m, 4H), 1.7 (m, 1H), 2.8 (m, 1H), 3.33 (s, 3H), 3.36 (s, 3H), 3.9 ppm (d,J=5.6Hz, 1 H); 13C NMR (75 MHz, CDCl3, 25°C, TMS): 21.5, 23.97, 24.5, 41.5, 50.6, 54.8, 55.2, 108.9 ppm; EI MS: m/z (%): 130 (M-31, 7), 86 (M-75, 100), 75 (67), 43 (80); HRMS (ESI): for C8H19NO2 [M+H]+: calcd. 162.1494; found 162.1482.

(S)-(-)-3b: Optical rotation: [D25=-20.4 (c= 1 in MeOH).

(R)-(+)-3b: Optical rotation: [D25=+20.9 (c= 1 in MeOH).

4.2.3. 1-(2-Phenylethyl)-2,2-dimethoxyethylamine 3c

rac-3c: Colorless oil (20.7g, 43%);b.p.100°C /0.5-1mmHg; GC tR=14.4 min; 1H NMR (300 MHz, CDCl3,25°C, TMS1.4 (s, 2H), 1.5 (m, 1H), 1.8 (m, 1H), 2.6 (m, 1H), 2.8 (m, 2H), 3.29 (s, 3H), 3.34 (s, 3H), 3.97 (d, J=5.4Hz, 1 H), 7-7.3 ppm (m, 5H); 13CNMR (75 MHz, CDCl3,25°C, TMS): 32.5, 34.2, 52.5, 54.97, 55.15, 108.5, 125.9, 128.43, 128.48, 142.3 ppm; HRMS (ESI): for C12H19NO2 [M+H]+: calcd. 210.1494; found 210.1494.

(S)-(-)-3c: chiral HPLC (Chiralcel OD-H, hexane/ iPrOH 90/10 v/v): tR=6.9 min, Optical rotation: [D25=-18.0 (c= 1 in MeOH).

(R)-(+)-3c:chiral HPLC (Chiralcel OD-H, hexane/ iPrOH 90/10 v/v): tR=9.9 min; Optical rotation: [D25=+17.8 (c= 1 in MeOH).

4.2.4. 1-Phenyl-2,2-dimethoxyethylamine 3d (Boon 1957; Suzuki and Ishida 1998)

rac-3d: Colorless oil (5.3g, 46%);b.p.118°C /5mmHg; GC tR=12.3 min; 1H NMR (300 MHz, CDCl3, 25°C, TMS): 2.5 (s, 2H), 3.2 (s, 3H), 3.45 (s, 3H), 4.0 (d, J=6.2Hz, 1 H), 4.3 (d, J=6.2Hz, 1 H), 7.15-7.45 ppm (m, 5H); 13C NMR (75 MHz, CDCl3, 25°C, TMS): 55.3, 55.65, 58.05, 108.9, 127.4, 127.7, 128.3, 141.5 ppm.

(S)-(+)-3d: chiral HPLC (Chiralcel OD-H, hexane/ iPrOH 90/10 v/v): tR=6.7 min; Optical rotation: [D25=+9.1 (c= 1 in MeOH).

(R)-(-)-3d: chiral HPLC (Chiralcel OD-H, hexane/ iPrOH 90/10 v/v): tR=8.2 min; Optical rotation: [D25= -8.9 (c= 1 in MeOH).

4.2.5. 1-Cyclohexyl-2,2-dimethoxyethylamine 3e

rac-3e: Colorless oil (18.1g, 24%);b.p. 100-110°C /5mmHg; GC tR=12.2 min; 1H NMR (300 MHz, CDCl3,25°C, TMS): 1.1 (s, 2H), 1.05-1.25 (m, 6 H), 1.45-1.75 (m, 5H), 2.6 (dd, 1 H, J=5.8 Hz, J=6 Hz), 3.3 (s, 3H), 3.34 (s, 3H), 4.1 ppm (d, J=6 Hz, 1 H); 13C NMR (75 MHz, CDCl3, 25°C, TMS): 26.4, 26.6, 26.7, 27.4, 30.7, 39.15, 54.6, 54.74, 57, 106.4 ppm; HRMS (ESI): for C10H21NO2 [M+H]+: calcd. 188.1645; found 188.1646.

(S)-(+)-3e: Optical rotation: 0[D251 (c= 15 in MeOH).

(R)-(-)-3e: Optical rotation: -1[D250 (c= 15 in MeOH).

4.3.Optical resolution of racemic 1-benzyl-2,2-dimethoxyethylamine rac-3a with N-acetyl-(L)-leucine (L)-4

In a 100ml two-necked flask equipped with a magnetic stirrer, a condenser and a thermometer, racemic 1-benzyl-2,2-dimethoxyethylamine rac-3a (1 g, 5.1 mmol) was introduced into a 6% solution of N-acetyl-(L)-leucine (L)-4 (0.44 g, 2.55 mmol) in iPrOH. The medium was stirred overnight at ambient temperature. The solid was filtered, washed with 10 mL of cyclohexane, and then oven-dried at 40°C under vacuum: white solid (0.26g, 28% / (L)-4); 1H NMR (200 MHz, [D6]DMSO,25°C, TMS): 0.85 (dd, 6H, J=6.3 Hz, J=6.6 Hz), 1.5 (m, 3H), 1.8 (s, 3H), 2.8-2.85 (AB syst., 1H), 3.04-3.1 (AB syst., 1H), 3.33 (s, 3H), 3.35 (s, 3H), 4.08 (d, 1H, J=5.4 Hz), 4.1-4.2 (m, 2H), 7.2-7.3 (m, 5H), 7.94 ppm (d, 1H, J=8.1 Hz); 13C NMR (75 MHz, [D6]DMSO, 25°C, TMS): 21.4, 22.37, 22.83, 24.26, 37.11, 38.3, 50.68, 53.57, 54.56, 54.61, 106.44, 125.94, 128.1, 129.20, 138.75, 168.82, 174.45 ppm; HRMS (ESI): for C11H17NO2 [M+H]+: calcd. 196.1338; found 196.1336 and for C8H14NO3 [M+H]+: calcd. 174.1130; found 174.1134.

The salt was treated with aqueous solution of sodium hydroxide and the aqueous phase is extracted with dichloromethane. The solvent was removed under reduced pressure yielding a colorless oil composed of enriched (R)-1-benzyl-2,2-dimethoxyethylamine (0.14 g, 28%/ (L)-4, ee(R)=83% determined by chiral HPLC).

4.4.Optical resolution of racemic 1-benzyl-2,2-dimethoxyethylamine rac-3a with N-acetyl-(L)-phenylalanine (L)-5

In a 250 mL three-necked flask equipped with a mechanical stirrer, a condenser and a thermometer, racemic 1-benzyl-2,2-dimethoxyethylamine rac-3a (6 g, 30.8 mmol) and N-acetyl-(L)-phenylalanine (L)-5 (3.18 g, 15.4 mmol) were added to 94 g of iPrOH ( 6% solution). The medium was stirred and heated at 50°C for 3 h, and then kept at 40°C for 2 h. Heating was switched off and stirring was maintained overnight.

Isolation of (R)-1-benzyl-2,2-dimethoxyethylamine (R)-3a

The precipitate was filtered off, washed with cyclohexane (approximately 100 mL) (filtrate 1), and then oven-dried at 40°C under vacuum. (R)-1-Benzyl-2,2-dimethoxyethylammonium N-acetyl-(L)-phenylalaninate, (R)-3a.(L)-5, was obtained as a white solid (3.06g, 50% relative to the N-acetyl-(L)-phenylalanine (L)-5); m.p.159°C; [D25=+42.2 (c= 1 in MeOH);1H NMR (200 MHz, [D6]DMSO, 25°C, TMS1.78 (s, 3H), 2.63-2.74 (AB syst., 1H), 2.85 (m, 2H), 3.05-3.14 (AB syst., 1H), 3.2-3.4 (m, 1H), 3.33 (s, 3H), 3.38 (s, 3H), 4.2 (d, J=4.8 Hz, 1 H), 4.32 (m, 1H), 7.1-7.4 (m, 10H), 7.86 ppm (d, 1H, J=8.1 Hz); 13C NMR (75 MHz, [D6]DMSO, 25°C, TMS): 22.56, 36.06, 37.31, 53.36, 54.51, 54.85, 55.12, 105.25, 125.95, 126.23, 127.88, 128.27, 129.16, 129.29, 137.96, 138.59, 168.66, 173.71 ppm; HRMS (ESI): for C11H17NO2 [M+H]+: calcd. 196.1338; found 196.1337 and for C11H12NO3 [M+H]+: calcd. 208.0974; found 208.0973.

The salt (R)-3a.(L)-5 was triturated in 53 g of iPrOH (solution at 5.5%) and the medium was heated at 50°C for approximately 1.5 h. Heating was switched off and stirring was maintained overnight.

The resulting solid was filtrated, washed with cyclohexane (50 mL), oven-dried at 40°C and then treated with an aqueous solution of sodium hydroxide. The aqueous phase was extracted with CH2Cl2. After solvent concentration, (R)-1-benzyl-2,2-dimethoxyethylamine was obtained (1.23g, 41% relative to (L)-5, ee(R)=97% determined by chiral HPLC).

Isolation of enriched (S)-1-benzyl-2,2-dimethoxyethylamine (S)-3a

Filtrate 1 was concentrated and the solid residue was triturated in cyclohexane (ca 100 mL), filtered under vacuum and washed with cyclohexane (60 mL). After drying and treatment with an aqueous solution of sodium hydroxide, enriched (S)-1-benzyl-2,2-dimethoxyethylamine was obtained (1.29g, 43% relative to (L)-5, ee(S)=74% determined by chiral HPLC).

Optical resolution of racemic 1-benzyl-2,2-dimethoxyethylamine rac-3a with N-acetyl-(D)-phenylalanine (D)-5 was performed according to a mirrored experimental procedure and yielded(S)-1-benzyl-2,2-dimethoxyethylamine (1.32 g, 44% relative to (D)-5 ee(S)99% determined by chiral HPLC)

(S)-1-benzyl-2,2-dimethoxyethylammonium N-acetyl-(D)-phenylalaninate: m.p.159°C; [D25=-39.6 (c= 1 in MeOH);1H NMR (200 MHz, [D6]DMSO, 25°C, TMS): 1.78 (s, 3H), 2.63-2.74 (AB syst., 1H), 2.85 (m, 2H), 3.05-3.14 (AB syst., 1H), 3.2-3.4 (m, 1H), 3.33 (s, 3H), 3.38 (s, 3H), 4.2 (d, J=4.8 Hz, 1 H), 4.32 (m, 1H), 7.1-7.4 (m, 10H), 7.86 ppm (d, 1H, J=8.1 Hz); 13C NMR (75 MHz, [D6]DMSO,25°C, TMS): 22.56, 36.06, 37.31, 53.36, 54.51, 54.85, 55.12, 105.25, 125.95, 126.23, 127.88, 128.27, 129.16, 129.29, 137.96, 138.59, 168.66, 173.71 ppm; HRMS (ESI): for C11H17NO2 [M+H]+: calcd. 196.1338; found 196.1337 and for C11H12NO3 [M+H]+: calcd. 208.0974; found 208.0973.

4.5.Optical resolutions of rac-3b-e

The resolutions of racemic 1-dimethoxymethyl-3-methyl-butylamine rac-3b, racemic 1-(2-phenylethyl)-2,2-dimethoxyethylamine rac-3c, racemic 1-phenyl-2,2-dimethoxyethylamine rac-3d with N-acetyl-(L)-phenylalanine (L)-5 orN-acetyl-(D)-phenylalanine (D)-5 and optical resolution of racemic 1-cyclohexyl-2,2-dimethoxyethylamine rac-3e with N-acetyl-(L)-leucine (L)-4 were performed according to experimental procedures similar to those described in 4.3. and 4.4..

●(R)-1-dimethoxymethyl-3-methyl-butylammonium N-acetyl-(L)-phenylalaninate, (R)-3b.(L)-5 (50% relative to (L)-5); m.p. 134-136°C; [D25=+42.7 (c= 1 in MeOH);1H NMR (200 MHz, [D6]DMSO, 25°C, TMS): 0.83 (m, 6H), 1.28 (m, 2H), 1.7-1.79 (m, 1H), 1.75 (s, 3H), 2.76-3.1 (m, 3H), 3.33 (s, 3H), 3.35 (s, 3H), 4.09-4.3 (m, 2H), 7.1-7.3 (m, 5H), 7.72 ppm (d, 1H, J=7.8 Hz); 13C NMR (75 MHz, [D6]DMSO,25°C, TMS): 21.58, 22.58, 23.42, 23.48, 37.28, 38.80, 50.05, 54.53, 54.90, 54.07, 106.01, 125.88, 127.82, 129.09, 138.65, 168.50, 173.45 ppm; HRMS (ESI): for C8H19NO2 [M+H]+: calcd. 162.1494; found 162.1495 and for C11H12NO3 [M+H]+: calcd. 208.0974; found 208.0975.

●(S)-1-dimethoxymethyl-3-methyl-butylammonium N-acetyl-(D)-phenylalaninate, (S)-3b.(D)-5 (50% relative to (D)-5). Nmr data identical to (R)-3b.(L)-5. [D25=-42.4 (c= 1 in MeOH).

●(S)-1-(2-phenylethyl)-2,2-dimethoxyethylammonium N-acetyl-(L)-phenylalaninate, (S)-3c.(L)-5 (recrystallized, 9% relative to (L)-5);m.p.160°C; [D25=+40.6 (c= 1 in MeOH);1H NMR (200 MHz, [D6]DMSO, 25°C, TMS): 1.55 (m, 2H), 1.7 (s, 3H), 2.75 (m, 5H), 3.27 (s, 3H), 3.3 (s, 3H), 4.25 (m, 2H), 7-7.3 (m, 10H), 7.72 ppm (d, 1H, J=7.8Hz); 13C NMR (75 MHz, [D6]DMSO,25°C, TMS): 22.3, 30.2, 30.6, 36.8, 51.7, 53.5, 55.4, 56.15, 103.2, 128.2, 128.5, 129.05, 137.7, 140.9, 169.3, 173.1 ppm; HRMS (ESI): for C12H19NO2 [M+H]+: calcd. 210.1494; found 210.1492 and for C11H12NO3 [M+H]+: calcd. 208.0974; found 208.0972.

●(R)-1-(2-phenylethyl)-2,2-dimethoxyethylammonium N-acetyl-(D)-phenylalaninate, (R)-3c.(D)-5 (recrystallized, 11% relative to (D)-5). Nmr data identical to (S)-3c.(L)-5. [D25=-39.9 (c= 1 in MeOH).

●(S)-1-phenyl-2,2-dimethoxyethylammonium N-acetyl-(L)-phenylalaninate, (S)-3d.(L)-5 (56% relative to (L)-5);m.p.172°C; [D25=+45.2 (c= 1 in MeOH);1H NMR (200 MHz, [D6]DMSO, 25°C, TMS): 1.72 (s, 3H), 2.9 (m, 2H), 3.13 (s, 3H), 3.3 (s, 3H), 4 (d, J=6 Hz, 1 H), 4.26 (m, 1H), 4,4 (d, J=6 Hz, 1 H), 7.1-7.5 (m, 10H), 7.83 ppm (d, 1H, J=8.1 Hz); 13C NMR (75 MHz, [D6]DMSO,25°C, TMS): 22.5, 37.2, 54.3, 54.5, 54.7, 56.4, 106.6, 126.0, 127.4, 127.9, 128, 129.1, 138.4, 139.5, 168.8, 173.5 ppm; HRMS (ESI): for C10H15NO2 [M+H]+: calcd. 182.1181; found 182.1181 and for C11H12NO3 [M+H]+: calcd. 208.0974; found 208.0977.

●(R)-1-phenyl-2,2-dimethoxyethylammonium N-acetyl-(D)-phenylalaninate, (R)-3d.(D)-5 (70% relative to (D)-5). Nmr data identical to (S)-3d.(L)-5; [D25=+45.3 (c= 1 in MeOH).

●(S)-1-cyclohexyl-2,2-dimethoxyethylammonium N-acetyl-(L)-leucinate, (S)-3e.(L)-4 (6% relative to (L)-4);1H NMR (200 MHz, [D6]DMSO,25°C, TMS0.85 (dd, 6H, J=6.3 Hz, J=6.6 Hz), 1.0-1.8 (m, 13H), 1.81 (s, 3H), 2.7 (m, 1H), 3.31 (s, 3H), 3.33 (s, 3H), 4.07-2 (m, 2H), 4.29 (d, 1H, J=5.7 Hz), 7.81 ppm (d, 1H, J=8.1 Hz); 13C NMR (75 MHz, [D6]DMSO, 25°C, TMS): 21.6, 22.5, 22.9, 24.32, 25.7, 25.9, 26, 26.9, 29.3, 37.7, 41.1, 51.25, 54.4, 54.5, 56.06, 104.3, 168.6, 174.7 ppm; HRMS (ESI): for C10H21NO2 [M+H]+: calcd. 188.1651; found 188.1648 and for C8H14NO3 [M+H]+: calcd. 174.1130; found 174.1133.

4.6.Procedure for the preparation of oximes 6 (Scheme 5)

4.6.1.1,1-Dimethoxy-3-phenyl-propan-2-one oxime 6a

Optically enriched 1-benzyl-2,2-dimethoxyethylamine 3a (0.62 g, 3.2 mmol, 83% ee, determined by chiral HPLC analyses) was dissolved, with stirring, in 10 g H2O. Sodium tungstate dihydrate (0.08 g, 0.24 mmol, 7.5% equiv) was added under stirring. The mixture was then cooled to 0°C and a 30% aqueous solution of hydrogen peroxide (9.6 mmol, 3 equiv) was then added dropwise. Stirring was maintained overnight at room temperature. The reaction medium was washed with 8 mL of a saturated aqueous solution of Na2SO3 and extracted with CH2Cl2. After solvent removal under reduced pressure, 1,1-dimethoxy-3-phenyl-propan-2-one oxime 6a was obtained as a yellow oil (0.52 g, crude yield=78%, relative to 3a); GC tR=15 min; 1H NMR (200 MHz, CDCl3,25°C, TMS): 3.2 (s, 6H), 3.65 (s, 2H), 4.6 (s, 1H), 7.1-7.4 ppm (m, 5H); 13C NMR (75 MHz, CDCl3,25°C, TMS): 30.15, 54.2, 103.4, 126.2, 128.2, 129.4, 136.6, 155.7 ppm; HRMS (ESI): for C11H15NO3 [M+H]+: calcd. 210.1130; found 210.1129.

4.6.2.1,1-Dimethoxy-4-methyl-pentan-2-one oxime 6b

1-Isobutyl-2,2-dimethoxyethylamine 3b (0.5 g, 3.1 mmol, 76% ee) (3.1 mmol) was dissolved, with stirring, in a methanol (1 g) / H2O (1 g) mixture in the presence of sodium tungstate dihydrate (0.12 g, 0.36 mmol, 12% equiv). A slight exotherm is observed when the reactants were brought into contact. The medium was left to stir at room temperature. A 30% aqueous solution of hydrogen peroxide (1.06 g, 9.3 mmol, 3 equiv) was then added dropwise for 1 h. A slight exotherm also occured during the addition. Once the addition was complete, the medium was kept under stirring for 1 h, and then methanol was added (3 mL) in order to obtain homogenous medium. The reaction was monitored by GC analyses and the medium was treated once the disappearance of the starting -aminoacetal was observed by GC (approximately 5-7 h).

After methanol removal under reduced pressure, 10 mL of methyl tert-butyl ether (MTBE) were added to the residue, followed by 8 mL of a saturated aqueous solution of Na2SO3. The aqueous layer was separated and extracted. The organic extracts were dried (MgSO4), filtered and evaporated to dryness. 1,1-dimethoxy-4-methyl-pentan-2-one oxime 6b was obtained as a yellow oil (0.4 g, crude yield=70%, relative to 3b); GC tR=10.5 min; 1H NMR (200 MHz, CDCl3, 25°C, TMS): 0.95 (d, 6H, J=6.6 Hz), 2.15 (m, 1H), 2.3 (d, 2H, J=6.9 Hz), 3.4 (s, 6H), 4.7 ppm (s, 1H); 13C NMR (75 MHz, CDCl3, 25°C, TMS): 23.05, 26.2, 32.9, 54.4, 104.4, 157.2 ppm; HRMS (ESI): for C8H17NO3 [M+H]+: calcd. 176.1287; found 176.1285.

4.7.Procedure for the reduction of oximes 6 to racemic -aminoacetals rac-3 (Scheme 5)

4.7.1.Reduction of 1,1-dimethoxy-3-phenyl-propan-2-one oxime 6a

In an autoclave reactor equipped with a mechanical stirrer, a thermocouple and a gas feed, 1,1-dimethoxy-3-phenyl-propan-2-one oxime 6a (0.5 g, 2.4 mmol) and an aqueous suspension of Raney nickel at 50% (2.5 g) were added to 64 g of 95% ethanol. After the reactor has been swept with nitrogen, the medium was placed under 50 bar of hydrogen with stirring at ambient temperature for 40 h. The reaction was monitored by GC analyses and the reduction was stopped once the disappearance of the starting material was observed by GC.

The reaction medium was filtered through Celite®. The filtrate was evaporated to dryness and racemic 1-benzyl-2,2-dimethoxyethylamine rac-3a, was obtained (0.35 g, yellow oil, crude yield=75% relative to 6a). Chiral HPLC analysis was carried out in order to check that a racemic mixture of 3a was obtained.