Stereoselective Addition of Titanium Enolates to Functionalized Acetals: A Novel Approach to the γ-Amino Acid of Bistramides and FR252921

Abstract

Dialkyl acetals containing other functional groups can participate in stereoselective coupling reactions with chiral titanium enolates. Such an approach provides the protected γ-amino acid present in bistramides and FR252921 in a highly efficient manner.

Key words

stereoselective reactions - crossed aldol-like condensation - titanium enolates - acetals - bistramide - FR252921

References and Notes

• 1 Misra M. Luthra R. Singh KL. Sushil K. In Comprehensive Natural Products   Vol. 4:  Barton DHR. Nakanishi K. Meth-Cohn O. Pergamon; Oxford: 1999.  p.25 
• For recent reviews on aldol reactions, see:
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• Dimethyl acetals a and b are commercially available. The other acetals (c-f) have been prepared following standard procedures reported in the literature. See:
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• 10 Dibenzyl acetals g-i have been prepared from the corresponding dimethyl acetal, see: Vidal-Pascual M. Martínez-Lamarca C. Hoffmann HMR. Org. Synth.  2005,  83:  61 
• 11 This pattern has been established in preceding reports mentioned in ref. 4 and was supported by structural studies, see: Cosp A. Larrosa I. Anglada JM. Bofill JM. Romea P. Urpí F. Org. Lett.  2003,  5:  2809 
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9

The stoichiometry, the reaction temperature, and time were carefully evaluated.

14

Enantiomeric adducts ent-3 are obtained from ent-1, which in turn is prepared from the commercially available (R)-valinol.

15

Preparation of Methyl Ester 8
Neat TiCl₄ (0.12 mL, 1.1 mmol) was added dropwise to a solution of ent-1 (217 mg, 1.0 mmol) in CH₂Cl₂ (8 mL), at 0 ˚C under N₂. The yellow suspension was stirred for 5 min at 0 ˚C, cooled at -78 ˚C, and a solution of i-Pr₂NEt (0.19 mL, 1.1 mmol) in CH₂Cl₂ (1 mL) was added. The dark red enolate solution was stirred for 2 h at -50 ˚C. Then, 1 M SnCl₄ in CH₂Cl₂ (1.1 mL, 1.1 mmol), followed by acetal i (314 mg, 1.1 mmol) in CH₂Cl₂ (1 mL), was successively added dropwise at -78 ˚C. The resulting mixture was stirred at -78 ˚C for 30 min and kept at -20 ˚C for 2 h. The reaction was cooled at -78 ˚C and quenched by the addition of sat. NH₄Cl (8 mL) with vigorous stirring. The layers were separated. The aqueous layer was re-extracted with CH₂Cl₂, and the combined organic extracts were dried (Na₂SO₄), filtered, concentrated, and analyzed by HPLC. A solution of the residue and a crystal of DMAP in MeOH (8 mL) was stirred for 3.5 h at r.t. under N₂, diluted in Et₂O, and washed with 2 M NaOH, 2 M HCl, sat. NaHCO₃, and brine. The organic layer was dried (Na₂SO₄), filtered, and concentrated. Purification of the resultant oil through a pad of SiO₂ (CH₂Cl₂) afforded 141 mg (0.38 mmol, 77% yield) of methyl ester 8. Colorless oil. R _f = 0.2 (CH₂Cl₂). [α]_D +16.1 (c 0.95, CHCl₃). IR (film): ν = 2948, 1773, 1715, 1395, 1196, 1071 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 7.79-7.76 (2 H, m, ArH), 7.71-7.67 (2 H, m, ArH), 7.31-7.04 (5 H, m, ArH), 4.57 (1 H, d, J = 11.3 Hz, PhCH _xH_y), 4.52 (1 H, d, J = 11.3 Hz, PhCH_x H _y), 4.01 (1 H, ddd, J = 7.3, 5.8, 4.5 Hz, CHOBn), 3.91-3.82 (2 H, m, CH ₂N), 3.65 (3 H, s, OCH ₃), 2.85-2.76 (1 H, m, COCHCH₃), 1.33 (3 H, d, J = 7.0 Hz, COCHCH ₃). ^¹³C NMR (100.6 MHz, CDCl₃): δ = 174.6 (C), 168.2 (C), 137.7 (C), 133.8 (CH), 132.0 (C), 128.1 (2 × CH), 127.5 (CH), 123.2 (CH), 78.3 (CH), 72.7 (CH₂), 51.8 (CH₃), 42.7 (CH), 38.3 (CH₂), 12.6 (CH₃). ESI-HRMS: m/z calcd for C₂₁H₂₂NO₅ [M + H]⁺: 368.1492; found: 368.1488.

17

Selected Data for Methyl Ester 11
[α]_D +34.6 (c 1.3, CHCl₃). IR (film): ν = 2950, 2101, 1737, 1455, 1285, 1262, 1197, 1172, 1098, 1065 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 7.38-7.25 (5 H, m, ArH), 4.65 (1 H, d, J = 11.3 Hz, PhCH _xH_y), 4.57 (1 H, d, J = 11.3 Hz, PhCH_x H _y), 3.83 (1 H, ddd, J = 7.5, 5.7, 3.2 Hz, CHOBn), 3.68 (3 H, s, OCH ₃), 3.44 (1 H, dd, J = 13.2, 3.2 Hz, CH _xH_yN₃), 3.30 (1 H, dd, J = 13.2, 5.7 Hz, CH_x H _yN₃), 2.92-2.84 (1 H, m, COCHCH₃), 1.13 (3 H, d, J = 7.1 Hz, COCHCH ₃). ^¹³C NMR (100.6 MHz, CDCl₃): δ = 174.6 (C), 137.6 (C), 128.4 (CH), 127.9 (CH), 127.8 (CH), 79.9 (CH), 72.8 (CH₂), 51.8 (CH₃), 51.2 (CH₂), 42.0 (CH), 12.7 (CH₃). ESI-HRMS: m/z calcd for C₁₃H₁₇N₃NaO₃ [M + Na]⁺: 286.1162; found: 286.1174.