Asymmetric Vinylogous Direct Aldol Reaction Using Aluminum Tris[2,6-bis(4-alkylphenyl)phenoxide]

Abstract

Diastereoselective vinylogous direct aldol reaction was realized by use of chiral α,β-unsaturated esters and aldehydes in the presence of aluminum tris[2,6-bis(4-alkylphenyl)phenoxide]s. The reaction involves novel 1,7-asymmetric induction and direct coupling of an α,β-unsaturated ester with an aldehyde, through in situ deprotonation of the γ-proton of the ester component by LTMP.

asymmetric synthesis - chiral auxiliaries - aldol reactions - aluminum - host-guest systems

References

1a Casiraghi G. Zanardi F. Battistini L. Appendino G. Chemtracts  1999,  12:  547 

1b Saito S. Yamamoto H. Chem.-Eur. J.  1999,  5:  1959 

1c Casiraghi G. Zanardi F. Battistini L. Appendino G. Rassu G. Chem. Rev.  2000,  100:  1929 

2a Paterson I. Smith JD. J. Org. Chem.  1992,  57:  3261 

2b Cahard D. Poirier J.-M. Duhamel P. Tetrahedron Lett.  1998,  39:  7093 

2c ATPH was used in the synthesis of Callipeltoside Aglycon, see: Paterson I. Davies RDM. Marquez R. Angew. Chem. Int. Ed.  2001,  40:  603 

2d The dienolates of g- or b-heteroatom-substituted a,b-unsaturated carbonyl compounds are prone to vinylogous aldol reaction, see: Krüger J. Carreira EM. J. Am. Chem. Soc.  1998,  120:  837 

2e See also: Rassu G. Pinna L. Spanu P. Zanardi F. Battistini L. Casiraghi G. J. Org. Chem.  1997,  62:  4513 

2f

See also ref.¹

3a Bluet G. Campagne J.-M. Tetrahedron Lett.  1999,  40:  5507 

3b Bluet G. Campagne J.-M. J. Org. Chem.  2001,  66:  4293 

4a Saito S. Shiozawa M. Nagahara T. Nakadai M. Yamamoto H. J. Am. Chem. Soc.  2000,  122:  7847 

4b Saito S. Shiozawa M. Yamamoto H. Angew. Chem. Int. Ed.  1999,  38:  1769 

4c Saito S. Ito M. Shiozawa M. Yamamoto H. J. Am. Chem. Soc.  1998,  120:  813 

4d Saito S. Yamazaki S. Yamamoto H. Angew. Chem. Int. Ed.  2001,  40:  3613 

4e Saito S. Sone T. Murase M. Yamamoto H. J. Am. Chem. Soc.  2000,  122:  10216 

4f For detailed mechanistic aspects of the present vinylogous aldol reaction, see: Saito S. Nagahara H. Shiozawa M. Nakadai M. Yamamoto H. J. Am. Chem. Soc.  2003,  125:  6200 

4g For a review of ATPH, see: Saito S. Yamamoto H. Chem. Commun.  1997,  1585 

5 Me-ATPH was prepared by the procedure similar to ATPH. The corresponding phenol was prepared via four steps from commercial 2,6-dibromophenol. For experimental details, see the forthcoming paper: Ito H. Nagahara T. Ishihara K. Saito S. Yamamoto H. Angew. Chem. Int. Ed.  2004, , in press

6

The use of a less amount of the ester, ATPH, and LTMP (1.0:2.2:1.2 equiv) proved less productive. See also ref.^4b

7

Typical Procedure: The reaction of menthyl crotonate (2a) with benzaldehyde (1a) is representative. To an anhydrous toluene (5.0 mL) solution of Me-ATPH (3.96 mmol) were added 2a (179 mg, 0.80 mmol) and 1a (41 µL, 0.40 mmol) at -78 °C under argon. After the mixture was stirred for 20 min, LTMP [generated by treatment of a solution of 2,2,6,6-tetramethylpiperidine (155 µL, 0.92 mmol) in THF (5.0 mL) with a 1.48 M hexane solution of n-BuLi (0.62 mL, 0.92 mmol) at 0 °C for 30 min] was transferred by a steel cannula to the solution at -78 °C. The reaction mixture was stirred at this temperature for 1 h, quenched with aq NH₄Cl, and the resulting suspension was extracted with Et₂O. The organic layer was dried over Na₂SO₄ and concentrated. The residue was purified by column chromatography on silica gel (Et₂O-hexane, 1:2) to give aldol adduct 3a (88% yield, 60% de) as pale yellow solids. 2,6-Bis(4-methylphenyl)phenol was recovered in more than 90% yield before the aldol product came off the column. Spectral and analytical data of 3a: IR (neat): 3480, 3020, 2959, 2359, 1705, 1653, 1456 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 7.38-7,26 (m, 5 H), 6.95 (m, 1 H), 5.90 (dt, J = 1.5, 15.6 Hz, 1 H), 4.84 (m, 1 H), 4.73 (dt, J = 4.2, 10.8 Hz, 1 H), 2.64 (m, 2 H), 1.98 (m, 1 H), 1.92 (m, 1 H), 0.89 (dd, J = 4.5, 6.9 Hz, 6 H), 0.75 (d, J = 6.9 Hz, 3 H), 2.10-0.80 (m, 7 H). ¹³C NMR (75 MHz, CDCl₃): δ = 166.0, 144.6, 143.6, 128.5, 127.8, 125.7, 124.2, 74.1, 73.0, 47.0, 41.9, 40.9, 34.2, 31.3, 26.2, 23.5, 22.0, 20.7, 16.4. Anal. Calcd for C₂₁H₃₀O₃: C, 76.33; H, 9.15. Found: C, 76.12; H, 9.43. The de was determined by chiral HPLC analysis after converting 3a into the corresponding diol {e.g., [α]_D ²⁵ = +20.9 (c = 1.13, CHCl₃) for 73% ee}. Retention time data (column: OD-H; hexane-i-PrOH = 30:1 with a flow rate of 0.5 mL/min). (1S)-5-Hydroxy-1-phenyl-3-pentenol: t _R = 84.2 min; (1R)-diol: t _R = 90.7 min. The absolute configuration of 3a was determined by conversion to the known sample, 3-acetoxy-3-phenylpropionic acid, as described in the literature procedure, see ref. 3b. γ-Adduct 5a was also derived to the above diol by reduction of the ester carbonyl and partial reduction of the triple bond with AlH₃.

8

Significant effects of second equivalent of ATPH, which presumably activates the aldehyde partner, needs further investigation. In the absence of the second ATPH, considerable decrease in chemical yields was consistently observed.

9 C₃-symmetry in chiral recognition, see: Moberg C. Angew. Chem. Int. Ed.  1998,  37:  248 

10

Me-ATPH-2a complex: ¹H NMR (300 MHz, toluene-d ₈):
δ = 7.70-6.50 (m, 39 H), 5.99 (qd, J = 7.2, 25.4 Hz, 1 H), 4.76 (d, J = 25.6 Hz, 1 H), 3.66 (m, 1 H), 2.05 (s, 18 H), 1.68 (br s, 1 H), 1.36 (m, 2 H), 1.20 (br d, J = 11.7 Hz), 0.93 (d, J = 6.9 Hz, 3 H), 0.78 (d, J = 6.9 Hz, 3 H), 0.64 (d, J = 6.9 Hz, 3 H), 0.60 (d, J = 6.0 Hz, 3 H), 1.15-0.56 (m, 4 H), 0.50 (br d, J = 11.7 Hz, 1 H). The Me-ATPH-2a complex is highly likely to adopt a most favorable diastereomeric conformation with a negligible formation of other distinct diastereomers. See also ref.⁵ for the X-ray single crystal structure of a homochiral ester complex of ATPH.