Asymmetric Aldol Reaction of Alkenyl Esters with α-Keto Esters Catalyzed by Chiral Tin Alkoxides

Abstract

A catalytic enantioselective aldol reaction of alkenyl esters with α-keto esters was achieved by using an (R)-BINOL-derived chiral tin dibromide possessing 4-t-butylphenyl groups at the 3- and 3′-positions as a chiral precatalyst in the presence of sodium methoxide and methanol. Optically active aldol products possessing a chiral tertiary carbon were diastereoselectively obtained with up to 92% ee and moderate to high yields, not only from cyclic alkenyl esters, but also from acyclic ones under the influence of the chiral tin methoxide generated in situ.

Key words

aldol reaction - alkenyl ester - asymmetric catalysis - α-keto esters - tin catalysis

Publication History

Received: 16 August 2021

Accepted after revision: 10 October 2021

Accepted Manuscript online:
10 October 2021

Article published online:
18 November 2021

• References and Notes


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• 7 To generate a chiral tin iodide methoxide with high purity, it is necessary to transform the corresponding chiral tin dibromide into a chiral tin diiodide, followed by treatment with 1 equiv of NaOMe. Indeed, the addition of 8 mol% of NaI to the chiral tin dibromide 4a (8 mol%) resulted in lower enantioselectivity.
• 8 The Lewis acidity of a tin enolate generated from R*₂SnI(OMe) is anticipated to be lower than that of a tin enolate generated from R*₂SnBr(OMe), judging from the electronegativities of iodine (2.4) and bromine (2.7). The former tin enolate is considered to be more nucleophilic, resulting in a higher yield and, in contrast, its longer Sn–I bond might contribute to the formation of a more rigid transition-state structure because of the weaker steric hindrance, leading to a higher enantioselectivity.
• 9 Methyl Hydroxy(1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)phenylacetate (3aa); Typical Procedure A mixture of chiral tin dibromide 4a ⁶ (16.5 mg, 0.02 mmol), NaI (6.0 mg, 0.04 mmol), and MeOH (25 μL, 0.625 mmol) in anhyd hexane (3 mL) was stirred for 10 min. A 1 M solution of NaOMe in MeOH (20 μL, 0.02 mmol) was added and the resulting mixture was stirred for 30 min. The α-keto ester 2a (40.6 mg, 0.25 mmol) and alkenyl trifluoroacetate 1a (90.9 mg, 0.375 mmol) were added at 0 °C, and the resulting mixture was stirred for 3 h at 0 °C. The mixture was then treated with solid KF (0.5 g) and brine (3 mL) at r.t. for 5 min. The resulting precipitate was removed by filtration and the filtrate was extracted with EtOAc (×3). The combined organic extracts were washed with brine, dried (Na₂SO₄), and concentrated in vacuo. The crude product was purified by column chromatography [silica gel; hexane–EtOAc (12:1 to 6:1)] to give a white solid; yield: 72.7 mg [94%; dr 85:15 (¹H NMR), ee 72% (major diastereomer; HPLC)]; mp 105–106 °C; [α]_D ^{16. 9} –96.1 (c 1.05, CHCl₃; 85:15 mixture of diastereomers: major isomer 72% ee). HPLC [Daicel Chiralpak AD-H, hexane–i-PrOH (9:1), 1.0 mL/min]: t ₁ = 25.4 min (minor), t ₂ = 34.5 min (major). IR (neat): 3437, 2958, 1729, 1660, 1599, 1449, 1436, 1382, 1317, 1264, 1229, 1204, 1089, 1060, 1009 cm^–1. ¹H NMR (400 MHz, CDCl₃, major isomer): δ = 1.74 (dq, J = 13.0, 3.7 Hz, 1 H), 2.39–2.55 (m, 1 H), 2.83–2.93 (m, 2 H), 3.05 (dd, J = 13.8, 4.3 Hz, 1 H), 3.80 (s, 3 H), 5.10 (s, 1 H, OH), 7.22 (d, J = 7.5 Hz, 1 H), 7.29–7.41 (m, 4 H), 7.47–7.51 (m, 3 H), 8.02 (dd, J = 8.0, 0.8 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃, major isomer): δ = 26.8, 29.6, 52.7, 58.2, 81.1, 125.8 (2 C), 126.7, 127.5, 128.1, 128.3 (2 C), 128.6, 132.4, 134.0, 139.2, 144.3, 173.8, 200.6. MS (ESI): m/z [M + Na]⁺calcd for C₁₉H₁₈NaO₄: 333.1097; found: 333.1093.
• 10 Libman J, Sprecher M, Mazur Y. Tetrahedron 1969; 25: 1679
• 11 We synthesized dibenzyltin diiodide from dibenzyltin dibromide by treatment with two equivalents of NaI in acetone at r.t. The generation of dibenzyltin iodide methoxide (δ = –249.9) was confirmed by ¹¹⁹Sn NMR (186.5 MHz, CDCl₃) of a 1:1 mixture of Bn₂SnI₂ (δ = –131.4) and NaOMe (1 M MeOH solution) in CDCl₃.
• 12 The relative and absolute stereochemistries of the aldol products have not yet been determined.