A Concise Synthesis of (S)-(+)-Ginnol Based on Catalytic Enantioselective Addition of Commercially Unavailable Di(n-alkyl)zinc to Aldehydes and Ketones

Abstract

Catalytic, enantioselective n-alkyl addition of commercially unavailable di(n-alkyl)zinc reagents, which were prepared by a refined version of Charette’s procedure with Grignard reagents, to aldehydes and ketones was developed. To minimize the side reactions in the catalysis by chiral phosphoramide ligand (1) or 3,3′-diphosphoryl-BINOL ligand (2), a preparation of di(n-alkyl)zinc reagents with a 1:2.5:1.6 molar ratio of ZnCl₂/NaOMe/RMgCl under solvent-free conditions was essential. Optically pure (S)-(+)-ginnol (17) was readily synthesized in one step for the first time by the catalytic enantioselective n-nonylation of icosanal.

Key words

alcohol - asymmetric catalysis - ginnol - Grignard ­reagent - zinc

References and Notes

• Textbooks and reviews for Grignard reagents:
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11

During the preliminary investigation, we found that chiral ligand 1 was less suitable for the n-alkylation of non-aromatic aldehydes. This is probably due to the flexibility of non-aromatic aldehydes, which can avoid significant repulsion in the transition states using chiral ligand 1 (Figure  [¹] ). Also see refs. 7 and 8.

Figure 1

13

General Procedure for the Preparation of Salt-free Di( n -alkyl)zinc Reagents: To a test tube equipped with a magnetic stirrer and charged with ZnCl₂ (682 mg, 5 mmol) and NaOMe (676 mg, 12.5 mmol), was added Et₂O (5 mL) at r.t. under a nitrogen atmosphere. The suspension was stirred for 20 min and cooled to 0 ˚C for another 10 min. RMgCl in Et₂O (8 mmol, titrated before use) was added dropwise with vigorous stirring over 10 min at 0 ˚C [If RMgCl in Et₂O solution was not commercially available, RMgCl was prepared from RCl (1 equiv), LiCl (1.1 equiv), and magnesium turnings (1.5 equiv) in Et₂O, and the suspension was allowed to stir at 35 ˚C for 12 h before titration]. The mixture was centrifuged for 10 min (4,000 rpm) and the Et₂O solution of R₂Zn reagent was gently transferred via cannula into a well-dried pyrex Schlenk tube to be stored prior to use.
General Procedure for the Catalytic Enantioselective Addition of Di( n -alkyl)zinc Reagents to Aldehydes: A well-dried pyrex Schlenk tube was charged with 1 (22.8 mg, 0.05 mmol) and the salt-free R₂Zn reagent (0.4-0.6 M in Et₂O, 1.5 mmol) at r.t. under a nitrogen atmosphere. Et₂O was removed under reduced pressure to generate the solvent-free R₂Zn reagent containing 1 in situ. Aldehyde (0.5 mmol) was added to the mixture at r.t. and the resulting mixture was stirred at r.t. for 2 h. After hydrolysis with saturated NH₄Cl (10 mL), the product was extracted with Et₂O (3 × 10 mL) and washed with brine (10 mL). The combined extracts were dried over MgSO₄, the organic phase was concentrated under reduced pressure and the crude product was purified by neutral silica gel column chromatography (n-hexane-Et₂O) to give the desired products.
Catalytic, Enantioselective Synthesis of ( S )-(+)-Ginnol (17): A well-dried pyrex Schlenk tube was charged with 2 (68.7 mg, 0.10 mmol) and the salt-free (n-C₉H₁₉)₂Zn reagent (0.44 M in Et₂O, 3.4 mL, 1.5 mmol) at r.t. under a nitrogen atmosphere. Et₂O was removed under reduced pressure to generate the solvent-free (n-C₉H₁₉)₂Zn reagent containing 2 in situ. Toluene (1.5 mL) and THF (0.7 mL) were then added and the mixture was stirred at r.t. for 1 h. Icosanal (148.3 mg, 0.5 mmol) was added to the mixture, which was stirred at r.t. for 12 h. After hydrolysis with saturated aqueous NH₄Cl (10 mL), the product was extracted with EtOAc (3 × 10 mL) and washed with brine (10 mL). The combined extracts were dried over MgSO₄, and the organic phase was concentrated under reduced pressure. The crude product was purified by neutral silica gel column chromatography (n-hexane-Et₂O) to give ginnol (172.5 mg, 81% yield). ^¹H NMR (400 MHz, CDCl₃): δ = 0.88 (t, J = 6.9 Hz, 6 H), 1.20-135 (m, 48 H), 1.42 (m, 4 H), 1.56 (s, 1 H), 3.58 (m, 1 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 14.2, 22.7, 25.7, 29.3, 29.4, 29.8, 32.0, 37.6, 72.1. IR (KBr): 3449, 2917, 2850, 1467, 1561, 1101 cm^-¹. HRMS (EI): m/z [M]⁺ calcd for C₂₉H₆₀O: 406.4538; found: 406.4535. [α]_D ^²0 +1.8 (>99% ee, c 2.0, CHCl₃) {Lit.^¹²a [α]_D ^²0 +2.18 (c 1.1, CHCl₃) for (S)-ginnol}. Enantioselectivity was confirmed by HPLC analysis of the diastereotopic (R)-MTPA-esters of the resulting ginnol. Chiral HPLC, Daicel chiralpack AD-3 × 2 at 4 ˚C; n-hexane-i-PrOH, 2000:1; flow rate = 0.1 mL/min; t _R = 100.3 min [major, (S)-derivative], 103.5 min [minor, (R)-derivative].