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

 

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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.

References and Notes

• Textbooks and reviews for Grignard reagents:
• 1a Lai Y.-H. Synthesis  1981,  585 
  Google Scholar
• 1b Wakefield BJ. Organomagnesium Methods in Organic Chemistry   Academic Press; San Diego / CA: 1995. 
  Google Scholar
• 1c Silverman GS. Rakita PE. Handbook of Grignard Reagents   Marcel Dekker; New York: 1996. 
  Google Scholar
• 1d Richey HG. Grignard Reagents: New Development   Wiley; Chichester / UK: 2000. 
  Google Scholar
• 1e Knochel P. Dohle W. Gommermann N. Kneisel FF. Kopp F. Korn T. Sapountzis I. Vu VA. Angew. Chem. Int. Ed.  2003,  42:  4302 
  Google Scholar
• 1f Knochel P. Handbook of Functionalized Organometallics   John Wiley & Sons; Weinheim / Germany: 2005. 
  Google Scholar
• 1g Rappoport Z. Marek I. The Chemistry of Organomagnesium Compounds In The Patai Series: The Chemistry of Functional Groups   Wiley; Chichester / UK: 2008. 
  Google Scholar
• Textbooks for preparations of organometallic reagents from Grignard reagents:
• 2a Schlosser M. Organometallics in Synthesis, A Manual   2nd ed.:  Wiley; Chichester: 2001. 
  Google Scholar
• 2b Yamamoto H. Oshima K. Main Group Metals in Organic Synthesis   Wiley-VCH; Weinheim: 2004. 
  Google Scholar
• 2c Knochel P. Handbook of Functionalized Organometallics   Wiley-VCH; Weinheim: 2005. 
  Google Scholar
• 2d Crabtree RH. Mingos DMP. Comprehensive Organometallic Chemistry III   Elsevier; Oxford: 2006. 
  Google Scholar
• For reviews, see:
• 3a Soai K. Niwa S. Chem. Rev.  1992,  92:  833 
  Google Scholar
• 3b Pu L. Yu H.-B. Chem. Rev.  2001,  101:  757 
  Google Scholar
• 3c Bolm C. Hildebrand JP. Muñiz K. Hermanns N. Angew. Chem. Int. Ed.  2001,  40:  3284 
  Google Scholar
• 3d Hatano M. Miyamoto T. Ishihara K. Curr. Org. Chem.  2007,  11:  127 
  Google Scholar
• 3e Hatano M. Ishihara K. Synthesis  2008,  1647 
  Google Scholar
• 4a Muramatsu Y. Harada T. Angew. Chem. Int. Ed.  2008,  47:  1088 
  Google Scholar
• 4b Muramatsu Y. Harada T. Chem. Eur. J.  2008,  14:  10560 
  Google Scholar
• 4c Muramatsu Y. Kanehira S. Tanigawa M. Miyawaki Y. Harada T. Bull. Chem. Soc. Jpn.  2010,  83:  19 
  Google Scholar
• 5 Côté A. Charette AB. J. Am. Chem. Soc.  2008,  130:  2771 
  CrossrefGoogle Scholar
• MIB is an advantageous alternative to Noyori’s DAIB [3-exo-(dimethylamino)isoborneol], see:
• 6a Kitamura M. Suga S. Kawai K. Noyori R. J. Am. Chem. Soc.  1986,  108:  6071 
  Google Scholar
• 6b Nugent WA. Chem. Commun.  1999,  1369 
  Google Scholar
• 6c Rosner R. Sears PJ. Nugent WA. Blackmond DG. Org. Lett.  2000,  2:  2511 
  Google Scholar
• 7 Hatano M. Miyamoto T. Ishihara K. Org. Lett.  2007,  9:  4535 
  CrossrefPubMedGoogle Scholar
• 8a Hatano M. Miyamoto T. Ishihara K. Adv. Synth. Catal.  2005,  347:  1561 
  Google Scholar
• 8b Hatano M. Miyamoto T. Ishihara K. Synlett  2006,  1762 
  Google Scholar
• 8c Hatano M. Miyamoto T. Ishihara K. J. Org. Chem.  2006,  71:  6474 
  Google Scholar
• Significantly low enantioselectivities (<20% ee) of the products in the n-alkylation of aldehydes were sometimes observed using a 1:2:2 molar ratio of ZnCl₂/NaOMe/RMgCl. Probably, from a small amount of remaining RMgCl, a highly active zinc(II)-ate complex [R₃Zn]^-[MgCl]⁺ would be generated. See:
• 9a Hatano M. Suzuki S. Ishihara K. J. Am. Chem. Soc.  2006,  128:  9998 
  Google Scholar
• 9b Hatano M. Suzuki S. Ishihara K. Synlett  2010,  321 
  Google Scholar
• It has been reported that LiCl generally improves the activity of Grignard reagents, see:
• 10a Krasovskiy A. Knochel P. Angew. Chem. Int. Ed.  2004,  43:  3333 
  Google Scholar
• 10b Armstrong DR. García-Álvarez P. Kennedy AR. Mulvey RE. Parkinson JA. Angew. Chem. Int. Ed.  2010,  49:  3185 
  Google Scholar
• 12a Beckmann S. Schühle H. Z. Naturforsch., B  1968,  23:  471 
  Google Scholar
• 12b Fuhrhop J.-H. Bedurke T. Hahn A. Grund S. Gatzmann J. Riederer M. Angew. Chem., Int. Ed. Engl.  1994,  33:  350 
  Google Scholar
• 12c Kusumi T. Takahashi H. Hashimoto T. Kan Y. Asakawa Y. Chem. Lett.  1994,  23:  1093 
  Google Scholar
• 12d Schwink L. Knochel P. Tetrahedron Lett.  1994,  35:  9007 
  Google Scholar
• 12e Langer F. Schwink L. Devasagayaraj A. Chavant P.-Y. Knochel P. J. Org. Chem.  1996,  61:  8229 
  Google Scholar
• 12f Berkenbusch T. Brückner R. Tetrahedron  1998,  54:  11471 
  Google Scholar
• 12g Dommisse A. Wirtz J. Koch K. Barthlott W. Kolter T. Eur. J. Org. Chem.  2007,  3508 
  Google Scholar

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.

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].