Synlett 2010(13): 2024-2028  
DOI: 10.1055/s-0030-1258129
CLUSTER
© Georg Thieme Verlag Stuttgart ˙ New York

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

Manabu Hatanoa, Tomokazu Mizunoa, Kazuaki Ishihara*a,b
a Graduate School of Engineering, Nagoya University, Furo-cho, Chikusa, Nagoya 464-8603, Japan
b Japan Science and Technology Agency (JST), CREST, Furo-cho, Chikusa, Nagoya 464-8603, Japan
Fax: +81(52)7893222; e-Mail: ishihara@cc.nagoya-u.ac.jp;
Further Information

Publication History

Received 15 May 2010
Publication Date:
09 July 2010 (eFirst)

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 
  • 1b Wakefield BJ. Organomagnesium Methods in Organic Chemistry   Academic Press; San Diego / CA: 1995. 
  • 1c Silverman GS. Rakita PE. Handbook of Grignard Reagents   Marcel Dekker; New York: 1996. 
  • 1d Richey HG. Grignard Reagents: New Development   Wiley; Chichester / UK: 2000. 
  • 1e Knochel P. Dohle W. Gommermann N. Kneisel FF. Kopp F. Korn T. Sapountzis I. Vu VA. Angew. Chem. Int. Ed.  2003,  42:  4302 
  • 1f Knochel P. Handbook of Functionalized Organometallics   John Wiley & Sons; Weinheim / Germany: 2005. 
  • 1g Rappoport Z. Marek I. The Chemistry of Organomagnesium Compounds In The Patai Series: The Chemistry of Functional Groups   Wiley; Chichester / UK: 2008. 
  • Textbooks for preparations of organometallic reagents from Grignard reagents:
  • 2a Schlosser M. Organometallics in Synthesis, A Manual   2nd ed.:  Wiley; Chichester: 2001. 
  • 2b Yamamoto H. Oshima K. Main Group Metals in Organic Synthesis   Wiley-VCH; Weinheim: 2004. 
  • 2c Knochel P. Handbook of Functionalized Organometallics   Wiley-VCH; Weinheim: 2005. 
  • 2d Crabtree RH. Mingos DMP. Comprehensive Organometallic Chemistry III   Elsevier; Oxford: 2006. 
  • For reviews, see:
  • 3a Soai K. Niwa S. Chem. Rev.  1992,  92:  833 
  • 3b Pu L. Yu H.-B. Chem. Rev.  2001,  101:  757 
  • 3c Bolm C. Hildebrand JP. Muñiz K. Hermanns N. Angew. Chem. Int. Ed.  2001,  40:  3284 
  • 3d Hatano M. Miyamoto T. Ishihara K. Curr. Org. Chem.  2007,  11:  127 
  • 3e Hatano M. Ishihara K. Synthesis  2008,  1647 
  • 4a Muramatsu Y. Harada T. Angew. Chem. Int. Ed.  2008,  47:  1088 
  • 4b Muramatsu Y. Harada T. Chem. Eur. J.  2008,  14:  10560 
  • 4c Muramatsu Y. Kanehira S. Tanigawa M. Miyawaki Y. Harada T. Bull. Chem. Soc. Jpn.  2010,  83:  19 
  • 5 Côté A. Charette AB. J. Am. Chem. Soc.  2008,  130:  2771 
  • 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 
  • 6b Nugent WA. Chem. Commun.  1999,  1369 
  • 6c Rosner R. Sears PJ. Nugent WA. Blackmond DG. Org. Lett.  2000,  2:  2511 
  • 7 Hatano M. Miyamoto T. Ishihara K. Org. Lett.  2007,  9:  4535 
  • 8a Hatano M. Miyamoto T. Ishihara K. Adv. Synth. Catal.  2005,  347:  1561 
  • 8b Hatano M. Miyamoto T. Ishihara K. Synlett  2006,  1762 
  • 8c Hatano M. Miyamoto T. Ishihara K. J. Org. Chem.  2006,  71:  6474 
  • 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 
  • 9b Hatano M. Suzuki S. Ishihara K. Synlett  2010,  321 
  • 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 
  • 10b Armstrong DR. García-Álvarez P. Kennedy AR. Mulvey RE. Parkinson JA. Angew. Chem. Int. Ed.  2010,  49:  3185 
  • 12a Beckmann S. Schühle H. Z. Naturforsch., B  1968,  23:  471 
  • 12b Fuhrhop J.-H. Bedurke T. Hahn A. Grund S. Gatzmann J. Riederer M. Angew. Chem., Int. Ed. Engl.  1994,  33:  350 
  • 12c Kusumi T. Takahashi H. Hashimoto T. Kan Y. Asakawa Y. Chem. Lett.  1994,  23:  1093 
  • 12d Schwink L. Knochel P. Tetrahedron Lett.  1994,  35:  9007 
  • 12e Langer F. Schwink L. Devasagayaraj A. Chavant P.-Y. Knochel P. J. Org. Chem.  1996,  61:  8229 
  • 12f Berkenbusch T. Brückner R. Tetrahedron  1998,  54:  11471 
  • 12g Dommisse A. Wirtz J. Koch K. Barthlott W. Kolter T. Eur. J. Org. Chem.  2007,  3508 
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. 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].