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DOI: 10.1055/s-0030-1258129
A Concise Synthesis of (S)-(+)-Ginnol Based on Catalytic Enantioselective Addition of Commercially Unavailable Di(n-alkyl)zinc to Aldehydes and Ketones
Publication History
Publication Date:
09 July 2010 (online)
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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.
Key words
alcohol - asymmetric catalysis - ginnol - Grignard reagent - zinc
- 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
References and Notes
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.
![](https://www.thieme-connect.de/media/synlett/201013/y015_f1.gif)
Figure 1
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].