Organic Syntheses Procedure

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Org. Synth. 2005, 82, 34

DOI: 10.15227/orgsyn.082.0034

AN EFFICIENT, HIGHLY DIASTEREO- AND ENANTIOSELECTIVE HETERO-DIELS-ALDER CATALYST. PREPARATION OF (2S,6R)-6-(tert-BUTYLDIMETHYL-SILYLOXYMETHYL)-2-METHOXY-2,5-DIHYDROPYRAN

[(Silane, [[(2R,6S)-3,6-dihydro-6-methoxy-2H-pyran-2-yl]methoxy]-(1,1-dimethylethyl)dimethyl)-]

Submitted by David E. Chavez and Eric N. Jacobsen¹.

Checked by E. J. J. Grabowski and Michele Kubryk.

1. Procedure

A. (1R,2S)-1-[3-Adamantyl)-2-hydroxy-5-methylbenzyliden-amino]indan-2-ol. An oven-dried, 300-mL, three-necked, round-bottomed flask is equipped with a magnetic stirbar, fitted with a reflux condenser and thermometer, and purged with a nitrogen atmosphere by means of an inlet fitted to the condenser. The flask is charged with 2-adamantyl-4-methylphenol (12.1 g, 50.0 mmol, 1 eq) (Note 1), freshly distilled toluene (110 mL) (Note 2), and 2,6-lutidine (4.28 g, 4.67 mL, 40.00 mmol, 0.8 eq); the open neck of the flask is capped with a septum. Neat stannic chloride (SnCl₄) (2.60 g, 1.17 mL, 10.00 mmol, 0.2 eq) is added by syringe over 10 min (Note 3). The solution turns pale yellow in color, and a pale yellow precipitate is also observable. The mixture is allowed to stir at room temperature for 20 min, then the septum is removed and solid paraformaldehyde (6.00 g, 200 mmol) is added in one portion against a gentle nitrogen counterflow (Note 4). The mixture is stirred an additional 10 min, the nitrogen inlet is replaced with a nitrogen balloon, the reaction flask is placed in a 90-95°C bath, and heating is maintained at this temperature for 6 hr. The reaction mixture is then allowed to cool to room temperature and filtered through a pad of premixed Celite^® and silica gel (1:1, 12 g). The filter pad is washed with ethyl acetate (200 mL), and the combined organic filtrates are washed with water (350 mL), 1 N HCl (350 mL), and brine (350 mL), and then dried over anhydrous Na₂SO₄. Concentration is effected by rotary evaporation, followed by removal of trace solvent on a high vacuum pump (0.5 mm) (13.4 g crude, 99.5%) (Note 5). Absolute ethanol (200 mL) is added and the mixture is heated gently until complete dissolution occurs (Note 6). (1R,2S)-1-Amino-2-indanol (7.83 g, 52.50 mmol, 1.05 equiv. 2) is added in one portion. The reaction mixture is then heated at 80°C for 45 min, cooled to room temperature, and allowed to stand for 3-5 hours. The yellow solid product is isolated filtration, washed with cold ethanol (50 mL), and dried in the air (15.1 g, 75.2% over 2 steps) (Note 7).

B. Chromium(III) Cl Complex 1a. To a 200-mL round-bottomed flask is added chromium(III) chloride-tetrahydrofuran complex (1:3) (2.80 g, 7.48 mmol, 1 equiv.) and (1R,2S)-1-[3-adamantyl)-2-hydroxy-5-methylbenzyliden-amino]indan-2-ol (3.00 g, 7.48 mmol, 1 equiv.). The reaction mixture is placed under a nitrogen atmosphere, and dichloromethane (CH₂Cl₂, 60 mL) is added followed by dropwise addition of 2,6-lutidine (1.74 mL, 14.96 mmol, 2 equiv). The solution is stirred for 3 hr, diluted with CH₂Cl₂ (300 mL), and washed with water (3 × 180 mL), then brine (180 mL) (Note 8). The organic phase is dried over anhydrous Na₂SO₄, filtered, and concentrated by rotary evaporation. The resulting solid is triturated with acetone (10 mL), filtered, washed with an additional portion of acetone (10 mL), and air-dried to give the chromium complex 1a as a brown solid (2.3 g). Water (2 mL) is added to the filtrate (Note 9) and the solution allowed to stand uncovered at 23°C overnight. The resulting precipitate is filtered and washed with cold acetone to give an additional 600-800 mg of the chromium complex 1a (combined yield 2.9-3.1 g, 80 – 85%) (Notes 10, 11).

C. (2S,6R)-6-(tert-Butyldimethylsilyloxymethyl)-2-methoxy-2,5-dihydro-pyran. 1-Methoxybutadiene (2.40 g, 2.89 mL, 28.7 mmol, 1.11 equiv.) is added dropwise to a stirring mixture of (tert-butyldimethylsilyloxy)acetaldehyde (90%, 5.00 g, 5.46 mL, 25.8 mmol, 1 equiv.), (1R, 2S) chromium(III) chloride complex 1a (200 mg, 0.19 mmol, 1.5 mol% (Note 12) and 4Å molecular sieves (Note 13) under N₂ at 0°C. The reaction mixture is allowed to stir at 0°C for 1 h and then warmed to room temperature and allowed to stir for an additional 16 hr. Distillation of this mixture (Kügelrohr, 110°C, 0.5 mm) affords the cycloadduct (6.0 g, 90%) as a colorless oil (Note 14) in >99% ee (Note 15).

2. Notes

1. The purity of the 2-adamantyl-4-methylphenol is important; in particular, the material should be free of 2,6-diadamantyl-4-methylphenol.

2. All reagents were obtained from commercial suppliers (Acros, Aldrich Chemical Company, Inc., or Strem Chemicals, Inc.). Toluene was distilled from sodium, and dichloromethane was distilled from calcium hydride. All other reagents were used as received without further purification.

3. The use of a syringe containing a teflon plunger prevents clogging during the addition of SnCl₄.

4. Caution must be taken to prevent the fluffy solid paraformaldehyde from dispersing outside of the flask during this addition process.

5. This procedure for the synthesis of 2-adamantyl-5-methylsalicylaldehyde is a modification of the method reported by Casiraghi.² The aldehyde can be recrystallized from hexanes, but purification is not essential for successful formation of the Schiff base. The purified aldehyde has the following spectral and physical properties: mp 151.5-152°C; IR (KBr) 3200-2500, 1649, 1607, 1524, 1447, 1416, 1356, 1312, 1244, 1221, 1163, 1105, 1084, 1040, 963, 864 cm⁻¹; ¹H NMR pdf (500 MHz, CDCl₃) δ 1.78 (s, 6H), 2.08 (s, 3H), 2.12 (s, 6H), 2.31 (s, 3H), 7.14 (d, J = 1.5 Hz, 1H), 7.26 (d, J = 1.5 Hz, 1H), 9.8 (s, 1H), 11.65 (s, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 20.5, 28.9, 36.9, 40.1, 120.3, 128.2, 131.2, 135.4, 138.1, 159.3, 197.1; Calcd for C₁₈H₂₂O₂: C, 79.96; H, 8.20. Found: C, 79.70; H, 8.16.

6. The aldehyde is observed to dissolve completely between 60-70°C.

7. The product exhibits the following physical and spectroscopic properties: mp 219-221°C; [α]²⁶D +70.0 (c. 100, THF); IR (KBr disk) 3584, 2905, 2849, 1624, 1597 cm⁻¹; ¹H NMR pdf (500 MHz, DMSO- d_6-) δ 1.69 (m, 6H), 1.99 (m, 3H), 2.05 (m, 6H), 2.23 (s, 3H), 2.95 (dd, J = 6.0, 15.5 Hz, 1H), 3.11 (dd, J = 6.1, 15.5 Hz, 1H), 4.54 ('q', J = 5.7 Hz, 1H), 4.73, (d, J = 5.5 hz, 1H), 5.23, (d, J = 4.9 hz, 1H), 7.01 (s, 1H), 7.09 (s,1H), 7.18-7.31 (m, 4H), 8.61 (s, 1H), 10.94 (s, 1H); ¹³C-NMR (ppm): 20.2, 28.3, 36.2, 36.5, 39.0, 39.7, 73.9 (2 carbons), 118.2, 124.7, 125.0, 125.7, 126.6, 127.4, 127.9, 129.6, 130.0, 136.4, 141.0, 142.0, 158.5, 166.5; HRMS (m/z) (Cl NH₃) calcd for C₂₇H₃₅NO₂ (M)⁺ 401.2355, found 401.2341.

8. The water washes should be carried out with gentle shaking in order to avoid formation of intractable emulsions.

9. If partial concentration occurs during filtration, the filtrate should be diluted with acetone prior to addition of water such that the total volume is 20 mL. Upon addition of water, a small amount of precipitate may form. This should be redissolved by gently warming the solution or by addition of a minimal amount of acetone.

10. X-Ray quality crystals are obtained by recrystallization from acetone/water. The solid state structure of complex 1 is that of a dimer bearing a bridging water molecule and one terminal water molecule on each metal center.³ This dimeric complex exhibits the following spectral properties: IR (KBr): 3414, 2903, 2847, 1618, 1537, 1433, 1340, 1305, 1228, 1168, 1078 cm⁻¹. LRMS (FAB): calcd for dimer C₅₄H₆₈Cl₂N₂O₇Cr₂, (M-2Cl-2H₂O)⁺, 920, found 919. A dehydrated sample suitable for elemental analysis was prepared as follows: Chlorotrimethylsilane (39.0 µL, 0.31 mmol) was added to a solution of Cr(III)Cl complex (50.0 mg, 0.048 mmol) in dry tert-butyl methyl ether (2 mL). The mixture was stirred for 2 hr under nitrogen to give a green precipitate. The mixture was concentrated in vacuo, suspended in dry tert-butyl methyl ether (2 mL), filtered and the residue washed with dry tert-butyl methyl ether. The residue was then dried under high vacuum (0.5 mm). Anal. Calcd for [C₂₇H₂₉ClCrNO₂ + 2HCl]: C, 57.92; H, 5.58; Cr, 9.29; N 2.50. Found: C, 57.49; H, 5.73; Cr, 9.00; N, 2.48.

11. For certain applications (see, for example, the first entry in Table 1), superior results in HDA reactions are obtained with catalyst 1b, wherein the chloride counterion of 1a is replaced with SbF₆. Preparation of catalyst 1b is achieved as follows: A flame-dried, 50-mL, foil wrapped round-bottomed flask equipped with a stirbar was charged with complex 1a (100 mg, 0.97 mmol, 1 equiv) and silver hexafluoroantimonate (66.8 mg, 0.19 mmol, 2 equiv). The flask was placed under a nitrogen atmosphere, tert-butyl methyl ether (30 mL) was added, and the mixture allowed to stir for 3 hr. The reaction mixture was then filtered through Celite^® and the isolated solids are washed with tert-butyl methyl ether (20 mL). The filtrates were combined and concentrated by rotary evaporation to afford the desired SbF₆ complex 1b as a brown solid (165 mg). IR (KBr) 3378, 2973, 2905, 1615, 1538, 1229, 1069 cm⁻¹. LRMS (m/z) (FAB) mass calcd for C₂₇H₃₅CrNO₂, (M)⁺ 451; found 451; calcd for 2[C₂₇H₃₅CrNO₂], (2M)⁺, 902; found 902; calcd for 2C₂₇H₃₅CrNO₂, + H₂O], (2M+H₂O)⁺, 920; found 921.

12. The catalyst loading was calculated based on the number of equivalents of chromium relative to the limiting aldehyde substrate.

13. The molecular sieves (1.6 mm pellets) are powdered with a mortar and pestle and activated in a vacuum oven (130°C) overnight before use. Alternatively, commercially available finely powdered 4 Å molecular sieves (<5 micron) may be used.

14. The product has the following spectral and physical properties: [α]²⁶D +55.3 (c 1.14, CDCl₃); R_f = 0.70 (1:1 ether/hexanes); IR (thin film) 2955, 2934, 2888, 2858, 1471, 1400, 1339, 1255, 1204, 1129, 1112, 1080, 1057 cm⁻¹; ¹H NMR pdf (500 MHz, CDCl₃) δ 0.07 (s, 6H), 0.89 (s, 9H), 2.08 (m, 2H), 3.47 (s, 3H), 3.65 (dd, J = 6.5, 10.4 Hz, 1H), 3.76 (dd, J = 5.6, 10.4 Hz, 1H), 3.85 ('q', J = 6.3 Hz, 1H), 5.02 (m, 1H), 5.65 ('dq', J = 3.7, 10.2 Hz, 1H), 5.97 ('dq', J = 5.3, 10.2 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 5.2, 5.3, 18.4, 25.9, 26.8, 55.2, 65.5, 72.6, 97.7, 127.0 128.5; HRMS (m/z) (Cl) calc. for C₁₃H₃₀NO₃Si (M+NH₄)⁺ 276.1995, found 276.2003.

15. Enantiomeric excess was determined by GC analysis following conversion to (R)-6-(tert-butyldimethylsilyoxymethyl)-5,6-dihydropyran-2-one, according to the following procedure: Pyridinium dichromate (1.04 g, 2.75 mmol) was added to a solution of the acetal (256 mg, 1.38 mmmol) and acetic acid (3 mL) in CH₂Cl₂ (20 mL) at 23°C. The mixture was stirred overnight, diluted with 1:1 ether/hexanes (20 mL), and filtered through a pad of MgSO₄. The residue remaining in the reaction flask was washed thoroughly with 1:1 ether/hexanes (4 × 20 mL) and the extracts were filtered. The combined filtrates were filtered once more through a fresh pad of MgSO₄ and concentrated in vacuo. Kügelrohr distillation (210-220°C, 10 mm) afforded the product lactone (267 mg, 57.0%). GC analysis using a commercial chiral column (Cyclodex β. 135°C, isothermal) revealed the product to be in >99% ee (t_R(major) = 50.23 min). [α]²⁶D +79 (c 1.00, CDCl₃). R_f = 0.17 (10% ether/hexanes). IR (thin film) 2955, 2930, 2859, 1732, 1471, 1407, 251, 1136, 1093, 1043 cm⁻¹. ¹H NMR pdf (500 MHz, CDCl₃) δ 0.06 (s, 6H), 0.87 (s, 9H), 2.40 ('dt', J = 4.6, 18.6 Hz, 1H), 2.51 (ddd, J = 2.6, 11.1, 18.6 Hz, 1H), 3.78 (dd, J = 5.4, 10.9 Hz, 1H), 3.80 (dd, J = 4.64, 10.9 Hz, 1H), 4.45 (dddd, J = 4.4, 4.6, 5.4, 11.1 Hz, 1H), 5.99 (d, J = 9.7 Hz, 1H), 6.89 (ddd, J = 2.6, 5.8, 9.7 Hz, 1H). ¹³C NMR (125 MHz, CDCl₃) δ −5.4, 18.3, 25.8, 64.2, 77.8, 121.1, 145.0, 163.9. HRMS (m/z) (Cl) Calcd for C₁₂H₂₆NO₃Si (M+NH₄)⁺ 260.1682. Found 260.1679.

Handling and Disposal of Hazardous Chemicals

The procedures in this article are intended for use only by persons with prior training in experimental organic chemistry. All hazardous materials should be handled using the standard procedures for work with chemicals described in references such as "Prudent Practices in the Laboratory" (The National Academies Press, Washington, D.C., 2011 www.nap.edu). All chemical waste should be disposed of in accordance with local regulations. For general guidelines for the management of chemical waste, see Chapter 8 of Prudent Practices.

These procedures must be conducted at one's own risk. Organic Syntheses, Inc., its Editors, and its Board of Directors do not warrant or guarantee the safety of individuals using these procedures and hereby disclaim any liability for any injuries or damages claimed to have resulted from or related in any way to the procedures herein.

3. Discussion

This procedure describes a practical synthesis of the chiral tridentate Schiff base complex 1a, and the use of this complex to catalyze an efficient, highly diastereo- and enantioselective hetero-Diels-Alder (HDA) reaction. The unique characteristic of this catalyst, and the derived SbF₆ complex 1b (see (Note 11)), lies in their demonstrated ability to promote asymmetric hetero-Diels-Alder reactions between aldehydes and dienes bearing a single oxygen substituent.⁴ Reactions proceed generally with excellent diastereo- and enantioselectivity, and provide access to enantiomerically enriched dihydropyran derivatives from simple achiral starting materials (Table 1). This HDA methodology has already been showcased in several natural product syntheses.⁵ More recently, the same catalyst system has been applied to highly enantioselective inverse demand hetero-Diels-Alder reactions between conjugated aldehydes and ethyl vinyl ether.³

The method for the synthesis of complex 1a described herein represents a significant improvement over the procedure first reported in 1999.⁴ The use of air- and moisture-sensitive CrCl₂ is now avoided, and the necessity of conducting the metal-insertion step in a glove box is thereby precluded. Instead, the use of the (Cr(III)Cl₃·[C₄H₈O]₃) complex allows the reaction to be conducted in a fume hood. Additionally, the procedure for the formylation of 2-adamantyl-4-methylphenol has been adapted such that purification of the resulting aldehyde by recrystallization is no longer necessary. Finally, and perhaps most important, catalysts prepared by the new procedure displays measurably higher enantioselectivity in a variety of HDA reactions.³

**Table 1**

The hetero-Diels-Alder reaction illustrated in this procedure utilizes commercially available 1-methoxy-1,3-butadiene and (t-butyldimethyl-silyloxy)acetaldehyde. The reaction is carried out with 1.5 mol% catalyst under solvent-free conditions. The dihydropyran is isolated in 90% yield, >97:3 dr, and >99% ee by direct distillation of the reaction mixture. The product can be oxidized to the corresponding lactone readily and in one step, providing efficient access to a substructure that occurs in several interesting natural products (i.e., fostriecin^5b, callystatin A^6a, ratjadone^6b).

References and Notes

Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138.
Casiraghi, G.; Casnati, G.; Puglia, G.; Sartori, G.; Terenghi, G. J. Chem. Soc., Perkin Trans. 1980, 1862.
Gademann, K.; Chavez, D. E.; Jacobsen, E. N. Angew. Chem. Int. Ed. 2002, 41, in press.
Dossetter, A. G.; Jamison, T. F.; Jacobsen, E. N. Angew. Chem. Int. Ed. 1999, 38, 2398.
(a) FR901464: Thompson, C. F.; Jamison, T. F.; Jacobsen, E. N. J. Am. Chem. Soc. 2000, 122, 10482; J. Am. Chem. Soc. 2001, 121, 9974 (b) Fostriecin: Chavez, D. E.; Jacobsen, E. N. Angew. Chem., Int. Ed. Engl. 2001, 40, 3667; c) Ambruticin: Liu, P.; Jacobsen, E. N. J. Am. Chem. Soc. 2001, 123, 10772; (d) Apicularin A: Bhattacharjee, A.; De Brabander, J. K. Tetrahedron Lett. 2000, 41, 8069. (e) Laulilamide: Paterson, I.; De Savi, C.; Tutdge, M. Org. Lett. 2001, 3, 3149.
(a) Callystatin A: Crimmins, M. T.; King, B. W. J. Am. Chem. Soc. 1998, 120, 9084; (b) Ratjadone: Christman, M.; Bhatt, U.; Quitschalle, E.: Claus, E.; Kalesse, M. Angew. Chem. Int. Ed. 2000, 39, 4364.

Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)

2-(1-Adamantyl)-4-methylphenol:
Phenol, 4-methyl-2-tricyclo[3.3.1.13,7]-dec-1-yl-; (41031-50-9)

(1R,2S)-1-Aminoindan-2-ol:
1H-Inden-2-ol, 1-amino-2,3-dihydro-,(1S-cis); (126456-43-7)

(1R,2S)-1-[(3-Adamantyl)-2-hydroxy-5-methylbenzylidenamino]indan-2-ol:
1H-Inden-2-ol, 2,3-dihydro-1-[[(2-hydroxy-5-methyl-3-tricyclo[3.3.1.13,7]dec-1-decylphenyl)methylene]amino]-, (1R,2S)-; (231963-92-1)

Chromium(III) Cl Complex: Chromium, chloro[(1R,2S)-2,3-dihydro-1-[[[2-(hydroxy-κO)-5-methyl-3-tricyclo[3.3.1.13,7dec-1-ylphenyl]methyl-ene]amino-κN]-1H-indene-2-olato-(2-)-κO],(SP-4-4); (231963-76-1)

1-Methoxy-1,3-butadiene:
1,3-Butadiene, 1-methoxy-; (3036-66-6)

(tert-Butyldimethylsilyloxy)acetaldehyde:
Acetaldehyde, [[(1,1-dimethylethyldimethylsilyl]oxy]-; (102191-92-4)

(2S,6R)-6-(tert-Butyldimethylsilyloxymethyl)-2-methoxy-2,5-dihydropyran:
Silane, [[(2R,6S)-3,6-dihydro-6-methoxy-2H-pyran-2-yl]methoxy](1,1-dimethylethyl)dimethyl-; (231963-89-6)

Notes

References/EndNotes

Article Compounds

Authors