Stereoselective Synthesis of Functionalized Spiro[4.5]decanes by Claisen Rearrangement of Bicyclic Dihydropyrans

Abstract

A functionalized spiro[4.5]decane framework was ­synthesized by the Claisen rearrangement of 4-substituted bicyclic dihydropyrans in a highly stereoselective fashion.

Key words

pericyclic reactions - rearrangements - spiro compounds - stereoselective synthesis - terpenoids

References

• 2 For a recent example of stereoselective synthesis of spiro[4.5]decane framework, see: Maulide N. Vanherck J.-C. Markò IE. Eur. J. Org. Chem.  2004,  3962 ; and references therein
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• 12 The relative stereochemistry shown for 5a was not determined at this point, however, this stereochemistry was predicted from the results of the nucleophilic addition to the carbonyl group in simple 6-substituted dihydropyrones. For example of methylation, see: Trost BM. Gunzner JL. Dirat O. Rhee YH. J. Am. Chem. Soc.  2002,  124:  10396 ; this prediction is also supported by the stereochemistry of 12 derived from rearrangement product 11
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1

Visiting scientist from Sankyo Co., Ltd.

8

All new compounds were fully characterized by ¹H NMR and ¹³C NMR, IR and mass spectra. Data for the selected compounds follow.
Compound 4: R _f = 0.38 (hexane-EtOAc = 75:25). ¹H NMR (300 MHz, CDCl₃): δ = 5.88 (dq, J = 15.4, 6.4 Hz, 1 H), 5.66 (ddq, J = 15.4, 7.2, 1.5 Hz, 1 H), 4.88 (ddd, J = 12.5, 7.2, 4.3 Hz, 1 H), 2.60-2.50 (m, 5 H), 2.41 (dd, J = 16.9, 4.1 Hz, 1 H), 1.92 (quint., J = 7.5 Hz, 2 H), 1.77 (dd, J = 6.4, 1.5 Hz, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 189.74, 178.39, 131.37, 127.79, 114.01, 81.57, 40.87, 32.73, 25.43, 19.11, 17.73. IR (neat): 1779, 1666, 1613, 1426, 1154, 965 cm^-1. HRMS (EI): m/z calcd for C₁₁H₁₄O₂: 178.0994; found: 178.0987.
Compound 5b (>95% dr by ¹H NMR analysis): R _f = 0.56 (hexane-EtOAc = 90:10). ¹H NMR (300 MHz, CDCl₃): δ = 5.70 (dq, J = 15.3, 6.2 Hz, 1 H), 5.55 (dd, J = 15.3, 7.3 Hz, 1 H), 4.38-4.27 (m, 2 H), 2.42-2.08 (m, 5 H), 1.94 (ddd, J = 13.4, 6.5, 2.2 Hz, 1 H), 1.81-1.72 (m, 2 H), 1.63 (d, J = 6.2 Hz, 3 H), 0.82 (s, 9 H), 0.00 (s, 3 H), -0.01 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 153.00, 130.39, 128.96, 110.59, 77.37, 64.69, 38.81, 31.37, 28.90, 25.80, 19.18, 18.24, 17.71, -4.61, -4.88. IR (neat): 1686 cm^-1. HRMS (ESI): m/z calcd for C₁₇H₃₀O₂NaSi: 317.1907; found: 317.1897.
Compound 9 (>95% dr by ¹H NMR analysis): R _f = 0.52 (hexane-EtOAc = 75:25). ¹H NMR (400 MHz, CDCl₃): δ = 5.73 (ddt, J = 9.8, 4.0, 2.9 Hz, 1 H), 5.61 (dq, J = 9.8, 2.9 Hz, 1 H), 3.17 (dq, J = 20.8, 2.9 Hz, 1 H), 2.86-2.73 (m, 2 H), 2.61-2.57 (m, 1 H), 2.36-2.29 (m, 1 H), 2.24-2.15 (m, 1 H), 2.01-1.80 (m, 3 H), 1.12 (d, J = 7.1 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 214.01, 204.38, 131.05, 122.54, 68.28, 41.40, 40.64, 37.99, 30.98, 19.82, 16.19. IR (neat): 1737, 1704 cm^-1. HRMS (ESI): m/z calcd for C₁₁H₁₄O₂Na: 201.0886; found: 201.0889.
Compound 11 (>95% dr by ¹H NMR analysis): R _f = 0.51 (hexane-EtOAc = 90:10). ¹H NMR (400 MHz, CDCl₃): δ = 5.52-5.40 (m, 2 H), 4.13 (dd, J = 9.5, 6.1 Hz, 1 H), 2.27-2.20 (m, 4 H), 2.06-1.87 (m, 3 H), 1.81-1.62 (m, 2 H), 0.89 (d, J = 7.4 Hz, 3 H), 0.78 (s, 9 H), 0.00 (s, 3 H), -0.03 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 220.52, 131.07, 123.14, 66.03, 56.41, 39.95, 37.20, 33.17, 29.10, 25.80, 18.69, 17.94, 17.59, -4.13, -5.26. IR (neat): 1734 cm^-1. HRMS (ESI): m/z calcd for C₁₇H₃₀O₂NaSi: 317.1907; found: 317.1903.
Compound 12 (>95% dr by ¹H NMR analysis): R _f = 0.81 (hexane-EtOAc = 75:25). ¹H NMR (400 MHz, CDCl₃): δ = 5.64-5.48 (m, 2 H), 4.21 (d, J = 3.7 Hz, 1 H), 4.17 (dd, J = 5.6, 4.4 Hz, 1 H), 2.20-1.63 (m, 7 H), 1.49 (s, 3 H), 1.38 (s, 3 H), 1.35-1.25 (m, 2 H), 0.98 (d, J = 7.1 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 131.89, 123.29, 97.55, 74.81, 64.26, 46.54, 36.48, 30.34, 30.12, 30.10, 26.07, 19.89, 19.51, 15.43. IR (neat): 1092 cm^-1. HRMS (ESI): m/z calcd for C₁₄H₂₂O₂Na: 245.1512; found: 245.1500.
Compound 14 (67% dr by ¹H NMR analysis): R _f = 0.42 and 0.34 (hexane-EtOAc = 90:10). ¹H NMR (400 MHz, CDCl₃): δ = 5.94 (dt, J = 5.2, 1.6 Hz, 1 H), 5.77 (ddt, J = 9.6, 5.2, 2.0 Hz, 0.33 H), 5.68 (ddt, J = 9.6, 0.8, 3.6 Hz, 0.33 H), 5.64-5.57 (m, 1.33 H), 3.59 (s, 2 H), 3.42 (s, 1 H), 2.94 (br d, J = 20.4 Hz, 0.67 H), 2.71-2.64 (m, 1.33 H), 2.48 (ddq, J = 18.0, 1.2, 5.2 Hz, 0.33 H), 2.37-2.05 (m, 4.33 H), 1.94-1.68 (m, 2.33 H), 1.12 (d, J = 6.8 Hz, 1 H), 1.00 (d, J = 7.2 Hz, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 219.53, 218.52, 142.51, 142.34, 133.27, 131.07, 124.79, 124.11, 114.79, 111.26, 59.60, 58.99, 54.87, 53.57, 39.70, 38.56, 37.28, 37.19, 36.93, 36.04, 27.28, 23.23, 18.97, 18.51, 16.55, 16.47. IR (neat): 2961, 1732, 1670, 1222, 1128 cm^-1. HRMS (EI): m/z calcd for C₁₃H₁₈O₂: 206.1307; found: 206.1306.
Compound 16 (52% dr by ¹H NMR analysis): R _f = 0.30 and 0.21 (hexane-EtOAc = 75:25). ¹H NMR (400 MHz, CDCl₃): δ = 9.74 (s, 0.48 H), 9.57 (s, 0.52 H), 5.77-5.58 (m, 2 H), 4.01 (br s, 0.52 H), 3.78 (br s, 0.48 H), 2.72-2.57 (m, 1 H), 2.48-1.78 (m, 8 H), 1.09 (d, J = 7.3 Hz, 1.56 H), 1.03 (d, J = 7.6 Hz, 1.44 H). ¹³C NMR (100 MHz, CDCl₃): δ = 219.53, 202.31, 201.53, 130.95 130.88, 122.35, 121.56, 79.47, 78.78, 58.49, 53.68, 40.33, 39.92, 38.86, 37.44, 32.42, 31.91, 30.99, 19.91, 19.06, 17.39, 16.42. IR (neat): 3471, 1730 cm^-1. HRMS (ESI): m/z calcd for C₁₂H₁₆O₃Na: 231.0991; found: 231.0986.

19

Under the thermal condition at lower temperature (165 °C), no formation of spiro[4.5]decane 11 was observed.

20

Experimental Procedure. A solution of 5b (109 mg, >95% dr) in dry toluene (3.7 mL) was heated at 250 °C for 11 h in a sealed tube. The resulting mixture was cooled to r.t. and concentrated. Purification by silica gel column chromatography (hexane-EtOAc = 98:2) gave 75 mg (69% yield, >95% dr by ¹H NMR analysis) of 11 as a colorless clear oil.