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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
J Org Chem. Author manuscript; available in PMC 2010 September 18.
Published in final edited form as:
PMCID: PMC2749648
NIHMSID: NIHMS139103

Silylene-Mediated Ring Contraction of Homoallylic Ethers to Form Allylic Silanes

Abstract

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(—)-Isopulegol derivatives undergo a ring contraction under silylene-mediated conditions to provide cyclopentane products. Silylene transfer to other homoallylic ethers did not provide the ring contraction products. Allylic silane products were elaborated to determine the stereochemical course of the ring contraction reaction. A mechanism for the transformation is proposed.

Cyclopentane units are found in many natural and non-natural products, including alkaloids, steroids, prostaglandins, triquinanes, and guaianes.1-6 The ring contraction of a six-membered carbocyclic compound is an efficient way to assemble a cyclopentane, because the reorganization of the bonds can occur with high selectivity.7-12 This reorganization leads to compounds not easily accessed by other syntheses.13 In this Note, we report the ring contraction of six-membered carbocyclic homoallylic ethers to form five-membered carbocyclic allylic silanes by treatment with silylene intermediates.

As part of our investigations into silylene transfer reactions to homoallylic ethers,14 we examined the reaction of (—)-isopulegol derivative 1 under the optimized reaction conditions. Subjection of benzyl ether 1 to cyclohexene silacyclopropane 2 and AgO2CCF3 did not provide the expected silylmethyl allylic silane product. Instead, the five-membered ring allylic silane product 3 was isolated as a single stereoisomer (eq 1).

equation image
(1)

Alteration of the protecting group on the homoallylic ether provided similar ring contraction products. When alkyl ether 4 was treated to the reaction conditions, allylic silane 5 was observed (eq 2). Treatment of silyl ether 6 to the reaction conditions provided allylic silane 7 (eq 2). Both allylic silanes were found to be predominantly one stereoisomer, as indicated by 1H NMR and 13C NMR spectroscopy.15,16

equation image
(2)

A variety of homoallylic ethers were subjected to the reaction conditions, but they did not undergo rearrangement. epi-Isopulegol derivative 8 underwent silylene transfer to the alkene17 to form silacyclopropane 9 as a mixture of diastereomers that was not stable to purification (eq 3). The product did not undergo further transformations upon heating. The same result was observed with both five-membered ring ether 10 and seven-membered ring ether 12 (eq 4). The lack of ring-contraction of the five-membered ring silacyclopropane 11 (eq 4) may be the result of too much ring strain involved in contraction to the four-membered ring.18 Differences in conformational preferences and flexibility between six- and seven-membered rings may cause the seven-membered ring system of silacyclopropane 13 to align orbitals differently,19 thus preventing ring contraction.

equation image
(3)
equation image
(4)

The structure and relative stereochemistry of allylic silane 3 was determined by X-ray crystallography of a derivative. Allylic silane 3 underwent hydroboration, followed by oxidation, to form oxasilacyclopentane 14 as a single isomer (eq 5).20 Oxasilacyclopentane 14 was then subjected to modified Tamao—Fleming oxidation conditions21-23 to remove the di-tert-butylsilylene moiety, providing diol 15 (eq 6). The stereochemistry and connectivity of diol 15 was established by X-ray crystallography.24

equation image
(5)
equation image
(6)

A stepwise mechanism is proposed to account for the contraction of the original six-membered ring to form the five-membered ring (Scheme 1). Silylene transfer to the double bond of 1 would form silacyclopropane adduct 16 as one diastereomer.25 The oxygen atom can then complex to the Lewis-acidic silicon atom26 to form the conformationally favored trans-fused ring system 17 (Figure 1).27,28 The cis-fused ring system (20) appears to encounter steric hindrance due to a t-Bu group being forced over the cyclohexane ring.29 The ring-contracting step forms silacyclopropylcarbinyl cation 18 with inversion of configuration. Carbocation 18 undergoes silacylcopropylcarbinyl cation rearrangement30,31 to form ylide 19. The nucleophilic pentavalent silicon atom can then reform the terminal alkene, providing allylic silane 3.30,31

Scheme 1
Proposed Mechanism for the Formation of Allylic Silane 3.
Figure 1
Proposed Conformations of Ylide 20.

In summary, silylene transfer to (—)-isopulegol derivatives provided allylic silanes by a ring contraction. Similar five- and seven-membered ring systems underwent silylene transfer to the alkene, but did not provide ring contraction products. A mechanism for the transformation was proposed utilizing a silylene ylide intermediate and a silacyclopropylcarbinyl rearrangement.

Experimental Section

Allylic silane 3

To a solution of homoallylic ether 1 (0.394 g, 1.60 mmol) in 8.0 mL of toluene was added cyclohexene silacyclopropane 2 (0.470 g, 2.09 mmol). AgO2CCF3 (0.004 g, 0.02 mmol) was then added. The brown solution was then placed under an Ar atmosphere and allowed to stir for 1 hour at 50 °C, at which point the mixture was concentrated in vacuo. Purification by flash chromatography (hexanes) provided 0.402 g (65%) of 3 as a colorless oil: 1H NMR (500 MHz, CDCl3) δ 7.28–7.35 (m, 4H), 7.19–7.23 (m, 1H), 4.91–5.01 (m, 2H), 4.74–4.76 (m, 2H), 2.22–2.32 (m, 1H), 2.01–2.07 (m, 2H), 1.80–1.93 (m, 1H), 1.61–1.77 (m, 5H), 1.02–1.29 (m, 20H), 0.89 (d, J = 6.6, 3H), 0.71–0.79 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 147.7, 142.1, 128.3, 126.8, 126.2, 113.2, 66.6, 44.7, 43.7, 41.1, 34.3, 32.4, 32.3, 30.1, 29.8, 25.0, 23.8, 23.2, 21.5; IR (thin film) 2951, 2860, 2360, 1112, 820, 726 cm-1; HRMS (ESI) m / z calcd for C25H42OSiNa (M + Na)+ 409.2903, found 409.2910.

Homoallylic ether 4

To a 0 °C solution of sodium hydride (0.710 g, 29.6 mmol) in 50 mL of THF was added (—)-isopulegol (2.50 mL, 14.8 mmol) dropwise followed by methyl iodide (1.01 mL, 16.3 mmol). The reaction mixture was warmed to room temperature and stirred for twelve hours. The solution was then cooled to 0 °C and diluted with 20 mL of H2O. The aqueous layer was extracted twice with 20 mL of EtOAc. The combined organic layers were washed with 20 mL of brine, dried over Na2SO4, and concentrated in vacuo. Purification by flash chromatography (95:5 hexanes:EtOAc) provided 2.35 g (95%) of 4 as a colorless oil: 1H NMR (500 MHz, CDCl3) δ 4.77–4.79 (m, 2H), 3.33 (s, 3H), 3.08–3.13 (m, 1H), 2.15–2.17 (m, 1H), 1.98–2.03 (m, 1H), 1.73 (s, 3H), 1.61–1.67 (m, 3H), 1.33–1.44 (m, 2H), 0.93–0.96 (m, 3H), 0.82–0.89 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 148.2, 110.9, 80.7, 56.1, 51.9, 39.2, 34.6, 31.6, 31.3, 22.4, 19.6; IR (thin film) 2923, 2869, 1454, 1371, 1106, 885 cm-1; HRMS (ESI) m / z calcd for C11H20ONa (M + Na)+ 191.1412, found 191.1419.

Allylic silane 5

To a solution of homoallylic ether 4 (0.017 g, 0.01 mmol) in 0.7 mL of benzene-d6 was added cyclohexene silacyclopropane 2 (0.029 g, 0.13 mmol). AgO2CCF3 (0.001 g, 0.005 mmol) was then added. The brown solution was then heated for 1 hour at 50 °C, at which point the mixture was concentrated in vacuo. Purification by flash chromatography (hexanes) provided 0.022 g (71%) of 5 as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 4.72–4.77 (m, 2H), 3.62 (s, 3H), 2.26–2.29 (m, 1H), 2.09–2.12 (m, 1H), 1.93–2.00 (m, 2H), 1.82 (s, 3H), 1.67–1.75 (m, 2H), 1.14–1.20 (m, 3H), 1.10 (s, 9H), 1.09 (s, 9H), 0.98–1.07 (m, 3H); 13C NMR (125 MHz, CDCl3) δ 147.6, 113.1, 53.1, 44.3, 43.4, 41.3, 34.4, 32.5, 32.2, 30.1, 29.6, 27.1, 24.9, 23.1, 21.7; IR (thin film) 2948, 2859, 1469, 1189, 1116, 819 cm-1; HRMS (ESI) m / z calcd for C19H37OSi (M — H)+ 309.2614, found 309.2623.

Allylic silane 7

To a solution of homoallylic ether 6 (0.027 g, 0.01 mmol) and cyclohexene silacyclopropane 2 (0.029 g, 0.13 mmol) in 0.7 mL of benzene-d6 was added AgO2CCF3 (0.001 g, 0.005 mmol). The brown solution was then heated for 1 hour at 50 °C, at which point the mixture was concentrated in vacuo. Purification by flash chromatography (hexanes) provided 0.034 g (82%) of 7 as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 4.68–4.80 (m, 2H), 2.26–2.32 (m, 1H), 1.91–1.96 (m, 2H), 1.82 (s, 3H), 1.69–1.72 (m, 2H), 1.08 (s, 18H), 1.02–1.06 (m, 5H), 0.97–0.98 (m, 2H), 0.94 (s, 9H), 0.15 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 13C NMR (125 MHz, CDCl3) δ 123.2, 114.8, 44.7, 40.7, 33.7, 33.0, 31.3, 30.1, 29.6, 29.2, 28.2, 27.5, 27.1, 21.5, −1.3, −1.4; IR (thin film) 2952, 2859, 1469, 1253, 1043, 833 cm-1; HRMS (ESI) m / z calcd for C24H50OSi2Na (M + Na)+ 433.3298, found 433.3295.

Oxasilacyclopentane 14

To 0 °C solution of allylic silane 3 (0.440 g, 1.10 mmol) in 3.8 mL of THF was added 9-BBN (6.8 mL of a 0.5 M solution in THF, 3.3 mmol) dropwise. The reaction mixture was allowed to warm to room temperature for 8 hours. After cooling to 0 °C, 1.5 mL of NaOH (3 N) and 1.5 mL of 30% H2O2 was added. The heterogeneous mixture was warmed to room temperature and stirred for an additional 3 hours. The mixture was then saturated with K2CO3 and diluted with 5 mL of CH2Cl2. The layers were separated, and the organic layer was washed with 5 mL of brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. Purification by flash chromatography (95:5 hexanes:EtOAc) provided 0.250 g (75%) of 14 as a colorless oil: 1H NMR (500 MHz, CDCl3) δ 3.82–3.86 (m, 1H), 3.70–3.72 (m, 1H), 2.23–2.31 (m, 1H), 2.04–2.13 (m, 1H), 1.86–1.97 (m, 3H), 1.72–1.82 (m, 1H), 1.35–1.37 (m, 1H), 1.16–1.26 (m, 2H), 1.11 (s, 9H), 1.00–1.05 (m, 15H), 0.83–0.90 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 73.9, 45.4, 38.8, 37.0, 36.0, 34.6, 33.7, 33.3, 29.6, 29.0, 22.3, 21.3, 21.1, 17.0; IR (thin film) 2948, 2859, 1377, 1080, 985, 822 cm-1; HRMS (ESI) m / z calcd for C18H37OSi (M + H)+ 297.2614, found 297.2613. Anal. Calcd for C18H36OSi: C, 72.60; H, 12.24. Found: C, 72.84; H, 12.30.

Diol 15

To a solution of KH (0.120 g, 2.90 mmol) in 1.5 mL THF was added 18-crown-6 (0.780 g, 2.90 mmol). The solution was cooled to 0 °C, and cumene hydroperoxide (88%, 0.49 mL, 2.9 mmol) was added dropwise. The cooling bath was removed, and oxasilacyclopentane 14 (0.150 g, 0.490 mmol) was added by way of cannula in 0.5 mL of THF. The reaction mixture was heated to 50 °C for 2 hours, and Bu4NF (1.47 mL of a 1.00 M solution in THF, 1.47 mmol) was added. After 12 hours, the mixture was cooled room temperature, and the solution was diluted with 2 mL of saturated sodium thiosulfate and 5 mL of CH2Cl2. The layers were separated, and the organic layer was washed with 5 mL of brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. Purification by flash chromatography (70:30 hexanes:EtOAc) provided 0.480 g (57%) of diol 15 as a white solid: mp 97 °C; 1H NMR (500 MHz, CDCl3) 3.72–3.75 (m, 1H), 3.64–3.68 (m, 1H), 3.56–3.59 (m, 1H), 1.89–2.33 (m, 4H), 1.69–1.81 (m, 2H), 1.56–1.66 (m, 1H), 1.10–1.29 (m, 3H), 0.84–1.04 (m, 7H); 13C NMR (125 MHz, CDCl3) δ 79.9, 68.1, 44.4, 40.3, 37.7, 34.8, 33.8, 28.1, 21.0, 9.3; IR (thin film) 3307, 2917, 2861, 1454, 1029, 820 cm-1; HRMS (ESI) m / z calcd for C10H20O2Na (M + Na)+ 195.1361, found 195.1366. Anal. Calcd for C10H20O2: C, 69.72; H, 11.70. Found: C, 69.49; H, 11.83.

Supplementary Material

1_si_001

2_si_002

Acknowledement

This research was supported by the National Institute of General Medical Seiences of the National Institutes of Health (GM-54909). L.E.B. thanks the Department of Education (GAANN) for a predoctoral fellowship. K.A.W. thanks Amgen and Lilly for awards to support research. We thank Dr. Phil Dennison (UCI) for assistance with NMR spectroscopy, Dr. Joseph W. Ziller (UCI) for X-ray crystallography, and Dr. John Greaves and Ms. Shirin Sorooshian (UCI) for mass spectrometry.

Footnotes

Supporting Information Available Complete experimental procedures, X-ray data, and product characterization. This material is available free of charge via the Internet at http://pubs.acs.org.

References

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