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. Author manuscript; available in PMC: 2008 Dec 8.
Published in final edited form as: J Org Chem. 2007 Sep 13;72(21):7903–7908. doi: 10.1021/jo071272o

Diastereoselective Prins-type Reaction of Cycloalkenylcyclopropanol Silyl Ethers and α,β-Unsaturated Aldehyde Acetals

Ivan L Lysenko 1, Heong-Sub Oh 1, Jin Cha 1
PMCID: PMC2597285  NIHMSID: NIHMS62654  PMID: 17850161

Abstract

Electrophilic addition of 1-(1-cyclohexenyl)-1-cyclopropanol trimethylsilyl ether to α,β-unsaturated aldehyde acetals under Lewis acidic conditions proceeds with good to excellent diastereoselectivity to afford spirocyclobutanones containing three contiguous stereocenters. A convenient entry to enantioselective syntheses is available by use of a nonracemic C2-symmetric acetal. Elaboration of the resulting adducts provides ready access to medium-sized carbocycles.

Introduction

The release of strain arising from cleavage of cyclopropanes has been frequently utilized in organic synthesis.1 Heteroatom-substituted cyclopropanes display enhanced nucleophilicity and provide convenient methods for regio- and stereoselective ring-opening. For example, ring-opening reactions of cyclopropanols and siloxy derivatives have been extensively investigated and render them a “homoenol” or “homoenolate” equivalent.2–4 The juxtaposition of a cyclopropanol and an olefin or an alkyne generates unique conjunctive functionalities suitable for different modes of C–C bond formation, and the Trost group documented facile addition of the trimethylsilyl ethers of 1-vinylcyclopropanols to oxocarbenium ions (generated in situ from acetals).5,6 In the absence of overriding geometrical factors, electrophilic attack takes place preferentially at the double bond leading to formation of the corresponding spirocyclobutanones bearing three contiguous stereocenters (eq 1). It is not surprising that diastereocontrol proved to be difficult,5,7 and a handful of known diastereoselective examples reported have been limited primarily to intramolecular variants.5,8 We report herein diastereoselective Prins-type reactions of 1-(1-cyclohexenyl)-1-cyclopropanol trimethylsilyl ether (2) and α,β-unsaturated aldehyde acetals.

graphic file with name nihms62654e1.jpg (1)

Results and Discussion

Cyclopropanol 1, which was readily prepared by the Kulinkovich cyclopropanation of methyl 1-cyclohexene-1-carboxylate,9,10 was selected for a vinylogous homo-Prins - or homo-Mukaiyama-type reaction11 with acetals under Lewis acidic conditions (Scheme 1). Ring expansion induced by addition of an oxocarbenium ion to a trisubstituted olefin (e.g., 1-cyclohexenyl moiety) should provide ready access to a quaternary center.12 This straightforward procedure was applicable to a full range of acetals derived from aliphatic, α,β-unsaturated, aromatic aldehydes, and alkynals to give the corresponding spirocyclobutanones in excellent yields. Diastereoselectivity was found to be not only sensitive to reaction parameters (e.g., reaction temperatures, Lewis acids, the presence of lutidine, etc), but also modest (typically 3–4:1).

Scheme 1.

Scheme 1

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Coupling of 2 and Acetals 3a–e.

However, the use of α,β-unsaturated aldehyde acetals was shown to be an exception. Treatment of a mixture of TMS ether 2 and dimethylacetals 3a–e with TiCl4 at −78 °C afforded spirobutanones 4a–e in 93–99% (combined) yield and with good diastereoselectivity. Only the stereochemistry of the major isomers is shown in Scheme 1, where the product ratios were determined by GC-MS and also analysis of 1H NMR spectra. Formation of two (e.g., 4a and 4c) or three (e.g., 4b, 4d, and 4e) isomers was usually observed out of four possible diastereomers. Fortuitously, the major isomers were easily separated by silica gel chromatography from the remaining isomers in all cases. Cyclopropanols could also be used directly without silylation, but the resulting diastereoselectivity was often different from that obtained for the corresponding TMS ethers. For example, coupling of 1 and 3a afforded a 1:3 mixture of two products epimeric at the quaternary carbon in 85% yield and the minor isomer corresponded to 4a.

The unequivocal stereochemical determination of 4e was established by single crystal X-ray analysis.13 The stereochemical assignment of 4a–d was then made by the correlation study involving oxidative cleavage of the double bond of 4e (subsequent to desilylation) and 4a–d, in addition to difference NOE measurements or comparison of key coupling constants. TLC behavior of these isomers was also informative because of regular patterns apparent among several related spirobutanones (Scheme 2), the stereochemistry of which had previously been secured by single crystal X-ray analysis: Rf values of the indicated (S,R)-products (e.g., 4a–e) were lower than those of the respective (R,R)-isomers. The observed (S,R)-stereochemistry can be rationalized by synclinal approach of the vinylcyclopropanol to the oxocarbenium ion to avoid nonbonded interactions between the cyclopropane ring and the alkenyl substituent, as shown in the Newman projection I in Scheme 1.

Scheme 2.

Scheme 2

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Coupling Reactions of 2 with Aliphatic and Aryl Aldehyde Acetals.7

Conspicuous is the cis-stereochemical relationship between the two newly formed C–C bonds of 4a–e, which is indicative of the intermediacy of the stable tertiary cyclopropylcarbinyl cations II.7,14 The diastereofacial bias of ring expansion appears to be steric in origin; depending on substrates (e.g., 4a–e and 5A vs 6 and 7A), both net “cis” and “trans” addition are observed. The preferential formation of 4a–e (“cis” addition) might be attributed in part to the minimization of torsional strain during ring expansion (1,2-alkyl shift): as 1,2-alkyl shift occurs, “trans” addition would have to go through a fully eclipsed arrangement between the newly introduced side chain and the C–C=O bond.15

When (Z)-α,β-unsaturated aldehyde acetals were employed, complete isomerization to the E-double bond was observed, and this result is in accord with generation and subsequent trapping of oxocarbenium ions (Scheme 3). Diminished diastereoselectivity was observed for formation of 8.

Scheme 3.

Scheme 3

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Reactions of Z-α,β-Unsaturated Aldehyde Acetals.

As was the case with 7A/7B,7b,c a straightforward entry to enantioselective synthesis was available by utilizing a nonracemic C2-symmetric acetal (Scheme 4). Hydrobenzoin was chosen as a chiral auxiliary primarily because of its commercial availability and ease of removal. The coupling reaction of 2 and 9a,b resulted in both 1,2- and 1,4-addition, and no attempt was made to assign the stereochemistry of 11a,b. The placement of a bulky substituent at the β-position precluded 1,4-addition, as shown in the stereoselective (11:1) formation of 10c. The stereochemistry of the major products 10b,c was assigned by analogy to that of 10a, which had been secured by X-ray analysis.13 The observed 1,3-diastereofacial selectivity by the chiral C2-symmetric acetal is consistent with literature precedence.16

Scheme 4.

Scheme 4

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Use of Non-Racemic C2-Symmetric Acetals.

In order to probe the scope of the key coupling reaction, we next studied the reactions of 12 and 3a–c (Scheme 5). The diastereoselectivity exerted by 12 was considerably lower than that by 2, where the stereochemistry of 13a–c was tentatively assigned by analogy to 4a–c. The observed decrease in selectivity with the cyclopentene system 12 reflects a smaller difference in energy between the two transition states leading to “cis” and “trans” addition. As the final step involves rehybridization from the sp2 carbon to the sp3 quaternary carbon, both transition states involving cyclopentanes contain an increasing number of eclipsing interactions. On the other hand, cyclohexanes, in which a staggered arrangement is possible, presumably display a larger difference in energy between the two transition states corresponding to cis and trans addition. Acyclic di- and tri-substituted alkenyl cyclopropanols gave only low diastereoselectivity.

Scheme 5.

Scheme 5

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Reactions of 12 and Acetals 3a–c.

These addition products possess useful functionalities and are well suited for subsequent elaboration such as annulation of various ring sizes. To demonstrate the synthetic versatility of these products, functionalized seven- and eight-membered carbocycles 19–21 were next prepared from 4a by radical-induced fragmentation of the spirocyclobutanone moiety (Scheme 6).7a,b,17,18 Treatment of 4a with iodine in acetic acid provided a separable 2.5:1 mixture of 14 and 15 in 90% yield and with high diastereofacial selectivity. However, the low regiocontrol was surprising. The stereochemical assignment of 14 and 15 was supported by not only ample literature examples on electrophilic addition of allylic alcohol derivatives,19 but also several correlation studies (including preparation and elaboration of 16 and 17).20 The free radical-mediated cyclization–fragmentation reaction of 15 was next achieved by slow addition of n-tributyltin hydride in the presence of AIBN to give 19 as an easily separable mixture of two epimers (4.4:1, 82% yield), where the trans-ring junction stereochemistry resulted from 1,5-hydrogen transfer. Similarly, free radical-mediated cyclization–fragmentation of 14 and 18 proceeded smoothly to afford 20 and 21 in 84% and 75% yield, respectively. It is interesting to note that 20 was isolated as a mixture of all four diastereomers, whereas 21 was obtained as a ~2:1 mixture of two isomers.

Scheme 6.

Scheme 6

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Free Radical-Mediated Annulation of Medium-Sized Rings.

Conclusions

In summary, a family of coupling reactions between 1-(1-cyclohexenyl)-1-cyclopropanol TMS ether (2) and α,β-unsaturated aldehyde acetals has been developed to quickly assemble spirocyclobutanones containing three contiguous stereocenters. Particularly noteworthy is high diastereoselectivity obtained by employing α,β-alkenal acetals in marked contrast to modest selectivity (3–4:1) observed for other acetals. The resulting products contain useful functionalities such as a cyclobutanone and an allylic ether, which are well suited for elaboration. Mechanistic studies to elucidate dominant factors for diastereocontrol and other methods for diastereoselective functionalization of the coupling products will be reported in due course.

Experimental Section

Representative Procedure for Vinylogous Mukaiyama or Prins-type Reactions of Cycloalkenylcyclopropanol Silyl Ethers

To a cooled (−78 °C) solution of silylether 2 (421 mg, 2 mmol) and acetal 3d (559 mg, 3 mmol) in dichloromethane (20 mL) was added dropwise a solution of TiCl4 (570 mg, 3 mmol) in dichloromethane (3 mL). The reaction mixture was stirred at −78 °C for 15 min and then quenched by sequential addition of saturated NaCl (20 mL) and ether (40 mL). The organic layer was separated and the aqueous layer was extracted with ethyl ether (2 × 10 mL). The combined organic extracts were passed through a short pad of Na2SO4–Al2O3, and the filtrate was concentrated under reduced pressure. Purification of the residue by column chromatography (30 g SiO2, 15:1 to 10:1 hexanes–EtOAc) afforded 4d (491 mg, 84%) as colorless oil, in addition to two diastereomers (64 mg, 11%): IR (film) 1777 cm−1; 1H NMR (500 MHz, CDCl3) δ5.59 (dt, J = 15.5, 6.6 Hz, 1H), 5.18 (ddt, J = 15.5, 9.1, 1.6 Hz, 1H), 3.19 (t, J = 9.1 Hz, 1H), 3.15 (s, 3H), 2.95–2.84 (m, 2H), 2.04 (qd, J = 6.6, 1.4 Hz, 2H), 1.98 (tdd, J = 11.3, 7.6, 1.6 Hz, 1H), 1.78 (ddd, J = 13.5, 9.7, 3.7 Hz, 1H), 1.59 (m, 1H), 1.40–1.10 (m, 15H), 0.88 (t, J = 7.0 Hz, 3H), 0.82 (m, 1H); 13C NMR (125 MHz, CDCl3) δ215.4, 136.8, 129.1, 85.2, 66.9, 55.1, 45.5, 41.2, 33.8, 32.2, 31.6, 29.1, 28.8, 25.8, 25.1, 22.6, 22.0, 18.3, 14.0; HRMS calcd for C19H32O2 (M+) 292.2402, found 292.2412.

4a

IR (film) 1778 cm−1; 1H NMR 1H NMR (500 MHz, CDCl3) δ5.60 (dq, J = 15.2, 6.6 Hz, 1H), 5.19 (ddq, J = 15.2, 9.1, 1.5 Hz, 1H), 3.18 (t, J = 9.1 Hz, 1H), 3.12 (s, 3H), 2.96–2.84 (m, 2H), 1.95 (m, 1H), 1.80–1.66 (m, 2H), 1.72 (dd, J = 6.6, 1.5 Hz, 3H), 1.66–1.60 (m, 2H), 1.59–1.56 (m, 2H), 1.46 (m, 1H), 1.28–1.10 (m, 2H), 0.81 (m, 1H); 13C NMR (125 MHz, CDCl3) δ215.4, 131.1, 130.5, 85.1, 66.9, 55.1, 45.5, 41.2, 33.8, 25.7, 25.1, 22.0, 18.2, 17.7; HRMS calcd for C14H42O2 (M+) 222.1620, found 222.1623.

4b

IR (film) 1778 cm−1; 1H NMR (400 MHz, CDCl3) δ5.58 (dt, J = 15.4, 6.9 Hz, 1H), 5.19 (ddt, J = 15.4, 8.9, 1.4 Hz, 1H), 3.19 (t, J = 8.9 Hz, 1H), 3.13 (s, 3H), 2.97–2.83 (m, 2H), 2.04 (m, 2H), 1.96 (tdd, J = 11.4, 7.7, 1.6 Hz, 1H), 1.78 (ddd, J = 13.4, 9.7, 3.7 Hz, 1H), 1.74–1.35 (m, 8H), 1.31–1.10 (m, 2H), 0.89 (t, J = 7.7 Hz, 3H), 0.82 (m, 1H); 13C NMR (100 MHz, CDCl3) δ215.3, 136.5, 129.2, 85.2, 66.9, 55.1, 45.5, 41.2, 34.3, 33.8, 25.8, 25.1, 22.4, 22.1, 18.3, 13.7; HRMS calcd for C16H26O2 (M+) 250.1933, found 250.1938.

4c

IR (film) 1777 cm−1; 1H NMR (500 MHz, CDCl3) δ5.58 (dt, J = 15.5, 6.5 Hz, 1H), 5.19 (ddt, J = 15.5, 9.0, 1.5 Hz, 1H), 3.18 (t, J = 9.0 Hz, 1H), 3.14 (s, 3H), 2.97–2.85 (m, 2H), 2.08–2.03 (m, 2H), 1.96 (m, 1H), 1.78 (ddd, J = 12.5, 10.0, 3.5 Hz, 1H), 1.70 (m, 1H), 1.67–1.61 (m, 2H), 1.60–1.55 (m, 2H), 1.47 (m, 1H), 1.42–1.11 (m, 7H), 0.93–0.78 (m, 5H); 13C NMR (125 MHz, CDCl3) δ215.4, 136.8, 129.1, 85.2, 66.9, 55.1, 45.5, 41.2, 33.8, 32.1, 31.3, 28.9, 25.8, 25.1, 22.4, 22.0, 18.3, 14.0; HRMS calcd for C18H30O2 (M+) 278.2246, found 278.2247.

4e

IR (film) 1779 cm−1; 1H NMR (500 MHz, CDCl3) δ5.82 (d, J = 18.5 Hz, 1H), 5.74 (dd, J = 18.5, 7.5 Hz, 1H), 3.20 (dd, J = 9.5, 7.5 Hz, 1H), 3.15 (s, 3H), 2.97–2.86 (m, 2H), 1.97 (m, 1H), 1.80 (ddd, J = 13.0, 10.0, 3.5 Hz, 1H), 1.71 (ddd, J = 13.0, 5.0, 3.0 Hz, 2H), 1.67–1.56 (m, 2H), 1.56–1.43 (m, 2H), 1.30–1.12 (m, 2H), 0.85 (m, 1H), 0.06 (s, 9H); 13C NMR (125 MHz, CDCl3) δ215.3, 144.7, 136.4, δ87.9, 66.8, 55.6, 45.0, 41.2, 33.8, 25.6, 25.1, 22.0, 18.3, −1.3; HRMS calcd for C16H28O2Si (M+) 280.1859, found 280.1863.

5A

IR (film) 1774 cm−1; 1H NMR (360 MHz, CDCl3) δ3.44 (dd, J = 8.1, 7.3 Hz, 2H), 3.28 (s, 3H), 3.18 (dt, J = 9.0, 4.0 Hz, 1H), 2.87–3.01 (m, 2H), 2.26 (m, 1H), 2.07 (m, 1H), 1.85–1.99 (m, 2H), 1.59–1.73 (m, 5H), 1.47 (m, 1H), 1.26 (m, 2H), 0.97 (m, 1H); 13C NMR (90 MHz, CDCl3) δ215.0, 81.3, 67.1, 56.5, 44.3, 41.5, 34.3, 34.2, 28.8, 26.3, 25.4, 22.0, 18.6.

5B

IR (film) 1766 cm−1; 1H NMR (360 MHz, CDCl3) δ3.44–3.57 (m, 3H), 3.33 (s, δ3H), 2.91 (t, J = 8.4 Hz, 2H), 2.25 (dt, J = 11.0, 8.4 Hz, 1H), 1.74–1.82 (m, 2 H), 1.48–1.68 (m, 9H), 1.22 (m, 1H); 13C NMR (90 MHz, CDCl3) δ215.2, 80.2, 67.1, 58.2, 46.3, 41.6, 36.1, 35.8, 31.1, 25.9, 25.7, 23.3, 23.1.

5C (third isomer; structure not shown in Scheme 2)

IR (film) 1770 cm−1; 1H NMR 1H NMR (500 MHz, CDCl3) δ3.35–3.46 (m, 2H), 3.32 (s, 3H), 3.28 (td, J = 6.8, 3.2 Hz, 1H), 3.00 (ddd, J = 18.4, 10.0 Hz, 6.8 Hz, 1H), 2.90 (ddd, J = 18.4, 10.0, 6.4 Hz, 1H), 2.34 (m, 1H), 2.08 (m, 1H), 1.97 (m, 1H), 1.68–1.77 (m, 4H), 1.60–1.68 (m, 2H), 1.48 (m, 1H), 1.34 (m, 1H), 1.15–1.30 (m, 2H); 13C NMR (125 MHz, CDCl3) δ216.5, 80.8, 69.1, 57.8, 43.2, 42.2, 35.6, 34.6, 30.1, 25.6, 23.0, 22.0, 19.9.

10a

IR (film) 1778 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.20–7.24 (m, 3H), 7.10–7.14 (m, 3H), 6.95–7.02 (m, 4H), 5.16–5.27 (m, 2H), 4.72 (d, J = 8.0 Hz, 1H), 4.70 (br s, 1H, -OH), 4.41 (d, J = 8.0 Hz, 1H), 3.38 (t, J = 9.5 Hz, 1H), 3.23 (ddd, J = 18.0, 10.0, 5.0 Hz, 1H), 3.15 (ddd, J = 18.0, 10.0, 7.5 Hz, 1H), 2.01 (m, 1H), 1.88 (ddd, J = 12.6, 9.5, 3.7 Hz, 1H), 1.77 (m, 1H), 1.58–1.70 (m, 3H), 1.68 (d, J = 5.2 Hz, 3H). 1.44–1.54 (m, 2H), 1.28 (m, 1H), 1.16 (m, 1H), 0.73 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 218.3, 139.5, 137.2, 132.5, 130.3, 128.2, 128.1, 127.9, 127.7, 127.3, 127.1, 83.3, 79.6, 77.9, 66.9, 45.4, 41.9, 33.9, 25.9, 25.0, 22.0, 18.1, 17.7.

10b

IR (film) 1769 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.18–7.22 (m, 3H), 7.10–7.16 (m, 3H), 6.95–7.04 (m, 4H), 5.12–5.27 (m, 2H), 4.71 (d, J = 8.5 Hz, 1H), 4.45 (d, J = 8.5 Hz, 1H), 3.39 (dd, J = 9.3, 8.5 Hz, 1H), 3.24 (ddd, J = 18.0, 9.7, 4.9 Hz, 1H), 3.15 (ddd, J = 18.0, 9.7, 7.7 Hz, 1H), 1.98–2.03 (m, 2H), 1.89 (m, 1H), 1.76 (m, 1H), 1.58–1.72 (m, 3H), 1.42–1.57 (m, 2H), 1.10–1.40 (m, 10H), 0.88 (t, J = 7.3 Hz, 3H), 0.74 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 218.1, 139.5, 137.9, 137.1, 128.9, 128.2, 128.0, 127.8, 127.6, 127.2, 127.1, 83.2, 79.6, 77.9, 67.0, 45.5, 42.0, 33.9, 32.2, 31.4, 28.8, 25.7, 25.1, 22.5, 22.1, 18.2, 14.1.

10c

IR (film) 3565, 1778 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.20–7.24 (m, 3H), 7.05–7.12 (m, 3H), 6.98–7.12 (m, 2H), 6.94–6.97 (m, 2H), 5.71 (dd, J = 18.7, 8.1Hz, 1H), 5.50 (d, J = 18.7 Hz, 1H), 4.72 (d, J = 8.1 Hz, 1H), 4.38 (d, J = 8.1 Hz, 1H), 3.57 (dd, J = 9.6, 9.1 Hz, 1H), 3.22 (dd, J = 17.7, 9.6, 5.1 Hz, 1H), 3.15 (ddd, J = 17.7, 9.6, 7.1 Hz, 1H), 1.99 (m, 1H), 1.92 (ddd, J = 13.0, 9.6, 3.5 Hz, 1H), 1.78 (m, 1H), 1.55–1.70 (m, 4H), 1.51 (m, 1H), 1.42 (m, 1H), 1.29 (m, 1H), 1.17 (m, 1H), 0.75 (m, 1H), 0.06 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 218.3, 144.4, 139.7, 138.3, 137.0, 128.3, 128.1, 128.0, 127.8, 127.4, 127.0, 83.5, 82.3, 77.9, 66.9, 44.7, 42.0, 33.9, 25.4, 25.0, 22.0, 18.2, −1.4.

13a

IR (film) 1771 cm−1; 1H NMR (400 MHz, CDCl3) δ5.63 (dq, J = 15.4, 6.5 Hz, 1H), 5.22 (ddq, J = 15.4, 8.5, 1.6 Hz, 1H), 3.32 (dd, J = 10.1, 8.5 Hz, 1H), 3.15 (s, 3H), 2.93 (t, J = 8.3 Hz, 2H), 2.14–2.30 (m, 2H), 1.98 (m, 1H), 1.55–1.84 (m, 5H), 1.71 (dd, J = 6.5, 1.6 Hz, 3H), 1.19 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 216.3, 130.5, 129.8, 84.3, 71.9, 55.2, 50.3, 42.9, 37.7, 28.1, 23.2, 21.1, 17.7; HRMS calcd for C12H17O2 (M+–Me) 193.1229, found 193.1233.

13b

IR (film) 1778 cm−1; 1H NMR (400 MHz, CDCl3) δ5.61 (dt, J = 15.4, 6.9 Hz, 1H), 5.20 (ddt, J = 15.4, 8.5, 1.6 Hz, 1H), 3.34 (dd, J = 10.1, 8.5 Hz, 1H), 3.17 (s, 3H), 2.95 (t, J = 8.3 Hz, 2H), 2.14–2.32 (m, 2H), 1.93–2.04 (m, 2H), 1.80 (m, 1H), 1.55–1.68 (m, 3H), 1.35–1.45 (m, 2H), 1.18 (m, 1H), 0.89 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 216.3, 135.2, 129.4, 84.4, 72.0, 55.3, 50.4, 42.9, 37.8, 34.3, 28.2, 23.2, 22.4, 21.2, 13.6; HRMS calcd for C15H24O2 (M+) 236.1776, found 236.1779.

13c

IR (film) 1778 cm−1; 1H NMR (400 MHz, CDCl3) δ5.61 (dt, J = 15.4, 6.9 Hz, 1H), 5.20 (ddt, J = 15.4, 8.5, 1.6 Hz, 1H), 3.33 (dd, J = 10.1, 8.5 Hz, 1H), 3.18 (s, 3H), 2.94 (t, J = 8.3 Hz, 2H), 2.06–2.32 (m, 2H), 1.94–2.04 (m, 3H), 1.81 (m, 1H), 1.56–1.68 (m, 4H), 1.05–1.23 (m, 7H), 0.88 (t, J = 6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 216.3, 135.5, 129.2, 84.4, 72.0, 55.3, 50.4, 42.9, 37.8, 32.2, 31.3, 28.9, 28.2, 23.2, 25.5, 21.8, 14.1; HRMS calcd for C17H28O2 (M+) 264.2089, found 264.2096.

Preparation of 14 and 15

A mixture of cyclobutanone 4a (178 mg, 0.8 mmol), Hg(OAc)2 (318.7 mg, 1.0 mmol), and iodine (254 mg, 1.0 mmol) in acetic acid (4.0 mL) was stirred at room temperature for 4 h. The solvent was evaporated under reduced pressure. The residue was dissolved in ether, washed with brine and an aqueous sodium bicarbonate solution, dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by preparative TLC to afford 14 (209.3 mg, 64%) and 15 (84.1 mg, 26%).

14

IR (film) 1776, 1739 cm−1; 1H NMR (400 MHz, CDCl3) δ5.17 (dq, J = 9.7, 6.1 Hz, 1H), 4.13 (dd, J = 9.7, 1.2 Hz, 1H), 3.36 (s, 3H), 2.98 (ddd, J = 17.8, 9.7, 6.9 Hz, 1H), 2.85 (ddd, J = 17.8, 9.7, 4.9 Hz, 1H), 2.55 (dd, J = 9.3, 1.2 Hz, 1H), 2.10 (s, 3H), 1.99 (ddd, J = 12.2, 9.3, 3.4 Hz, 1H), 1.89 (dddd, J = 11.4, 9.7, 6.9, 1.6 Hz, 1H), 1.60–1.80 (m, 6H), 1.52 (d, J = 6.1 Hz, 3H), 1.20–1.40 (m, 2H), 1.12 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 213.2, 169.4, 80.5, 72.6, 66.5, 59.2, 46.8, 43.1, 41.1, 33.8, 27.6, 24.9, 22.0, 21.9, 21.3, 19.4.

15

IR (film) 1776, 1743 cm−1; 1H NMR (400 MHz, CDCl3) δ 5.37 (dd, J = 4.9, 1.8 Hz, 1H), 4.48 (qd, J = 6.9, 4.9 Hz, 1H), 3.38 (s, 3H), 3.34 (dd, J = 9.3, 1.8 Hz, 1H), 2.94 (ddd, J = 17.0, 9.7, 6.9 Hz, 1H), 2.81 (ddd, J = 17.0, 9.7, 5.3 Hz, 1H), 2.18 (s, 3H), 2.03 (m, 1H), 1.99 (d, J = 6.9 Hz, 3H), 1.85–1.58 (m, 7H), 1.08–1.36 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 213.6, 170.0, 84.8, 78.7, 66.6, 59.1, 43.6, 41.0, 33.9, 27.8, 25.1, 24.6, 23.5, 21.7, 21.0, 18.9.

16

IR (film) 2934, 2859 cm−1; 1H NMR (400 MHz, CDCl3) δ4.54 (hept, J = 6.1 Hz, 1H), 4.43 (dq, J = 10.1, 6.9 Hz, 1H), 3.80 (dd, J = 2.5, 0.8 Hz, 1H), 3.68 (dd, J = 10.1, 0.8 Hz, 1H), 3.59 (s, 3H), 2.14–2.28 (m, 2H), 2.04 (d, J = 6.9 Hz, 3H), 1.96 (m, 1H), 1.60–1.80 (m, 4H), 1.40–1.53 (m, 5H), 1.29 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 103.3, 78.9, 78.3, 68.9 (q, J = 32.8 Hz), 68.6 (q, J = 32.8 Hz), 62.0, 47.2, 43.6, 32.0, 31.0, 26.3, 26.2, 25.5, 24.4, 22.2, 21.3 (2 C’s).

17

IR (film) 2934, 2859 cm−1; 1H NMR (400 MHz, CDCl3) δ 4.46 (hept, J = 6.1 Hz, 1H), 4.26–4.34 (m, 2H), 3.80 (br s, 1H), 3.43 (s, 3H), 2.72 (m, 1H), 2.22 (m, 1H), 2.05 (dd, J = 12.6, 2.4 Hz, 1H), 1.95 (ddd, J = 13.0, 10.1, 3.7 Hz, 1H), 1.52–1.78 (m, 5H), 1.43 (d, J = 6.5 Hz, 3H), 1.34–1.48 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 109.3, 94.7, 94.5, 73.4, 69.7 (q, J = 33 Hz), 69.3 (q, J = 33 Hz), 59.3, 53.9, 39.5, 39.3, 34.3, 30.9, 29.3, 26.4, 21.6, 21.4, 19.5.

18

IR (film) 3434, 1764 cm−1; 1H NMR (400 MHz, CDCl3) δ 4.18 (dq, J = 9.3, 6.5 Hz, 1H), 4.01 (dd, J = 9.3, 1.8 Hz, 1H), 3.48 (s, 3H), 3.03 (dd, J = 9.3, 1.8 Hz, 1H), 2.84–3.00 (m, 2H), 2.06 (ddd, J = 11.8, 9.3, 3.2 Hz, 1H), 1.98 (m, 1H), 1.47–1.78 (m, 7H), 1.54 (d, J = 6.5 Hz, 3H), 1.18–1.38 (m, 2H), 1.07 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 214.0, 80.3, 70.0, 66.8, 58.8, 46.8, 46.5, 41.1, 33.9, 27.8, 25.0, 25.0, 21.9, 19.5.

Representative Procedure for Free radical cyclization

A solution of 15 (20 mg, 0.049 mmol) in benzene (5.0 mL) was heated at reflux under an argon atmosphere. A solution of n-Bu3SnH (30 mg, 0.1 mmol) and AIBN (1.6 mg, 0.01 mmol) in benzene (1.0 mL) was added over 6 h. The solvent was evaporated under reduced pressure and the residue was treated with Et3N.3HF complex (0.5 mL) in ether (3.0 mL). The resulting mixture was stirred for 1 h at room temperature and passed through a pad of SiO2. The filtrate was concentrated under reduced pressure. The crude product was purified by SiO2 (1.0 g) column chromatography using 10:1 hexanes-ethyl acetate as eluent to give 19 (11.3 mg, 82%) as a 4.4:1 mixture of diastereomers: (major diastereomer) IR (film) 1740, 1702 cm−1; 1H NMR (400 MHz, CDCl3) δ 5.08 (dd, J = 5.0, 2.8 Hz, 1H), 3.41 (dq, J = 6.5, 5.0 Hz, 1H), 3.35 (s, 3H), 3.24 (d, J = 2.8 Hz, 1H), 2.72 (m, 1H), 2.30 (ddd, J = 19.1, 6.5, 3.2 Hz, 1H), 2.12 (s, 3H), 1.55–1.80 (m, 7H), 1.05–1.22 (m, 5H), 1.01 (d, J = 6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 213.2, 170.5, 87.8, 79.6, 61.0, 44.7, 42.9, 38.5, 36.4, 36.0, 34.0, 26.6, 26.2, 21.1, 12.5 (There is an overlap corresponding to 2 C’s.); HRMS calcd for C16H26O4 (M+) 282.1831, found 282.1838.

21 (higher Rf; trans-ring junction isomer)

IR (film) 3435, 1693 cm−1; 1H NMR (400 MHz, CDCl3) δ 3.97 (apparent quintet, J = 6.1 Hz, 1H), 3.64 (d, J = 6.1 Hz, 1H), 3.40 (s, 3H), 3.30 (d, J = 4.5 Hz, 1H), 2.79 (dd, J = 6.1, 4.5 Hz, 1H), 2.73 (ddd, J = 15.0, 10.1, 2.8 Hz, 1H), 2.39 (ddd, J = 15.0, 10.1, 2.8 Hz, 1H), 1.95 (m, 1H), 1.45–1.56 (m, 6H), 1.03–1.40 (m, 3H), 1.27 (d, J = 6.5 Hz, 3H), 0.96–1.02 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 216.5, 84.0, 67.7, 60.7, 59.1, 45.5, 41.8, 37.1, 34.5, 32.9, 30.9, 26.5, 26.1, 21.7.

21 (lower Rf; cis-ring junction isomer)

IR (film) 3454, 1697 cm−1; 1H NMR (400 MHz, CDCl3) δ 4.22 (qd, J = 6.5, 2.4 Hz, 1H), 3.79 (dd, J = 10.9, 2.4 Hz, 1H), 3.42 (s, 3H), 2.57 (ddd, J = 12.2, 12.2, 2.8 Hz, 1H), 2.46 (dd, J = 10.9, 2.4 Hz, 1H), 2.40 (d, J = 6.5 Hz, 1H), 2.34 (ddd, J = 12.2, 6.5, 2.0 Hz, 1H), 2.12 (ddd, J = 12.6, 6.5, 2.8 Hz, 1H), 1.74–2.00 (m, 3H), 1.50–1.65 (m, 5H), 1.20–1.50 (m, 2H), 1.25 (d, J = 6.5 Hz, 3H), 1.07 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 213.3, 82.3, 68.2, 60.5, 57.4, 43.6, 42.6, 38.5, 33.6, 26.8, 26.6, 21.6, 21.2, 20.7.

Supplementary Material

1File002. Supporting Information Available.

1H and 13C NMR spectra of key intermediates. This material is available free of charge via the Internet at http://pubs.acs.org.

Acknowledgments

We thank the National Institutes of Health (GM35956) and the National Science Foundation (CHE0615604) for generous financial support.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

1File002. Supporting Information Available.

1H and 13C NMR spectra of key intermediates. This material is available free of charge via the Internet at http://pubs.acs.org.

NIHMS62654-supplement-1File002.pdf (4.8MB, pdf)

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