Stereoselective synthesis of alcohols. Part LIII. (E)-γ-Alkoxyallylboronates: generation and application in intramolecular allylboration reactions

Abstract

Alkoxyalkynes 9 may be hydroborated with pinacol borane, preferentially under Cp₂ZrHCl catalysis, to give the vinylboronates 10. The latter, when subjected to the Matteson–Brown homologation with LiCH₂Cl, give rise to the (E)-γ-alkoxyallylboronates 3 in good yield. This reaction sequence has been used to generate the (E)-γ-alkoxyallylboronates 14, 21, 26 and 31, which were the starting point for intramolecular allylboration reactions leading to the trans-disubstituted tetrahydropyrans 8 and 22, as well as hydrooxepans 27 and 32.

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Among the allylmetallation reactions of aldehydes^2,3 the addition of γ-substituted allylboronates 1 to aldehydes (Scheme 1) provides the greatest synthetic flexibility, because both the (E)- and (Z)-γ-substituted allylboronates are configurationally stable and add to aldehydes with high simple diastereoselectivity, translating the geometry of the double bond into the relative configuration of the two newly formed stereocenters in the product. For a review see ref. 3.

Scheme 1

The application of these reactions in synthesis is, however, compromised by the fact that not all γ-heterosubstituted allylboronates of interest are equally well accessible as both the (Z)- and the (E)-isomers. Problems are associated with the generation of the (E)-γ-alkoxyallylboronates, for which our initial procedure⁴ is moderately practicable at best.⁵ More recently, Miyaura and co-workers described a second route to these species by an iridium-catalyzed isomerization of γ-alkoxyvinylboronates 2 (Scheme 2).⁶

Yet, when structures such as 4 were to be attained by allylmetallation reactions, chemists frequently resorted to a multistep route (Scheme 2) involving the (E)-γ-silylallylboronates 5 as reagents, followed by conversion of the silyl residue in the adduct 6 to the desired oxygen functionality.⁷ Obviously, the route [italic v]ia the γ-silylallyl boronates 5 is not viable when one is interested in an intramolecular allylboration (Scheme 3) that should lead to heterocyclic compounds such as 8.

Scheme 2

Scheme 3

In the search for another route to (E)-γ-alkoxyallylboronates such as 7 we envisaged a homologation of vinylboronates to allylboronates,⁹[italic v]iz. the conversion of 10 into 3 (Scheme 3), a method that is increasingly gaining importance.¹⁰ This route would rely on the hydroboration of an alkoxyalkyne 9 to give 10. We hoped that the direct hydroboration of readily accessible alkoxyalkynes 9¹¹ with pinacol borane¹² should afford the desired vinylboronate 10.

Results and discussion

We started our investigation (Scheme 4) with the alcohol 11,¹³ which was converted to the alkoxyalkyne 12 in 65–80% yield following Greene's procedure.¹¹ Hydroboration of 12 with pinacol borane could be effected in ca. 70% yield by keeping the temperature below 50°C while accepting longer reaction times. Higher temperatures resulted in a competing retro-ene decomposition of 12 to give ketene and 1,1-dimethoxy-3-butene. The crude vinylboronate 13 was directly homologated with LiCH₂Cl at − 105°C to give the allylboronate 14 in ca. 80% conversion. The mixture of 14 and residual 13 was directly subjected to mild acetal hydrolysis with Yb(OTf)₃ in moist acetonitrile,¹⁴ resulting in the immediate formation of the desired trans-2-vinyltetrahydropyranol-3 8 in 66% yield from 12. Compound 8 was obtained as a single diastereomer. It was identified with reference to a sample prepared by intramolecular allylstannation following the procedure of Yamamoto and colleagues.¹⁵

Scheme 4

The clean conversion of the alcohol 11[italic v]ia the alkoxyalkyne 12 and the allylboronate 14 into the trans-vinyltetrahydropyranol 8 demonstrates the versatility of this route to (E)-γ-alkoxyallylboronates and their use in intramolecular allylboration reactions. In view of the general interest in trans-fused annelated oligo-tetrahydropyrans,¹⁶ we wanted to explore the subsequent conversion of 8 into the bicyclic bis-tetrahydropyran 22. This required the conversion of the vinyl group in 8 into a latent aldehyde function, such as a dimethyl acetal. This was accomplished in a series of standard transformations (Scheme 5): protection of the alcohol as an acetate 15 (86%), hydroboration of 15 to give the primary alcohol 16 using di-sec-isoamylborane (70%), Swern oxidation of the primary alcohol 16 to an aldehyde followed by in situ acetalization to give 17 (90%), and finally, cleavage of the acetate in 17 by K₂CO₃ in methanol to give the alcohol 18 (92%).

Scheme 5

The alcohol 18 is the starting point for a second round of intramolecular allylboration (Scheme 6). To this end, the alcohol 18 was converted to the alkoxyalkyne 19 as above (78%). We found that the hydroboration of alkoxyalkynes 9 to give the vinylboronate 10 (Scheme 3) could be carried out at room temperature when catalyzed with zirconocene hydrido chloride.¹⁷ This allowed us to similarly convert the alkoxyalkyne 19 in 87% yield to the vinylboronate 20. Subsequent transformation of 20 into the allylboronate 21 (95%) proceeded as usual. Liberation of the aldehyde from 21 with LiBF₄ in moist acetonitrile¹⁸ initiated the intramolecular allylboration, which resulted in the formation of 76% of the desired bicyclic bis-tetrahydropyran 22. The latter was obtained as a single diastereomer, attesting to the high asymmetric induction from the stereocenters resident in the cyclization precursor 21. For alternate syntheses of 22 see ref. 19.

Scheme 6

We recently showed²⁰ that hydroformylation is a good way to generate an aldehyde function in the presence of an allylboronate moiety. This opens the way to a domino hydroformylation–allylboration–hydroformylation sequence, allowing rapid access to annelated heterocyclic structures. It was therefore tempting to combine this technique with the generation of (E)-γ-alkoxyallylboronates described above. Model studies of this point were carried out starting from the homoallylic alcohol 23 (Scheme 7). The latter was converted to the alkoxyalkyne 24 in 78% yield. Hydroboration of 24 was effected with pinacol borane catalyzed by zirconocene hydrido chloride¹⁷ (69%). Subsequent homologation of 25 afforded the allylboronate 26 (65% over two steps).

Scheme 7

Hydroformylation of the latter (Scheme 7) was carried out in the presence of the BIPHEPHOS ligand²¹ to attain a high preference for the formation of the linear aldehyde over the branched aldehyde. This, however, entailed that the hydroformylation reaction became rather slow, requiring two days at 65°C and 5 bar of CO–H₂. In the end this treatment resulted in the expected domino hydroformylation–allylboration–hydroformylation reaction to give 48% of the lactols 27, which were obtained as a mixture of anomers. The products obtained could be separated into two diastereomeric sets of lactols 27a and 27b, which were obtained in a ca. 1:1 ratio. To facilitate structure assignment, each of these mixtures was oxidized²² with the Dess–Martin reagent²³ to a single lactone 28a and 28b, respectively. Assignment of the relative configuration was made by NMR NOE spectroscopy.

The fact that the two cyclization products 27a and 27b were obtained in a nearly 1:1 ratio indicates that asymmetric induction on the formation of a seven-membered hydro-oxepane ring was low.

At this point we did not know whether this was a singular event or characteristic of a more general feature. For this reason we investigated a second domino hydroformylation–allylboration–hydroformylation reaction leading to an annelated hydro-oxepane ring. To this end we converted the vinyltetrahydropyranol 8 into the alkoxyalkyne 29 (72%, Scheme 8). Zirconocene hydrido chloride catalyzed hydroboration,¹⁷ followed by homologation, furnished the allylboronate 31 (50% over two steps). The allylboronate was subjected to the hydroformylation conditions. The reaction turned out to be rather slow, requiring more than three days at 65°C. The products obtained (52%) were not the lactols, but the corresponding enol ethers 32. Apparently dehydration, to give 32, had occurred during the longer reaction period. The tricyclic compounds were again obtained as a 1:1 mixture of stereoisomers, presumably the trans-syn-trans32a and the trans-anti-trans isomer 32b. The individual structures were not assigned to the materials obtained.

Scheme 8

This made it clear that intramolecular allylboration to form hydro-oxepane rings is stereounselective, showing no asymmetric induction from the resident stereocenters present in the cyclization precursors 26 or 31. This contrasts to the high asymmetric induction found on intramolecular allylboration to give the tetrahydropyran ring in the cyclization of 21 to 22.

In conclusion, we have found a reliable route to (E)-γ-alkoxyallylboronates starting from alcohols, [italic v]ia alkoxyalkynes, hydroboration and homologation. The γ-alkoxyallylboronates 13, 21, 26 and 31 served as substrates for intramolecular allylboration reactions, giving rise to tetrahydropyrans 8 and 22 and the hydro-oxepane ring systems 27 and 32.

Experimental

All temperatures quoted are not corrected. ¹H-NMR and ¹³C-NMR spectra were obtained on: Bruker ARX-200, AC-300, ARX-400 and AMX-500 spectrometers. Boiling range of petroleum ether used: 40–60°C. Buffer (pH 7) was made with 56.2 g of NaH₂PO₄·2 H₂O and 213.2 g Na₂HPO₄·2 H₂O in 1.0 L of water. Flash chromatography was performed using silica gel Si60 (40–63 μm, E. Merck AG, Darmstadt).

4-Ethynyloxy-1,1-dimethoxybutane (12)

4,4-Dimethoxybutanol 11¹³ (1.740 g, 12.97 mmol) was added dropwise at 0°C into a suspension of potassium hydride (1.040 g, 25.93 mmol) in THF (50 mL). After stirring for 1.5 h the mixture was cooled to − 78°C. Trichloroethene (1.708 g, 13.0 mmol) was added and the mixture was allowed to reach room temperature. After stirring for 1 h the mixture was again cooled to − 78°C and a solution of n-butyllithium in hexane (1.58 M, 20.0 mL, 31.6 mmol) was added dropwise. The temperature was allowed to reach − 40°C over 1.5 h. Anhydrous methanol (3.95 g, 125 mmol) was added and the mixture was allowed to reach room temperature. Saturated aqueous NaHCO₃ solution (30 mL) was added, the phases were separated and the aqueous phase was extracted with ether (3 × 30 mL). The combined organic phases were dried (K₂CO₃) and concentrated. The residue was purified by filtration over a 7 cm layer of silica gel with petroleum ether containing 0.3% triethylamine to give 1.633 g (80%) of 12 as a slightly yellowish oil. ¹H-NMR (300 MHz, CDCl₃): δ = 1.51 (s, 1H), 1.65–1.73 (m, 2H), 1.75–1.85 (m, 2H), 3.31 (s, 6H), 4.08 (t, J = 6.2 Hz, 2H), 4.37 (t, J = 5.5 Hz, 1H). ¹³C-NMR (75 MHz, CDCl₃): δ = 23.9, 26.3, 28.4, 52.9, 78.6, 91.0, 104.0. C₈H₁₄O₃ requires C 60.74, H 8.92; found C 60.62, H 9.20%.

trans-2-Vinyltetrahydropyran-3-ol (8)

Freshly prepared pinacol borane¹² (712 mg, 5.56 mmol) was added at 0°C into a solution of 12 (173 mg, 1.09 mmol) in dichloromethane (0.7 mL). The mixture was stirred for 20 h at 42°C until TLC indicated complete conversion. The volatiles were removed at 10⁻² Torr to leave crude 13 (302 mg), which was purified by flash chromatography with petroleum ether–ether 5:1 containing 1% triethylamine. 13 (218 mg, 70%) was obtained as a colorless liquid. ¹H-NMR (300 MHz, CDCl₃): δ = 1.21 (s, 12H), 1.67 (m, 4H), 3.28 (s, 6H), 3.75 (br t, J = 5.9 Hz, 2H), 5.31 (m, 1H), 4.39 (d, J = 14.4 Hz, 1H), 7.00 (d, J = 14.4 Hz, 1H). ¹³C-NMR (75 MHz, CDCl₃): δ = 24.0, 24.7, 29.0, 52.7, 68.4, 82.6, 104.2, 163.9. The material was immediately converted to the allylboronate 14.

A solution of n-butyllithium in hexane (1.49 M, 4.36 mL, 6.50 mmol) was added under an argon atmosphere at − 105°C into a solution of the vinylboronate 13 (1.644 g, 5.03 mmol) and chloroiodomethane (473 μL, 6.5 mmol) in THF (25 mL). After reaching room temperature overnight pH 7 buffer solution (20 mL) was added, the phases were separated and the aqueous phase was extracted with ether (3 × 10 mL). The combined organic phases were washed with brine (10 mL), dried (Na₂SO₄) and concentrated. NMR analysis of the residue showed the presence of a 4:1 mixture of 14 :13, corresponding to a yield of 14 of 78%. The following NMR data of 14 could be recorded: ¹H-NMR (300 MHz, CDCl₃): δ = 1.45 (br d, J = 7.21 Hz, 2H), 4.74 (dt, J = 12.6 and 7.5 Hz, 1H), 6.18 (d, J = 12.6 Hz, 1H). ¹³C-NMR (75 MHz, CDCl₃): δ = 24.7, 29.0, 52.6, 68.6, 83.1, 98.9, 104.3, 146.1.

The mixture of 13 and 14 obtained was taken up in acetonitrile (30 mL). Water (0.6 mL) and ytterbium triflate (312 mg, 0.1 equiv.) were added. After stirring for 12 h ether (20 mL) and saturated aqueous NaHCO₃ solution (10 mL) were added. The phases were separated and the aqueous phase was extracted with ether (3 × 10 mL). The combined organic phases were washed with brine (10 mL), dried (Na₂SO₄) and concentrated by distillation over a short column. The residue was purified by flash chromatography with pentane–ether (1:1) and the eluates were concentrated at 0°C to leave the vinyltetrahydropyranol 8 (419 mg, 66%) as a single diastereomer. ¹H-NMR (300 MHz, CDCl₃): δ = 1.46 (m, 1H), 1.66–1.80 (m, 3H), 2.14 (m, 1H), 3.27–3.50 (m, 3H), 3.94 (m, 1H), 5.31 (ddd, J = 10.5, 1.6, 0.8 Hz, 1H), 5.38 (ddd, J = 17.3, 1.7, 1.2 Hz, 1H), 5.87 (ddd, J = 17.5, 10.6 7.0 Hz, 1H). ¹³C-NMR (75 MHz, CDCl₃): δ = 25.3, 31.6, 67.4, 69.5, 84.0, 118.8, 136.2. These data corresponded to a sample that was prepared according to the procedure given by Yamamoto et al.¹⁵

trans-3-Acetoxy-2-vinyltetrahydropyran (15)

Pyridine (2.50 mL) was added to a solution of trans-2-vinyl-tetrahydropyran-3-ol 8 (1.31 g, 10.2 mmol) in dichloromethane (20 mL). Acetyl chloride (1.09 mL, 15.3 mmol) was added dropwise at 0°C. After stirring for 2 h at 0°C and 2 h at room temperature diethyl ether (50 mL) was added, the mixture was filtered over a small pad of Kieselgur and the filtrate was concentrated. Flash chromatography (pentane–diethyl ether = 10:1) furnished 15 (1.50 g, 86%) as a colorless oil. R_f(PE–EtOAc 5:1) = 0.37. ¹H-NMR (300 MHz, CDCl₃): δ = 1.52 (tdd, J = 11.9, 11.0, 5.2 Hz, 1H), 1.65–1.86 (m, 2H), 2.02 (s, 3H), 2.10–2.22 (m, 1H), 3.42 (td, J = 11.0, 3.5 Hz, 1H), 3.64–3.73 (m, 1H), 3.97 (ddt, J = 11.3, 3.9, 2.0 Hz, 1H), 4.61 (ddd, J = 10.6, 9.2, 4.6 Hz, 1H), 5.17–5.24 (m, 1H), 5.26–5.36 (m, 1H), 5.80 (ddd, J = 17.3, 10.6, 6.7 Hz, 1H). These data correspond to those given in ref. 18. ¹³C-NMR (75 MHz, CDCl₃): δ = 21.1, 24.9, 29.2, 67.3, 71.2, 80.6, 117.9, 135.5, 170.0.

trans-3-Acetoxy-2-(2-hydroxyethyl)tetrahydropyran (16)

2-Methyl-2-butene (3.77 mL, 35.5 mmol) was added dropwise at 0°C into a solution of borane-dimethyl sulfide complex (1.71 mL, 17.8 mmol) in THF (1.7 mL). After stirring for 1 h at room temperature THF (4.6 mL) was added and the resulting solution was added dropwise at 0°C into a solution of trans-3-acetoxy-2-vinyltetrahydropyran 15 (1.21 g, 7.1 mmol) in THF (7 mL). After stirring for 30 min each at 0°C and 25°C the mixture was recooled to 0°C and hydrolyzed by addition of aqueous NaOAc solution (7 mL, 35 mmol) and 30% aqueous H₂O₂ (7 mL). After stirring for 12 h diethyl ether (20 mL) was added, the phases were separated and the aqueous phase was extracted with diethyl ether (5 × 20 mL). The combined organic phases were dried (Na₂SO₄) and concentrated. Flash chromatography of the residue with pentane–diethyl ether (1: 5) furnished 16 (937 mg, 70%) as a colorless oil. R_f(PE–Et₂O 1: 5) = 0.21. ¹H-NMR (300 MHz, CDCl₃): δ = 1.45 (tdd, J = 12.2, 11.0, 5.1 Hz, 1H), 1.59–1.80 (m, 3H), 1.81–1.93 (m, 1H), 2.05 (s, 3H), 2.12–2.23 (m, 1H), 3.33–3.53 (m, 2H), 3.72–3.85 (m, 2H), 3.93 (ddt, J = 11.3, 4.1, 1.9 Hz, 1H), 4.57 (ddd, J = 10.5, 9.5, 4.6 Hz, 1H). ¹³C-NMR (75 MHz, CDCl₃): δ = 21.0, 24.9, 29.1, 33.8, 60.6, 67.6, 71.6, 79.4, 170.1. C₉H₁₆O₄ requires C 57.43, H 8.57; found C 57.23, H 8.62%.

trans-3-Acetoxy-2-(2,2-dimethoxyethyl)tetrahydropyran (17)

Dimethyl sulfoxide (802 μL, 11.3 mmol) was added dropwise at − 78°C into a solution of oxalyl chloride (497 μL, 5.7 mmol) in dichloromethane (12 mL). After 5 min a solution of trans-3-acetoxy-2-(2-hydroxyethyl)tetrahydropyran 16 (710 mg, 3.77 mmol) in dichloromethane (4 mL) was added. After stirring for 20 min at − 78°C triethylamine (2.10 mL) was added and the mixture was allowed to reach 0°C slowly. Dichloromethane (20 mL) and saturated aqueous NH₄Cl solution (20 mL) were added. The phases were separated and the aqueous phase was extracted with dichloromethane (3 × 20 mL). The combined organic phases were dried (Na₂SO₄) and concentrated. The residue was taken up in a 1:1 (v/v) mixture of methanol and trimethoxymethane (9.4 mL). This mixture was stirred with DOWEX50 (38 mg) for 30 min. Diethyl ether (30 mL) was added and the mixture was filtered over a small pad of Al₂O₃ (neutral). The filtrate was concentrated and the residue was subjected to flash chromatography with pentane–diethyl ether (1:1) over silica gel that had been pretreated with triethylamine to give 17 (792 mg, 90%) as a colorless oil. R_f(PE–Et₂O 1:5) = 0.52. ¹H-NMR (300 MHz, CDCl₃): δ = 1.44 (tdd, J = 12.1, 11.0, 5.2 Hz, 1H), 1.56–1.84 (m, 3H), 1.91 (ddd, J = 14.3, 8.4, 2.3 Hz, 1H), 2.01–2.26 (m, 1H), 2.03 (s, 3H), 3.30–3.42 (m, 2H), 3.34 (s, 3H), 3.37 (s, 3H), 3.90 (ddt, J = 11.3, 3.9, 1.8 Hz, 1H), 4.49 (ddd, J = 10.3, 9.7, 4.6 Hz, 1H), 4.59 (dd, J = 8.3, 3.2 Hz, 1H). ¹³C-NMR (75 MHz, CDCl₃): δ = 21.1, 25.1, 29.3, 35.6, 53.0, 53.5, 67.5, 71.9, 76.1, 101.9, 170.1. C₁₁H₂₀O₅ requires C 56.88, H 8.68; found C 56.56, H 8.52%.

trans-3-Hydroxy-2-(2,2-dimethoxyethyl)tetrahydropyran (18)

Potassium carbonate (352 mg, 2.55 mmol) was added into a solution of trans-3-acetoxy-2-(2,2-dimethoxyethyl)tetrahydropyran 17 (592 mg, 2.5 mmol) in methanol (8.5 mL). After stirring for 4 h the solution was concentrated, the residue was taken up in diethyl ether (20 mL) and the mixture was filtered over Kieselgur. The filtrate was concentrated and subjected to flash chromatography with pentane–diethyl ether (1:2) to give 18 (448 mg, 92%) as a colorless oil. R_f(PE–Et₂O 1:5) = 0.25. ¹H-NMR (300 MHz, CDCl₃): δ = 1.31–1.48 (m, 1H), 1.61–1.74 (m, 2H), 1.83 (ddd, J = 14.6, 6.7, 4.2 Hz, 1H), 2.05–2.18 (m, 2H), 2.68 (br d, J = 4.4 Hz, 1H), 3.14 (ddd, J = 9.0, 6.6, 4.2 Hz, 1H), 3.24–3.40 (m, 2H), 3.36 (s, 3H), 3.37 (s, 3H), 3.83–3.92 (m, 1H), 4.62 (dd, J = 6.6, 4.2 Hz, 1H). ¹³C-NMR (75 MHz, CDCl₃) δ = 25.5, 32.4, 36.4, 52.8, 53.3, 67.6, 70.1, 79.0, 102.0. C₉H₁₈O₄ requires C 56.82, H 9.54; found: C 56.70, H 9.32.

trans-3-Ethynyloxy-2-(2,2-dimethoxyethyl)tetrahydropyran (19)

trans-3-Hydroxy-2-(2,2-dimethoxyethyl)tetrahydropyran 18 (395 mg, 2.07 mmol) was converted into 19 essentially as described for 12. The crude product was purified by flash chromatography over Al₂O₃ (neutral) with pentane–tert-butyl methyl ether (5:1) to give 19 (346 mg, 78%) as a colorless oil. R_f(PE–EtOAc 5:1) = 0.29. ¹H-NMR (300 MHz, CDCl₃): δ = 1.56 (s, 1H), 1.59–1.85 (m, 4H), 2.23 (ddd, J = 14.4, 8.3, 2.4 Hz, 1H), 2.34–2.49 (m, 1H), 3.27–3.43 (m, 2H), 3.33 (s, 3H), 3.34 (s, 3H), 3.73 (td, J = 9.6, 5.1 Hz, 1H), 3.82–3.93 (m, 1H), 4.64 (dd, J = 8.3, 3.7 Hz, 1H). ¹³C-NMR (75 MHz, CDCl₃): δ = 25.2, 27.7, 28.2, 35.0, 52.1, 53.1, 67.2, 75.7, 84.7, 88.7, 101.0. C₁₁H₁₈O₄ requires C 61.66, H 8.47; found C 61.48, H 8.47%.

(1S*,3R*,4S*,6R*)-3-Ethenyl-2,7-dioxabicyclo[4.4.0]decan-4-ol (22)

Pinacol borane¹² (193 mg, 1.51 mmol) and zirconocene hydrido chloride (35 mg, 0.137 mmol) were added into a solution of trans-3-ethynyloxy-2-(2,2-dimethoxyethyl)tetrahydropyran 19 (294 mg, 1.37 mmol) in dichloromethane (0.7 mL). After 1 day tert-butyl methyl ether (20 mL) was added and the mixture was poured into pH 7 buffer solution (15 mL). The phases were separated and the aqueous phase was extracted with tert-butyl methyl ether (3 × 15 mL). The combined organic phases were dried (Na₂SO₄) and concentrated. The residue was filtered over a 3 cm layer of silica gel (deactivated with triethylamine) using pentane–tert-butyl methyl ether 3:1 to give the vinylboronate 20 (405 mg, 87%) as a colorless oil. R_f(PE–EtOAc 2:1) = 0.36. ¹H-NMR (300 MHz, CDCl₃): δ = 1.25 (s, 12H), 1.37–1.52 (m, 1H), 1.59 (ddd, J = 14.2, 9.6, 3.7, Hz, 1H), 1.64–1.74 (m, 2H), 2.09 (ddd, J = 14.3, 8.2, 2.4 Hz, 1H), 2.17–2.28 (m, 1H), 3.31 (s, 3H), 3.32 (s, 3H), 3.28–3.40 (m, 2H), 3.59 (ddd, J = 10.1, 9.6, 4.5 Hz, 1H), 3.83–3.93 (m, 1H), 4.52 (d, J = 14.2 Hz, 1H), 4.62 (dd, J = 8.3, 3.7 Hz, 1H), 6.91 (d, J = 14.2 Hz, 1H). ¹³C-NMR (75 MHz, CDCl₃): δ = 24.7 (4C), 25.1, 29.5, 35.3, 52.1, 53.2, 67.5, 76.6, 78.2, 82.7 (2C), 101.4, 161.8.

Chloroiodomethane (105 μL, 1.4 mmol) was added to a solution of the vinylboronate 20 (380 mg, 1.11 mmol) in THF (5.5 mL) and the solution was cooled to − 105°C. n-Butyllithium (1.22 M in hexane, 1.18 mL, 1.44 mmol) was added and the mixture was allowed to reach room temperature overnight. tert-Butyl methyl ether (20 mL) was added and the mixture was poured into pH 7 buffer solution (20 mL). The phases were separated and the aqueous phase was extracted with tert-butyl methyl ether (3 × 20 mL). The combined organic phases were dried (Na₂SO₄) and concentrated, leaving the allylboronate 21 (375 mg, 95%) as a slightly yellowish oil. R_f(PE–EtOAc 5:1) = 0.37. ¹H-NMR (300 MHz, CDCl₃): δ = 1.24 (s, 12H), 1.32–1.51 (m, 3H), 1.58 (ddd, J = 14.4, 9.0, 3.7 Hz, 1H), 1.63–1.73 (m, 2H), 2.13–2.26 (m, 2H), 3.20–3.38 (m, 3H), 3.31 (s, 3H), 3.33 (s, 3H), 3.82–3.91 (m, 1H), 4.63 (dd, J = 8.3, 3.7 Hz, 1H), 4.92 (dt, J = 12.5, 7.6 Hz, 1H), 6.06 (dt, J = 12.5, 1.0 Hz, 1H). ¹³C-NMR (75 MHz, CDCl₃): δ = 24.7 (4C), 25.3, 29.6, 35.3, 52.0, 53.2, 67.5, 77.1, 77.9, 83.2 (2C), 101.5, 101.6, 144.7.

The allylboronate 21 (61 mg, 0.17 mmol) was taken up in acetonitrile (0.86 mL). Water (17 μL) and lithium tetrafluoroborate (48 mg, 0.51 mmol) were added. After 1 day tert-butyl methyl ether (20 mL) and saturated aqueous NaHCO₃ solution (10 mL) were added. The phases were separated and the aqueous phase was extracted with tert-butyl methyl ether (5 × 10 mL). The combined organic phases were dried (Na₂SO₄) and concentrated. Flash chromatography of the residue with pentane–diethyl ether (1: 5) furnished 22 (24 mg, 76%) as a colorless oil. R_f(diethyl ether) = 0.35. ¹H-NMR (500 MHz, CDCl₃): δ = 1.41–1.48 (m, 1H), 1.52 (q, J = 11.3 Hz, 1H), 1.69–1.77 (m, 2H), 1.83 (br d, J = 3.4 Hz, 1H), 2.06–2.11 (m, 1H), 2.40 (dt, J = 11.6, 4.3 Hz, 1H), 3.00–3.10 (m, 2H), 3.35–3.48 (m, 2H), 3.57 (dd, J = 8.7, 7.6 Hz, 1H), 3.89–3.94 (m, 1H), 5.35 (ddd, J = 10.5, 1.6, 0.8 Hz, 1H), 5.43 (ddd, J = 17.3, 1.6, 1.0 Hz, 1H), 5.85 (ddd, J = 17.4, 10.4, 7.2 Hz, 1H). NOE contacts between H-1 and H-3; H-4 and H-6; H-5ax and H-1; H-5ax and H-3. ¹³C-NMR (75 MHz, CDCl₃): δ = 25.5, 29.2, 37.8, 67.8, 69.0, 76.7, 77.6, 83.8, 119.6, 135.6. MS (EI) m/z (%) 28 (33), 43 (30), 55 (32), 71 (34), 84 (100), 127 (44). HRMS (EI): C₁₀H₁₆O₃ requires 184.1099; found 184.1101.

3-Ethynyloxy-2-methyl-5-hexene (24)

3-Hydroxy-2-methyl-5-hexene 23 (1.76 g, 15.4 mmol) was converted into 24 essentially as described for 12. The crude product was purified by bulb-to-bulb distillation (40°C, 0.01 mbar) to give 24 (1.657 g, 78%) as a colorless liquid. R_f(PE–MTBE 10:1) = 0.62. ¹H-NMR (200 MHz, CDCl₃): δ = 0.97 (d, J = 6.8 Hz, 3H), 0.99 (d, J = 6.8 Hz, 3H), 1.54 (s, 1H), 1.91–2.16 (m, 1H), 2.41–2.52 (m, 2H), 3.84 (dt, J = 6.5, 5.9 Hz, 1H), 5.09–5.23 (m, 2H), 5.85 (ddt, J = 17.1, 10.2, 6.9 Hz, 1H). ¹³C-NMR (75 MHz, CDCl₃): δ = 17.6, 18.1, 27.0, 30.6, 34.6, 90.4, 93.9, 118.0, 133.2. The material deteriorated too rapidly to obtain a correct elemental analysis.

3-Isopropyl-9-oxo-2,8-dioxa-trans-bicyclo[5.4.0.]undecanes (28)

3-Ethynyloxy-2-methyl-5-hexene 24 (170 mg, 1.23 mmol) was hydroborated as described for 22. The crude vinylboronate was filtered over silica gel using pentane–tert-butyl methyl ether (10:1) to give 25 (224 mg, 69%) as a colorless oil. R_f(PE–MTBE 10:1) = 0.43. ¹H-NMR (200 MHz, CDCl₃): δ = 0.84 (d, J = 6.8 Hz, 3H), 0.85 (d, J = 6.8 Hz, 3H), 1.18 (s, 12H), 1.70–1.92 (m, 1H), 2.17–2.31 (m, 2H), 3.53–3.68 (m, 1H), 4.42 (d, J = 14.0 Hz, 1H), 4.92–5.09 (m, 2H), 5.72 (ddt, J = 17.1, 10.1 6.9 Hz, 1H), 6.86 (d, J = 14.3 Hz, 1H). ¹³C-NMR (50 MHz, CDCl₃): δ = 17.7, 18.3, 24.7 (4C), 31.1, 35.5, 82.6 (2C), 85.5, 117.3, 134.3, 163.6.

The vinylboronate 25 was converted to the allylboronate 26 as described for 22 (200 mg, 95%) as a yellowish oil. R_f(PE–EtOAc 5:1) = 0.73. ¹H-NMR (200 MHz, CDCl₃): δ = 0.83 (d, J = 6.8 Hz, 3H), 0.84 (d, J = 6.8 Hz, 3H), 1.17 (s, 12H), 1.35–1.45 (m, 2H), 1.65–1.86 (m, 1H), 2.16–2.25 (m, 2H), 3.32 (q, J = 5.7 Hz, 1H), 4.83 (dt, J = 12.1, 7.4 Hz, 1H), 4.92–5.06 (m, 2H), 5.76 (ddt, J = 17.1, 10.1, 7.0 Hz, 1H), 5.99 (dt, J = 12.3, 1.5 Hz, 1H). ¹³C-NMR (75 MHz, CDCl₃): δ = 17.8, 18.4, 24.8 (4C), 31.1, 35.6, 83.1 (2C), 84.9, 100.9, 116.6, 135.1, 146.3.

Rh(CO)₂acac (1.8 mg, 0.007 mmol) and BIPHEPHOS²¹ (10.7 mg, 0.014 mmol) were dissolved in THF (1 mL). After 10 min a solution of the crude allylboronate 26 (190 mg, 0.68 mmol) in THF (2 mL) was added. The mixture was treated in an autoclave with 5 bar of CO–H₂ (1:1) for 2 days at 65°C. The mixture was concentrated and the residue was purified by flash chromatography with pentane–tert-butyl methyl ether (3:1) to give first the 1,3-cis-compound 27a (37 mg) as an anomeric mixture and then the 1,3-trans-compound 27b (33 mg) as an anomeric mixture.

27a: R_f(PE–EtOAc 5:1) = 0.24. ¹H-NMR (300 MHz, CDCl₃): characteristic signals δ = 0.86 (d, J = 6.8 Hz), 0.87 (d, J = 6.6 Hz, together 3H), 0.92 (d, J = 6.8 Hz), 0.94 (d, J = 6.8 Hz, together 3H), 4.76–4.82 (m, 0.55H), 5.20 (t, J = 3.1 Hz, 0.45H). ¹³C-NMR (75 MHz, CDCl₃): characteristic signals δ = 90.8, 96.1.

27b: R_f(PE–EtOAc 5:1) = 0.17. ¹H-NMR (300 MHz, CDCl₃): characteristic signals δ = 0.84 (d, J = 6.6 Hz), 0.85 (d, J = 6.8 Hz, together 3H), 0.99 (d, J = 6.6 Hz), 1.00 (d, J = 6.8 Hz, together 3H), 4.74 (m, 0.55H), 5.19 (t, J = 2.5 Hz, 0.45H). ¹³C-NMR (75 MHz, CDCl₃): characteristic signals δ = 90.3, 95.6.

To facilitate characterization the lactols 27 were oxidized to the lactones 28: 27a (28 mg, 0.13 mmol) was taken up in dichloromethane (1.3 mL). Pyridine (53 μL, 0.65 mmol) and Dess–Martin periodinane (66 mg, 0.16 mmol) were added at 0°C. After stirring for 8 h at room temperature the mixture was concentrated and the residue was purified by flash chromatography with pentane–tert-butyl methyl ether (5:1) to give the 1,3-cis-lactone 28a (15 mg, 54%) as a colorless oil. R_f(PE–EtOAc 5:1) = 0.29. ¹H-NMR (500 MHz, CDCl₃): δ = 0.88 (d, J = 6.8 Hz, 3H), 0.92 (d, J = 6.8 Hz, 3H), 1.55–1.83 (m, 5H), 1.86 (ddd, J = 9.5, 9.0, 7.6 Hz, 1H), 1.88 (ddd, J = 9.6, 9.1, 7.6 Hz, 1H), 2.11–2.19 (m, 2H), 2.55 (dt, J = 17.6, 7.7 Hz, 1H), 2.74 (ddd, J = 17.6, 8.9, 5.4 Hz, 1H), 3.27 (ddd, J = 8.7, 6.3, 5.4 Hz, 1H), 3.41 (td, J = 9.6, 6.2 Hz, 1H), 4.04 (td, J = 9.3, 4.8 Hz, 1H). NOE contacts between H-1 and H-3. ¹³C-NMR (125 MHz, CDCl₃): δ = 18.4, 18.9, 19.4, 26.0, 27.9, 31.5, 32.3, 34.0, 78.0, 82.3, 86.1, 171.4. MS (EI) m/z (%): 41 (35), 43 (42), 55 (55), 57 (52), 82 (76), 85 (100), 109 (40), 169 (34).

The 1,3-trans-lactol 27b furnished in the same manner the 1,3-trans-lactone 28b (20 mg, 63%) as a colorless oil. R_f(PE–EtOAc 5:1) = 0.21. ¹H-NMR (500 MHz, CDCl₃): δ = 0.87 (d, J = 6.8 Hz, 3H), 0.99 (d, J = 6.8 Hz, 3H), 1.38–1.55 (m, 3H), 1.69 (ddt, J = 13.4, 8.2, 6.7 Hz, 1H), 1.80–1.87 (m, 1H), 1.93 (dtd, J = 13.7, 8.6, 6.8 Hz, 1H), 1.97–2.03 (m, 1H), 2.06–2.13 (m, 1H), 2.25–2.32 (m, 1H), 2.49 (ddd, J = 17.3, 9.0, 6.4 Hz, 1H), 2.72 (dt, J = 17.3, 6.6 Hz, 1H), 3.31 (ddd, J = 11.3, 8.4, 5.3 Hz, 1H), 3.67 (td, J = 8.7, 6.4 Hz, 1H), 4.04 (ddd, J = 10.4, 9.5, 4.9 Hz, 1H). No NOE contacts between H-1 and H-3. ¹³C-NMR (125 MHz, CDCl₃): δ = 18.9, 19.7, 20.5, 27.1, 28.2, 31.9, 32.9, 35.4, 68.1, 82.3, 83.2, 171.1. MS (EI) m/z (%): 41 (35), 43 (40), 55 (56), 81 (27), 85 (73), 95 (34), 101 (35), 109 (29), 123 (47), 169 (100). HRMS(EI): C₁₂H₂₀O₃ requires 212.1412; found 212.1411.

trans-3-Ethynyloxy-2-vinyltetrahydropyran (29)

trans-3-Hydroxy-2-vinyltetrahydropyran 8 was converted into 29 essentially as described for 12. The crude product was filtered over 3 cm of silica gel, which had been deactivated with triethylamine, using pentane–diethyl ether (5:1) to give 29 (314 mg, 72%) as a slightly yellowish oil. R_f(PE–EtOAc 5:1) = 0.56. ¹H-NMR (300 MHz, CDCl₃): δ = 1.56 (s, 1H), 1.64–1.87 (m, 3H), 2.33–2.48 (m, 1H), 3.35–3.48 (m, 1H), 3.71–3.83 (m, 2H), 3.90–4.00 (m, 1H), 5.31 (d, J = 10.7 Hz, 1H), 5.42 (d, J = 17.1 Hz, 1H), 5.96 (ddd, J = 17.2, 10.6, 5.5 Hz, 1H). ¹³C-NMR (75 MHz, CDCl₃): δ = 24.9, 27.8, 28.0, 66.9, 79.1, 84.5, 88.7, 118.2, 134.6. C₉H₁₂O₂ requires C 71.03, H 7.95; found C 70.39, H 7.88%.

(1R*,3S*,8R*,11S*)- and (1R*,3R*,8S*,11S*)-2,7,12-trioxa-Δ⁵-tricyclo[9.4.0.0^3,8]pentadecenes (32)

trans-3-Ethynyloxy-2-vinyltetrahydropyran 29 (277 mg, 1.82 mmol) was converted into the vinylboronate as described for 22. The crude product was filtered over silica gel (prior deactivated with triethylamine) using pentane–tert-butyl methyl ether (5:1). The resulting vinylboronate 30 (321 mg, 63%) was obtained as a colorless oil. R_f(CH₂Cl₂ + 2% acetone) = 0.44. ¹H-NMR (500 MHz, CDCl₃): δ = 1.25 (s, 12H), 1.52 (tdd, J = 12.0, 10.9, 5.4 Hz, 1H), 1.63–1.77 (m, 2H), 2.19–2.28 (m, 1H), 3.42 (td, J = 11.1, 3.4 Hz, 1H), 3.64 (ddd, J = 10.2, 9.2, 4.4 Hz, 1H), 3.68–3.74 (m, 1H), 3.93–3.99 (m, 1H), 4.53 (d, J = 14.2 Hz, 1H), 5.22 (dt, J = 10.7, 1.3 Hz, 1H), 5.35 (dt, J = 17.3, 1.5 Hz, 1H), 5.89 (ddd, J = 17.3, 10.8, 5.5 Hz, 1H), 6.90 (d, J = 14.2 Hz, 1H). ¹³C-NMR (125 MHz, CDCl₃): δ = 24.7 (4C), 24.9, 67.3, 78.4, 80.1, 82.7 (2C), 117.3, 135.4, 161.9.

The vinylboronate 30 was converted into the allylboronate 31 as described for 22. The crude product was purified by filtration over silica gel with pentane–tert-butyl methyl ether (5:1). The allylboronate 31 (263 mg, 78%) was obtained as a colorless oil. R_f(PE–EtOAc 5:1) = 0.49. ¹H-NMR (300 MHz, CDCl₃): δ = 1.24 (s, 12H), 1.40–1.53 (m, 3H), 1.60–1.76 (m, 2H), 2.11–2.28 (m, 1H), 3.28–3.49 (m, 2H), 3.58–3.70 (m, 1H), 3.88–3.99 (m, 1H), 4.92 (dt, J = 12.3, 7.5 Hz, 1H), 5.20 (dt, J = 10.7, 1.7 Hz, 1H), 5.34 (dt, J = 17.3, 1.7 Hz, 1H), 5.97 (ddd, J = 17.5, 10.8, 5.5 Hz, 1H), 6.04 (dt, J = 12.4, 1.6 Hz, 1H). ¹³C-NMR (75 MHz, CDCl₃): δ = 24.8 (4C), 25.1, 29.7, 67.3, 78.2, 80.5, 83.2 (2C), 101.9, 116.6, 136.1, 144.9.

The hydroformylation of the allylboronate 31 was carried out as described for 28 for 80 h at 65°C under 5 bar of CO–H₂ (1:1). Flash chromatography of the crude product with pentane–tert-butyl methyl ether (5:1) furnished 32 (97 mg, 52%) as a 1:1 mixture of the two diastereomers. This mixture was not separated. R_f(PE–EtOAc 5:1) = 0.41. ¹H-NMR (500 MHz, CDCl₃): δ = 1.36–1.54 (m, 1.5H), 1.57–1.76 (m, 2.5H), 1.85–2.01 (m, 2H), 2.01–2.34 (m, 4H), 3.06 (ddd, J = 9.1, 7.2, 4.8 Hz, 0.5H), 3.13 (ddd, J = 10.4, 9.1, 5.0 Hz, 0.5H), 3.20 (ddd, J = 10.6, 9.1, 4.9 Hz, 0.5H), 3.26 (ddd, J = 11.1, 9.1, 4.1 Hz, 0.5H), 3.29–3.35 (m, 1H), 3.58–3.63 (m, 1H), 3.66 (td, J = 9.5, 2.7 Hz, 0.5H), 3.71 (td, J = 9.8, 5.7 Hz, 0.5H), 3.84 (ddt, J = 11.1, 4.0, 2.0 Hz, 0.5H), 3.89 (ddt, J = 11.3, 3.9, 2.0 Hz, 0.5H), 4.64 (td, J = 5.6, 2.1 Hz, 0.5H), 4.69 (td, J = 5.5, 2.3 Hz, 0.5H), 6.26 (dt, J = 5.9, 2.0 Hz, 0.5H), 6.28 (dt, J = 5.9, 1.9 Hz, 0.5H). ¹³C-NMR (75 MHz, CDCl₃): δ = 25.7, 26.0, 28.24, 28.27, 28.8, 29.0, 29.7, 31.4, 31.9, 32.0, 67.3, 68.0, 71.5, 74.9, 78.2, 79.3, 79.7, 81.4, 81.8, 83.4, 99.0, 99.6, 143.89, 143.91. MS (EI) m/z (%): 41 (26), 43 (26), 55 (30), 71 (79), 81 (41), 94 (29), 97 (100), 141 (32), 210 (33). HRMS(EI): C₁₂H₁₈O₃ requires 210.1256; found 210.1254.

Acknowledgements

This study has been supported by the Deutsche Forschungsgemeinschaft (SFB 260) and the Fonds der Chemischen Industrie as well as by the European Community, HCM Network Nr. ERB-CHRX-CT94-0620. We would like to thank these organizations for their support.

References

1. S. Breitfelder, A. Schlapbach and R. W. Hoffmann, Synthesis, 1998, 468.
2. (a) Y. Yamamoto and N. Asao, Chem. Re[italic v]., 1993, 93, 2207; (b) D. S. Matteson, Stereodirected Synthesis with Organoboranes, Springer, Berlin, 1995;; (c) J. A. Marshall, Chem. Re[italic v]., 1996, 96, 31.
3. For a review see: W. R. Roush in Houben-Weyl: Methods of Organic Chemistry, eds. G. Helmchen, R. W. Hoffmann, J. Mulzer and E. Schaumann, Thieme, Stuttgart, 1995, vol. E21b, pp. 1410–1486..
4. R. W. Hoffmann and B. Kemper, Tetrahedron Lett., 1981, 22, 5263.
5. (a) R. W. Hoffmann, B. Kemper, R. Metternich and T. Lehmeier, Liebigs Ann. Chem., 1985, 2246; (b) R. W. Hoffmann and R. Metternich, Liebigs Ann. Chem., 1985, 2390.
6. (a) T. Moriya, A. Suzuki and N. Miyaura, Tetrahedron Lett., 1995, 36, 1887; (b) Y. Yamamoto, T. Miyairi, T. Ohmura and N. Miyaura, J. Org. Chem., 1999, 64, 296.
7. (a) W. R. Roush and P. T. Grover, Tetrahedron, 1992, 48, 1981; (b) J. A. Hunt and W. R. Roush, J. Org. Chem., 1997, 62, 1112; For other allylmetallation routes to 4 see ref. 8..
8. (a) Y. Yamamoto, Y. Saito and K. Maruyama, J. Organomet. Chem., 1985, 292, 311; (b) K. Tamao, E. Nakajo and Y. Ito, J. Org. Chem., 1987, 52, 957; (c) K. Takai, K. Nitta and K. Utimoto, Tetrahedron Lett., 1988, 29, 5263; (d) J. A. Marshall and K. W. Hinkle, J. Org. Chem., 1996, 61, 105; (e) A. G. M. Barrett and J. W. Malecha, J. Org. Chem., 1991, 56, 5243; (f) A. G. M. Barrett and J. W. Malecha, J. Chem. Soc., Perkin Trans. 1, 1994, 1901.
9. (a) K. M. Sadhu and D. S. Matteson, Organometallics, 1985, 4, 1687; (b) H. C. Brown, S. M. Singh and M. V. Rangaishenvi, J. Org. Chem., 1986, 51, 3150.
10. (a) T. J. Michnick and D. S. Matteson, Synlett., 1991, 631; (b) R. H. Wallace and K. K. Zong, Tetrahedron Lett., 1992, 33, 6941; (c) H. C. Brown, A. S. Phadke and N. G. Bhat, Tetrahedron Lett., 1993, 34, 7845; (d) H. C. Brown and A. S. Phadke, Synlett., 1993, 927; (e) R. Soundararajan, G. Li and H. C. Brown, Tetrahedron Lett., 1994, 35, 8957; (f) R. Soundararajan, G. Li and H. C. Brown, Tetrahedron Lett., 1994, 35, 8961; (g) R. Soundararajan, G. Li and H. C. Brown, J. Org. Chem., 1996, 61, 100.
11. A. Moyano, F. Charbonnier and A. E. Greene, J. Org. Chem., 1987, 52, 2919.
12. C. E. Tucker, J. Davidson and P. Knochel, J. Org. Chem., 1992, 57, 3482.
13. R. W. Hoffmann and I. Münster, Liebigs Ann./Recueil, 1997, 1143.
14. J. Inanaga, Y. Yokoyama and T. Hanamoto, Tetrahedron Lett., 1993, 34, 2791.
15. J.-i. Yamada, T. Asano, I. Kadota and Y. Yamamoto, J. Org. Chem., 1990, 55, 6066.
16. (a) T. Yasumoto and M. Murata, Chem. Re[italic v]., 1993, 93, 1897; (b) E. Alvarez, M.-L. Candenas, R. Pérez, J. L. Ravelo and J. D. Martin, Chem. Re[italic v]., 1995, 95, 1953.
17. S. Pereira and M. Srebnik, Organometallics, 1995, 14, 3127.
18. B. H. Lipshutz and and D. F. Harvey, Synth. Commun., 1982, 12, 267.
19. (a) K. C. Nicolaou, C. V. C. Prasad, P. K. Somers and C.-K. Hwang, J. Am. Chem. Soc., 1989, 111, 5330; (b) Y. Yamamoto, J.-i. Yamada and I. Kadota, Tetrahedron Lett., 1991, 32, 7069.
20. R. W. Hoffmann, D. Brückner and V. J. Gerusz, Heterocycles, 2000, 52, 121.
21. (a) G. D. Cuny and S. L. Buchwald, J. Am. Chem. Soc., 1993, 115, 2066; (b) L. A. van der Veen, P. C. J. Kramer and P. W. N. M. van Leeuwen, Angew. Chem., 1999, 111, 349; (c) , Angew. Chem., Int. Ed., 1999, 38, 336.
22. T. J. Fleck and P. A. Grieco, Tetrahedron Lett., 1992, 33, 1813.
23. D. B. Dess and J. C. Martin, J. Org. Chem., 1983, 48, 4155.

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Footnote

† For part LII, see ref. 1.

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