Complementary Synthesis of Anti- and Syn-Hydroxymethyl 1,3-Diols via Regioselective Ring Opening of TIPS-Protected 2,3-Epoxy Alcohols: Toward Polypropionate Fragments

Abstract

Hydroxymethyl 1,3-diol motifs are common structural motifs in natural products, particularly in polypropionates with important therapeutic potential. However, general and complementary methods for their regio- and diastereoselective synthesis remain limited. In this study, we expanded a second-generation epoxide-based methodology involving the regioselective cleavage of TIPS-monoprotected cis- and trans-2,3-epoxy alcohols using alkenyl Grignard reagents. Regioselective ring opening of cis-epoxides provided anti-1,3-diols, while trans-epoxides afforded the corresponding syn-1,3-diols. The use of cis-propenylmagnesium bromide and vinyl Grignard reagents enabled direct access to cis- and terminal homoallylic 1,3-diols, respectively, with moderate to good yields (46–88%) and excellent regioselectivities (95:5). In contrast, reactions with trans-propenyl Grignard reagent led to partial alkene isomerization, limiting their synthetic utility. To address this, a complementary two-step approach employing propynyl alanate addition followed by sodium/ammonia reduction was incorporated, providing access to trans-homoallylic 1,3-diols with high diastereoselectivity. All 1,3-diols were characterized by NMR spectroscopy, confirming regioselective epoxide opening. These combined strategies offer a practical and modular platform for the synthesis of syn- and anti-hydroxymethylated 1,3-diols and their application to the construction of polypropionate-type fragments, supporting future efforts in the total synthesis of polyketide natural products.

1. Introduction

Hydroxymethyl 1,3-diols are structural motifs commonly found in natural products with significant medicinal potential [1,2]. The relative configuration between the primary alcohol (1-hydroxymethyl) and the secondary alcohol (3-hydroxy) can be either anti or syn (Figure 1).

The anti-1,3-diol motif is found in 16-membered macrolide antibiotics such as tylosins [3], mycinamicins (i.e., I, III, and IV) [4,5,6,7,8], aldgamacins [8,9,10], tianchimycin [11], swalpamycin [12,13], and the chalcomycins [14,15], all of which feature a glycosylated C20-primary alcohol (Figure 2). Other macrolides, such as tedanolide [16,17], contain the anti-1,3-diol at C16-C17 and the C29-primary alcohol, whereas scytophycin E contains a syn-1,3-diol with a hydroxymethyl group at C26 [18]. In contrast, the linear polypropionate myriaporones, (e.g., myraporone 4) have syn- and anti-1,3-diol motifs [17,19] (Figure 2), and the ansa chain of streptovaricin D features a functionalized methyl group at C10 [20,21]. Hydroxymethyl 1,3-diols are also present in other types of secondary metabolites such as terpenoids [22,23] and lignans [24,25], among others [26].

To date, few enantio- and stereoselective methods for the synthesis of anti- and syn-hydroxymethyl 1,3-homoallylic diols have been reported. In 2003, a stereoselective cross-metathesis strategy involving the Nozaki–Hiyama reaction, catalyzed by [Cr(Salen)] and functionalized allyl bromides, was reported [27]. This method led to the formation of homoallylic 1,3-diols in moderate yields with good syn-diastereoselectivity (up to 83:17 syn) and enantioselectivity (up to 81% ee). The anti-diastereo- and enantioselective carbonyl (hydroxymethyl) allylation of alcohols or aldehydes catalyzed by an iridium complex was described [28]. From alcohol substrates, good anti-diastereoselectivities (5:1 to 10:1) and excellent enantioselectivities (93–99% ee) were obtained. Similarly, reactions with aldehydes afforded comparable isolated yields (58–74%), anti-diastereoselectivities (4:1 to 14:1 dr), and enantioselectivities (95–99% ee).

The regioselective cleavage of 2,3-epoxy alcohols with carbon nucleophiles to form hydroxymethyl 1,3-diols has been reported using organoaluminum reagents such as Me₃Al [29,30], Me₂Al–C≡CTMS [29], and Ar₃Al [31], as well as organocuprates (e.g., R₂CuLi) [32] and lithium acetylides in the presence of BF₃·Et₂O [33]. These transformations introduce methyl, alkynyl, and aryl groups with varying degrees of regioselectivity.

Our group recently reported a second-generation methodology involving the regioselective cleavage of monoprotected 2,3-epoxy alcohols (1) with alkynylaluminum reagents to synthesize differentially protected homopropargylic hydroxymethyl 1,3- diols (2) (Scheme 1) [34,35]. A key advantage of this substrate-controlled approach is that the enantioenriched 2,3-epoxy alcohols (1), which can be prepared via asymmetric epoxidation, were selectively cleaved at C2 using propynylaluminum ate complexes, affording hydroxymethylated 1,3-homopropargylic diols (2) with high regioselectivity [34]. The diastereoselectivity of the resulting free 1,3-diol unit is syn for trans-epoxides and anti for cis-epoxides (Scheme 1). Subsequent reduction of the alkyne (2) yields complementary homoallylic diols (3), enabling the stereoselective synthesis of C2-syn and C2-anti-epoxy alcohols [35].

Grignard reagents in the presence of copper salts have also been used for regioselective epoxide openings to introduce alkyl and alkenyl groups [36,37]. Our group introduced the use of copper-catalyzed cis- and trans-1-propenyl Grignard reagents to cleave hindered and unprotected epoxides to construct syn/anti polypropionate units (Scheme 2), employing the first-generation methodology [38,39]. Unlike the alkynyl alane approach [40,41,42], this strategy directly installs the alkenyl moiety in the propionate unit, avoiding the need for alkyne cis/trans reduction.

The regioselective opening of benzyl-monoprotected cis- and trans-2,3-epoxy alcohols with Grignard reagents was first reported in 1983 by Tius and Fauq [36] and later in 2001 by Riccardis and co-workers [43]. They employed vinylic Grignard reagents such as CH=CHMgBr and CH₂=C(CH₃)MgBr in the presence of catalytic CuI to yield regioselective mixtures of homoallylic 1,3-diols and 1,2-diols. Both studies showed consistent results: anti-hydroxymethyl 1,3-diols were obtained with regioselectivities ranging from 72:18 to 83:17, while syn-hydroxymethyl 1,3-diols were obtained with regioselectivities between 80:20 and 84:16. To date, reported reactions with alkenyl Grignard reagents have been limited to monobenzyl-protected 2,3-epoxy alcohols, which exhibit regioselectivities ranging from moderate to good.

Despite these advances, no general and unified methodology currently enables the complementary synthesis of both syn- and anti-hydroxymethyl 1,3-homoallylic diols with high levels of enantio-, regio- and stereocontrol. To address this gap, we expanded our second-generation methodology by employing copper-catalyzed alkenyl Grignard reagents to investigate the regioselective cleavage of TIPS-monoprotected cis- and trans-2,3-epoxy alcohols (1) (Scheme 3).

Herein, we report the asymmetric synthesis of cis- and trans-epoxides (1), to demonstrate the viability of performing this methodology in an enantioenriched form. Although the copper-catalyzed alkenyl Grignard cleavage studies were carried out using racemic epoxides for cost-effectiveness, the development of the methodology did not depend on the use of optically active epoxides. This strategy enables the efficient and stereodivergent synthesis of homoallylic syn- and anti-hydroxymethyl 1,3-diols with excellent regioselectivity and provides a modular platform for the construction of polypropionate-type fragments commonly found in bioactive natural products.

2. Materials and Methods

2.1. General Considerations

All reactions were carried out in oven-dried glassware (overnight, 120 °C) under a nitrogen atmosphere. Standard handling techniques for air-sensitive compounds were employed for all the experiments, i.e., moisture or air sensitive compounds were transferred via syringe or stainless-steel cannulating needles through rubber septa to the glassware, which had previously been flame-dried under reduced pressure three times. All solvents were dried and purified in an MBraun Auto-SPS system before use. All commercially available compounds were used as received, without further purification unless otherwise noted. For the Sharpless asymmetric epoxidation, Ti(iOPr)₄ and DIPT tartrate were distilled under reduced pressure prior to use and allylic alcohols 5-Z and 5-E were prepared using a reported procedure [35]. Reactions were monitored by TLC using Sigma Silica Gel 60F (with or without UV indicator) plastic plates (0.25 mm). Components were visualized using ethanolic p-anisaldehyde solution or long-wave UV light. Unless otherwise noted, all products were purified by silica gel column chromatography and fully characterized. One-dimensional and two-dimensional ¹H NMR (500 or 300 MHz), ¹³C NMR (125 or 75 MHz), and ³¹P (121.5 MHz) spectra were obtained as solutions in deuterochloroform relative to CDCl₃ (δ 7.26 and 77.0 for ¹H and ¹³C NMR, respectively). NMR chemical shifts (δ) are given in ppm relative to TMS and coupling constants (J) in Hz. All reactions under microwave irradiation were performed in a CEM Discover 1–300 W system equipped with a built-in pressure measurement sensor and a vertically focused IR sensor (mode Discover Standard) following the general procedure. Optical rotations were measured employing a Rudolph Research Analytical polarimeter. Elemental analyses were performed by Atlantic Microlab, Inc. Norcross, GA, USA. Reported atomic percentages are within error limits of +0.4% as required by ACS journals.

2.2. General Synthetic Procedures

2.2.1. General Procedure A for the Synthesis of Optically Active Epoxy Alcohols via Sharpless Asymmetric Epoxidation

To a dry round-bottom flask containing activated powdered 4Å molecular sieves (50–60% w/w, previously heated overnight under reduced pressure to remove moisture) was added dry CH₂Cl₂ (0.2 M) and cooled to around −20 to −40 °C. Then, freshly distilled Ti(iOPr)₄ (1.0 equiv) and L-DIPT (1.2 equiv) were added. A TBHP solution (3 equiv) was then added. The solution was stirred at −20 to −40 °C for 30 min. The allylic alcohol (1 equiv) was then added, and the reaction mixture was stirred at −20 °C for 24 h. The reaction was placed in a −10 °C freezer for approximately 24–48 h until the TLC analysis indicated no remaining allylic alcohol. The reaction was vigorously stirred and quenched with water. The mixture was allowed to warm to room temperature and stirred for 1 h. A solution of 30% NaOH in brine was then added and stirred for an additional 30 min. The resulting emulsion was diluted in hexane and filtered through a pad of celite. After the filtrate had separated into two layers, the aqueous phase was extracted with hexane (3 times). The combined organic layer was dried over MgSO₄ and concentrated at reduced pressure. The crude product was purified by flash chromatography or distillation under reduced pressure to yield the pure optically active epoxide.

2.2.2. General Procedure B for the Epoxidation of Alkenes with Meta-Chloroperoxybenzoic Acid (m-CPBA) for the Synthesis of Racemic Epoxides

The allylic alcohol was dissolved in DCM (0.1 M) in a round-bottom flask. Then, m-CPBA (2 equiv) and a 0.5 M NaHCO₃ solution (0.3 M) were added. The reaction progress was monitored by TLC. When it was completed, the mixture was diluted with hexane and a saturated NaHCO₃ solution. The aqueous phase was extracted with hexane. The combined organic phase was washed twice with a 5% NaHSO₃ solution, then with saturated NaHCO₃ solution and brine. After drying over MgSO₄, the solvent was removed under reduced pressure.

2.2.3. General Procedure C for the Microwave-Assisted VO(acac)₂-Catalyzed Epoxidation of Alkenols with TBHP

VO(acac)₂ 0.014 equiv was added to a reaction tube followed by toluene (0.083 M), the alkenol 0.24 mmol, and TBHP (1.1 equiv). Microwave irradiation (150 W maximum) was applied for a temperature of 113 °C. The reaction was judged complete using TLC. After the irradiation period, the reaction was cooled to room temperature (approx. 20 min). The crude product mixture was diluted with saturated Na₂S₂O₃, the aqueous phase was extracted with hexane (3 times). The combined organic phase was dried under anhydrous MgSO₄ and, finally, concentrated under reduced pressure.

2.2.4. General Procedure D for the Copper-Catalyzed Cleavage of Epoxides Using Alkenylmagnesium Bromides

Mg powder (14.4 equiv) was added to a round bottom flask assembled with a dry ice condenser. Freshly distilled THF (2.3 M with respect to Mg) was added to the flask and spiked with I₂. After several minutes, the reaction mixture turned from yellow to turbid gray. Then, the dry ice condenser was cooled to −78 °C and alkenyl bromide (6 equiv) was added. After several minutes, the reaction was warmed and refluxed vigorously. The reaction was stirred for 1 h. The solution was transferred via a double-ended needle to a three-necked round bottom flask containing CuI (0.1 or 1.35 equiv) in ether (0.04 M) at −78 °C. The CuI had previously been heated overnight under reduced pressure to remove moisture. After 30 min, the epoxide was added at −78 °C. The reaction mixture was allowed to reach room temperature and stirred overnight. At this point, the reaction was quenched with a saturated solution of NH₄Cl (26 mL) and diluted in ether. The layers were separated, and the aqueous phase was extracted with ether. The combined organic phase was dried over MgSO₄, filtered through Celite pad, and concentrated under reduced pressure.

2.2.5. General Procedure E for the Alkynyl Substitution Reaction of Epoxy Alcohols (Alane Ate Procedure)

Following the procedure of Miyashita with some modifications [29], a three-neck round-bottom flask, equipped with a dry ice condenser, was charged with dry toluene (0.3 M) via syringe and the system was cooled to 0 °C. Then, n-BuLi was added to the reaction flask and TMS-acetylene was added via syringe or an excess of propine gas was bubbled, and the reaction turned milky white. After 30 min, Et₂AlCl was added via syringe and the solution was stirred for 4 h. Then, the mixture was cooled at −78 °C, followed by the addition of a solution of lithium alkoxide via a double-ended needle, which had been previously prepared from epoxy alcohol in toluene (0.15 M) and n-BuLi (1.1 equiv) at 0 °C for 30 min. The reaction was allowed to reach room temperature while stirring overnight. The reaction was quenched at 0 °C adding a 5% H₂SO₄ solution dropwise. The phases were separated, and the aqueous layer was extracted with three portions of hexane. The combined organic layer was dried over MgSO₄ and concentrated under reduced pressure.

2.2.6. General Procedure F for the trans Reduction of Alkynes with Na°/NH₃

The desired volume of liquid ammonia (0.08 M) was condensed into a round-bottom flask equipped with a dry-ice condenser and containing several Na° cubes (previously washed with hexane), which was partially immersed in a dry ice/acetone bath. Then, the ammonia was distilled into another flask similarly set through a double-ended needle or tygon line. The second flask contained ten equivalents of Na°. A solution of the alkyne in THF (0.4 M) and t-BuOH (1.2 equiv) was added dropwise through an addition funnel. The reaction mixture was allowed to reach room temperature while stirring overnight. The excess Na° was destroyed under an inert atmosphere with methanol, which was very carefully added. The solvent was removed under reduced pressure and the crude was dissolved in water and hexane. Then, the pH was neutralized with H₂SO₄, followed by the extraction of the aqueous phase with three portions of hexane. The combined organic phase was dried over MgSO₄ and concentrated by rotoevaporation.

2.2.7. General Procedure G for the Formation of Acetonides

A round-bottom flask containing the diol at 0 °C was charged with CH₂Cl₂ (0.1–0.3 M), PPTS (0.06 equiv), and 2-methoxypropene (3–5 equiv). The reaction was followed by TLC. When it was completed, the solvent was removed under reduced pressure. The crude was dissolved in hexane and filtered through a bed of celite. The hexane was then rotoevaporated.

2.2.8. General Procedure H for the Protection of Alcohols with TES-OTf

Dry DMF or DCM (0.35 M), dry DIEA or TEA (1.1–3.0 equiv), and the alcohol were combined into a flamed-dried round bottom flask at room temperature. After 30 min, the silylating reagent (1.1–3.0 equiv) was injected via syringe. The reaction mixture was monitored by TLC. When completed, the reaction was quenched by the addition of water and hexane (same volume as DMF or DCM). The aqueous phase was then extracted with three portions of hexane. The combined organic phase was dried under anhydrous MgSO₄ and finally concentrated under reduced pressure.

2.2.9. General Pro2cedure I for the Selective Deprotection of the 1° TES Silyl Ether in the Presence of a 2° TBS Ether

To a flask equipped with a reflux column, the bis-TES ether dissolved in THF (0.2 M) was added. To the mixture, a solution (2:1) containing HOAc (1 M) and water (2 M) was slowly added. After 10 min, the reaction was refluxed for several (3–8) hours. After disappearance of the starting material (TLC), the reaction was cooled to 0 °C and poured slowly into a suspension of NaHCO₃ in water (2 M). It was diluted with EtOAc, followed by the extraction of the aqueous phase with EtOAc (3 × 10 mL). The combined organic layers were dried over MgSO₄ and concentrated under reduced pressure.

2.3. Experimental and Characterization Data

2.3.1. Preparation of (-)-(2S,3R)-4-(triisopropylsilyloxy)-2-3-epoxy-1-butanol ((-)-1-cis

Following general procedure A, 4Å molecular sieves (0.18 g, 60% w/w), dry CH₂Cl₂ (7.0 mL, 0.18 M), Ti(iOPr)₄ (0.37 mL, 1.2 mmol, 1.0 equiv), L-DIPT (0.26 mL, 1.2 mmol, 1.2 equiv), TBHP (1.0 mL of a 3.80 M solution in toluene, 3.68 mmol, 3.0 equiv), and allylic alcohol 5-Z (0.3 g, 1.2 mmol) were used. After work up and concentration, the crude product was purified by flash chromatography 4:1 (hexane/ethyl acetate) to yield 0.27 g (83%) of the pure epoxide (-)-1-cis as a viscous oil, 80% ee was determined by ³¹P NMR analysis with the Alexakis method [44]. [$\alpha {]}_D^{20}=-9.9$, (c = 1.02, CHCl₃); ¹H NMR (CDCl₃) δ 4.03 (dd, J = 11.5, 5.0 Hz, 1H), 3.83 (m, J = 10.0, 6.0 Hz, 1H), 3.79 (dd, J = 10.0, 5.7 Hz, 1H), 3.76 (dd, J = 11.5, 5.5 Hz, 1H), 3.24 (ddd, J = 5.5, 5.5. 5.0 Hz, 1H), 3.25 (ddd, J = 6.0, 5.7, 5.5 Hz, 1H), 2.20 (bs, 1H), 1.08 (m, 21H). ¹³C NMR (CDCl₃) δ 61.9, 60.0, 56.3, 55.9, 17.8, 11.8. Derivative: ³¹P NMR (121.5 MHz, CDCl3) δ 142.3 (12%), 139.2 (88%). Anal. calcd. for C₁₃H₂₈O₃Si C, 59.95, H, 10.84. Found: C, 60.00; H, 10.86.

2.3.2. Preparation of (+)-(2R,3S)-4-(triisopropylsilyloxy)-2-3-epoxy-1-butanol (+)-1-cis

Following general procedure A, 4Å molecular sieves (0.18 g, 60% w/w), dry CH₂Cl₂ (7.0 mL, 0.18 M), Ti(iOPr)₄ (0.37 mL, 1.2 mmol, 1.0 equiv), D-DIPT (0.26 mL, 1.2 mmol, 1.2 equiv), and TBHP solution (1.0 mL of a 3.80 M solution in toluene, 3.68 mmol, 3.0 equiv) were reacted with the allylic alcohol 5-E (0.3 g, 1.2 mmol). After work up, solvent evaporation and flash column chromatography (4:1 hexane/ethyl acetate), 0.25 g (80%) of the pure epoxide (+)-1-cis was obtained as a viscous oil, 80% ee was determined by ³¹P NMR analysis with the Alexakis method [44]. ${[\alpha ]}_D^{20}=+8.4$ (c = 1.10, CHCl₃); ³¹P NMR (121.5 MHz, CDCl3) δ 142.3 (10%), 139.2 (90%). Anal. calcd. for C₁₃H₂₈O₃Si C, 59.95, H, 10.84. Found: C, 59.81; H, 10.95. Other spectroscopic data are essentially identical to (-)-1-cis.

2.3.3. Preparation of (-)-(2S,3S)-4-(triisopropylsilyloxy)-2-3-epoxy-1-butanol (-)-1-trans

Following the general procedure A, 4Å molecular sieves (0.29 g), dry CH₂Cl₂ (9.3 mL, 0.22 M), Ti(iOPr)₄ (0.41 mL, 1.35 mmol, 0.66 equiv), L-DIPT (0.31 mL, 1.47 mmol, 0.72 equiv), and TBHP solution (2.15 mL of a 3.80 M solution in toluene, 8.18 mmol, 4.0 equiv) were reacted with the allylic alcohol 5-E (0.5 g, 2.1 mmol). After work up, solvent evaporation and purification by Flash chromatography (4:1 hexane/ethyl acetate), 0.3 g (52%) of pure epoxide (-)-1-trans as a viscous oil was obtained. [$\alpha {]}_D^{20}=-10.9$ (c = 1.00, CHCl₃). Other spectroscopic data are essentially identical to (+)-1-trans.

2.3.4. Preparation of (+)-(2R,3R)-4-(triisopropylsilyloxy)-2-3-epoxy-1-butanol (+)-1-trans

Following the general procedure A, 4Å molecular sieves (12.3 g, 60% w/w), dry CH₂Cl₂ (93.0 mL, 0.22 M), Ti(iOPr)₄ (4.1 mL, 13.5 mmol, 0.66 equiv), D-DIPT (3.5 mL, 14.7 mmol, 0.72 equiv), and TBHP solution (20.1 mL of a 4.07 M solution in toluene, 81.8 mmol, 4.0 equiv) were reacted with the allylic alcohol 5-E (5.0 g, 20.5 mmol). After work up, solvent evaporation and purification by fractional distillation, 3.9 g (80%, Bp = 156 °C/0.1 mmHg) of pure epoxide (+)-1-trans as a viscous oil with 94% ee, determined by ³¹P NMR analysis with the Alexakis method [44]. ${[\alpha ]}_D^{20}=+13.9$ (c = 1.12, CHCl₃); ¹H NMR (CDCl₃) δ 3.97 (dd, J = 12.8, 1.9 Hz, 1H, 3.96 (dd, J = 11.7, 2.4 Hz, 1H) 3.80 (dd, J = 11.7, 4.0 Hz, 1H), 3.65 (dd, J = 12.8, 4.0 Hz, 1H), 3.17 (m, 2H), 1.06 (m, 21H). ¹³C NMR (CDCl₃): δ 62.7, 61.3, 56.1, 55.8, 17.9, 11.9. Anal. Calcd. for C₁₃H₂₈O₃Si C, 59.95; H, 10.84. Found: C 59.80; H, 10.98. ³¹P NMR (121.5 MHz, CDCl₃) δ 143.2 (3%), 141.5 (97%).

2.3.5. Preparation of (±)-(2R,3S)-4-(triisopropylsilyloxy)-2,3-epoxy-1-butanol (1-cis)

Following general procedure B, 10.0 g (40.9 mmol) of alkenol 5-Z, 410.0 mL of CH₂Cl₂, 8.48 g (49.1 mmol) of m-CPBA, and 138.0 mL of 0.5 M NaHCO₃ solution were used. After work up, solvent evaporation, and purification by fractional distillation under reduced pressure (bp 110–135 °C/1.6 mmHg), 8.8 g (82%) of the pure racemic epoxide 1-cis was obtained as a viscous oil. The spectroscopic data are essentially identical to (-)-1-cis and (+)-1-cis, as well as to the data reported in reference [35].

2.3.6. Preparation of (±)-(2S,3S)-4-(triisopropylsilyloxy)-2,3-epoxy-1-butanol (1-trans)

Following general procedure B, to a flask containing 5.0 g (17.5 mmol) of alkenol 5-E dissolved in 205.0 mL of CH₂Cl₂, 4.3 g (24.6 mmol) of m-CPBA slowly and stirred until it dissolved, followed by the addition of 70.0 mL of a 0.5 M NaHCO₃ solution. The reaction was stirred overnight. Work up and solvent evaporation yielded 5.0 g (95%) of crude as a viscous oil. The racemic epoxide 1-trans was used for the next step, without further purification. Anal. Calcd for C₁₃H₂₈O₃Si C, 59.95; H, 10.84. Found: C 59.63; H, 10.79. The spectroscopic data are essentially identical to (-)-1-trans and (+)-1-trans, as well as to the data reported in reference [35].

2.3.7. Preparation of (±)-(2S,3R)-2-((Z)-prop-1-enyl)-4-(triisopropylsilyloxy)butane-1,3-diol (3a)

Following general procedure D, 1.3 g of Mg powder (23.0 mmol, 14.4 equiv), 25.0 mL of THF, cis-1-bromopropene 2.0 mL (23.0 mmol, 6.0 equiv), 1.0 g CuI (5.2 mmol, 1.35 equiv), 130.0 mL of ether (0.04 M), and epoxide 1-cis (1.0 g, 3.8 mmol) were used. Work up and flash chromatography (4:1 hexane/ethyl acetate) yielded 0.76 g (66%) of alkenol 6a as a viscous oil, obtained as a 96:4 mixture of regioisomers. ¹H NMR (CDCl₃): δ 5.72 (dq, J = 10.5, 6.9 Hz, 1H), 5.45 (dd, J = 10.5, 10.5 Hz, 1H), 3.88 (ddd, J = 7.0, 4.0, 2.5 Hz, 1H,), 3.73 (dd, J = 10.5, 5.8 Hz, 1H), 3.66 (dd, J = 10.5, 5.2 Hz, 1H), 3.65 (dd, J = 12.0, 2.2 Hz, 1H), 3.62 (dd, J = 12.0, 7.0 Hz, 1H), 2.76 (dddd, J = 10.5, 5.8, 5.2, 4.0 Hz, 1H),2.70 (s, 1H), 2.50 (s, 1H), 1.64 (d, J = 6.9 Hz, 3H), 1.07 (m, 21H). ¹³C NMR (CDCl₃): δ 128.1, 127.1, 73.2, 65.5, 64.5 41.5), 17.9 (-), 13.3, 11.8. Anal. Calcd. for C₁₆H₃₄O₃Si: C, 63.52; H, 11.33. Found: C 63.55; H, 11.31. The spectroscopic data are essentially identical to the data reported in reference [35].

2.3.8. Preparation of (±)-(2R,3R)-2-[(Z)-1-propenyl]-4-[(triisopropylsilyl)oxy]-1,3-butanediol (3b)

Following general procedure D, Mg powder (6.73 g, 115.19 mmol, 14.4 eq.), THF (123 mL), cis-1-bromopropene (9.8 mL, 2.35 mmol, 6 equiv), CuI (0.37 g, 1.92 mmol, 0.1 equiv) in ether (48 mL), and epoxide 1-trans (5.0 g, 19.2 mmol) were used. After work up and flash chromatography (Alumina, 4:1 Hexane/EtOAc), 4.93 g (85%) of pure product 3b was obtained as a viscous oil. ¹H NMR (CDCl₃) δ 5.63 (dqd, J = 11.4, 6.9, 0.42 Hz, 1H), 5.10 (m, 1H), 3.80 (dd, J = 9.4, 6.7 Hz, 1H) 3.73 (dd, J = 9.4, 3.2 Hz, 1H), 3.66 (ddd, J = 9.6, 6.7, 3.2 Hz, 1H), 3.57 (dd, J = 10.9, 4.8 Hz, 1H), 3.50 (dd, J = 9.4, 6.7 Hz, 1H), 2.90 (s, 2H), 2.73 (m, 1H), 1.65 (dd, J = 6.9, 1.8 Hz, 3H), 1.05 (21H,). ¹³C NMR (CDCl₃) δ 128.8, 126.6, 75.4, 65.8, 65.9, 41.9, 17.9, 13.5, 11.8. IR (neat, cm⁻¹) 3372 (OH), 2941–2865 (CH), 1659 (=C), 1064, 1013 (C-O), 881 (Si-C), 680 (CH=CH). Anal. Calcd. for C₁₆H₃₄O₃Si: C, 63.52; H, 11.33. Found C, 63.19; H, 11.34. The spectroscopic data are essentially identical to the data reported in reference [38].

2.3.9. Preparation of (±)-(2R,3S)-2-((E)-prop-1-enyl)-4-(triisopropylsilyloxy)butane-1,3-diol (3c)

Following the general procedure D, Mg powder (6.73 g, 276.48 mmol, 14.4 equiv.), THF (123 mL), trans-1-bromopropene (0.6 mL, 6.9 mmol, 6.0 equiv), CuI (0.3 g, 1.8 mmol, 1.35 equiv) in ether (40.0 mL), and epoxide 1-cis (0.30 g, 1.15 mmol) were used. After work up and flash chromatography (1:1 Hexane/Ether), 0.15 g (42%) of an inseparable 66:34 trans/cis mixture of products 6c and 6a was obtained as a viscous oil.

Compound 3c was synthesized as mayor product using a two-step cleavage–reduction sequence, involving propynyl alane-mediated epoxide opening (General procedure D), followed by trans reduction with Na⁰/NH₃ (General procedure F). The spectroscopic data are essentially identical to that reported in references [34,35] and the synthesis is described in Section 2.3.17.

2.3.10. Preparation of (±)-(2R,3R)-2-((E)-prop-1-enyl)-4-(triisopropylsilyloxy)butane-1,3-diol (3d)

Following general procedure D, Mg powder (0.41 g, 16.56 mmol, 14.0 equiv.), THF (7.4 mL), trans-1-bromopropene (0.6 mL, 6.9 mmol, 6.0 equiv), CuI (0.3 g, 1.80 mmol, 1.35 equiv) in ether (40.0 mL), and epoxide 1-tras (0.30 g, 1.15 mmol) were used. After work up and flash chromatography (1:1 Hexane/Ether), 0.22 g (63%) of an inseparable 63:37 trans/cis mixture of products 3d and 3b was obtained as a viscous oil. Compound 3d was synthesized as major product using a two-step cleavage–reduction sequence, involving propynyl alane-mediated epoxide opening (General procedure D), followed by trans reduction with Na⁰/NH₃ (General procedure F). The spectroscopic data are essentially identical to reported in references [34,35], and the synthesis is described in Section 2.3.18.

2.3.11. Preparation of (±)-(2R,3S)-4-(triisopropylsilyloxy)-2-vinyl)butane-1,3-diol (3e)

Following general procedure D, 0.037 g (0.19 mmol, 0.1 equiv) of copper iodide, 5 mL (0.04 M) of ethyl ether, 11.5 mL (11.5 mmol, 6.0 equiv) of vinylmagnesium bromide, and 0.5 g (1.9 mmol, 1.0 equiv) of epoxide 1-cis were used. After work up and flash chromatography (9:1 Hexane/EtOAc), 0.45 g (81%) of the desired product 6e was yielded as a viscous oil. ¹H NMR (500 MHz, CDCl₃): δ 5.89 (ddd, J = 17.8, 9.1, 8.6 Hz, 1H), 5.20 (dd, J = 17.2, 10.4. Hz, 2H), 3.88 (m, 1H) 3.76 (m, 2H), 3.66 (m, 2H), 2.54 (s, 1H), 2.38 (m, 1H), 2.33 (m, 1H), 1.10 (m, 21H). ¹³C NMR (125 MHz, CDCl₃): δ 134.8, 118.6, 72.6, 65.5), 64.2, 48.4, 17.9, 11.9.

2.3.12. Preparation of (±)-(2R,3R)-4-(triisopropylsilyloxy)-2-vinyl)butane-1,3-diol (3f)

Following general procedure D, 0.02 g (0.11 mmol, 0.1 equiv) of copper iodide, 29 mL (0.04 M) of ethyl ether, 6.9 mL (6.9 mmol, 6.0 equiv) of vinylmagnesium bromide, and 0.3 g (1.15 mmol, 1.0 equiv) of epoxide 1-trans were used. After work up and flash chromatography (6:1 Hexane/EtOAc), 0.17 g (51%) of the desired product 6f was yielded as a viscous oil. ¹H NMR (500 MHz, CDCl₃): δ 5.62 (ddd, J = 18.3, 9.5, 8.6 Hz, 1H), 5.17 (dd, J = 18.3, 9.5 Hz, 2H), 3.86 (dd, J = 10.7, 7.2 Hz, 1H), 3.77 (m, 1H), 3.73 (m, 1H), 3.68 (dd, J = 10.7, 4.6 Hz, 1H), 3.57 (dd, J = 8.6, 7.8 Hz, 1H), 2.93 (s, 1H), 2.86 (s, 1H), 2.38 (dddd, J = 8.6, 8.6, 6.2, 6.0 Hz, 1H), 1.08 (m, 21H,). ¹³C NMR (125 MHz, CDCl₃): d 135.3, 118.5, 74.3, 65.8, 65.4, 41.8, 17.9, 11.9. The spectroscopic data are essentially identical to that reported in reference [45].

2.3.13. Preparation of (±)-(2R,3S)-4-(triisopropylsilyloxy)-2-(1-(trimethylsilyl)vinyl)butane-1,3-diol (3g)

Following general procedure D, Mg powder (0.39 g, 16.1 mmol, 14.0 equiv), 7.1 mL (2.27 M for Mg) of THF, 1-bromovinyl-1-trimethylsilane (1.1 mL, 6.9 mmol, 6.0 equiv), CuI (0.022 g, 0.115 mmol, 0.1 equiv) in ether (2.9 mL, 0.04 M for CuI), and 0.30 g (1.15 mmol) of epoxide 1-cis were used. After work up and flash chromatography (6:1 hexane/EtOAc), 0.23 g (54%) of pure product 3g was obtained as a viscous oil. ¹H NMR (500 MHz, CDCl₃) δ 5.82 (s, 1H), 5.63 (s, 1H), 3.92 (m, J = 6.0 Hz, 1H), 3.79–3.70 (m, 3H), 3.62 (dt, J = 11.4, 5.8 Hz, 1H), 2.73 (t, J = 5.7 Hz, 1H), 2.67 (m, J = 12.2, 6.4 Hz, 1H), 2.50 (s, 1H), 1.09 (m, 21H,), 0.11 (s, 9H). ¹³C NMR (126 MHz, CDCl₃) δ 150.2, 127.8, 72.9, 65.7, 63.5, 49.7, 17.9, 11.8, −1.37. Anal. Calcd. for C₁₈H₄₀O₃Si₂: C, 59.94; H, 11.18. Found: C, 60.03; H, 11.25.

2.3.14. Preparation of (±)-(2R,3R)-4-(triisopropylsilyloxy)-2-(1-(trimethylsilyl)vinyl)butane-1,3-diol (3h)

Following general procedure D, Mg powder (0.39 g, 16.10 mmol, 14.0 equiv), 7.1 mL (2.27 M for Mg) of THF, 1-bromovinyl-1-trimethylsilane (1.1 mL, 6.9 mmol, 6.0 equiv), CuI (0.022 g, 0.115 mmol, 0.1 equiv) in ether (2.9 mL, 0.04 M for CuI), and 0.30 g (1.15 mmol) epoxide 1-trans were used. After work up and flash chromatography (6:1 hexane/EtOAc), 0.19 g (46%) of pure product 3 h was obtained as a viscous oil. ¹H NMR (500 MHz, CDCl₃) δ 5.66 (s, 1H), 5.50 (s, 1H), 4.00 (ddd, J = 9.0, 8.2, 2.85 Hz, 1H), 3.77 (m, J = 10.0, 2.0 Hz, 1H) 3.74 (m, J = 9.4, 8.0, 2.9 Hz,1H), 3.54 (dd, J = 11.0, 10.0 Hz, 1H), 3.37 (dd, J = 9.4, 8.0 Hz, 1H), 2.43 (ddd, J = 9.0, 8.0,2.9 Hz, 1H), 1.06 (m, 21H), 0.08 (s, 9H). ¹³C NMR (126 MHz, CDCl₃) δ 149.6, 126.5, 76.6, 66.8, 66.3, 47.5, 17.9, 11.8, −1.70. Anal. Calcd. for C₁₈H₄₀O₃Si₂: C, 59.94; H, 11.18. Found: C, 59.75; H, 11.25.

2.3.15. Preparation of (±)-(2R,3S)-2-(prop-1-ynyl)-4-(triisopropylsilyloxy)butane-1,3-diol (2a) and the minor product (±)-(2R,3S)-3-((triisopropylsilyloxy)methyl)hex-4-yne-1,2-diol (6)

Following general procedure E, 213.0 mL of dry toluene (0.3 M), 25.9 mL (63.8 mmol 4.0 equiv) of n-BuLi (2.46 M in hexane), propyne gas, and 35.4 mL (63.8 mmol, 4.0 equiv) of Et₂AlCl (1.8 M in toluene) were added to a round bottom flask. Followed by the addition of a previously prepared solution of 4.15 g (15.9 mmol) of epoxy alcohol 1-cis in 106.0 mL of toluene (0.15 M) and 7.1 mL (17.5 mmol, 1.1 equiv) of n-BuLi (2.46 M in hexanes). After work up and solvent evaporation, 4.62 g (96%) of a 90:10 mixture of regioisomers 2a and 6 was obtained as a viscous oil. This mixture of products was used for the next step, without further purification. ¹H NMR (CDCl₃) δ 3.83 (m, J = 7.0, 5.0, 4.5 Hz), 3.81 (m, J = 15.0, 3.0 Hz, 2H), 3.78 (dd, J = 15.0, 2.0 Hz, 1H), 3.75 (dd, J = 9.0, 4.5 Hz, 1H), 2.81 (m, J = 5.0, 3.0, 2.0 Hz, 1H,), 2.64 (bs, 1H), 2.38 (bs, 1H), 1.83 (d, J = 3.0 Hz, 3H), 1.07 (m, 21H). ¹³C NMR (CDCl₃) δ 80.7, 75.1, 72.0, 65.3, 63.8, 38.0, 17.9, 11.8, 3.6. Anal. Calcd. for C₁₆H₃₂O₃Si: C, 63.95; H, 10.73. Found: C 63.74; H, 10.78.

Spectral data for the minor isomer (±)-(2R,3S)-3-((triisopropylsilyloxy)methyl)hex-4-yne-1,2-diol (6): ¹H NMR (CDCl₃) δ 3.92 (ddd, J = 6.7, 3.3, 3.2 Hz, 1H), 3.88 (dd, J = 12. 0, 6.0 Hz, 2H), 3.77 (dd, J = 11.3, 6.7 Hz, 1H), 3.67 (dd, J = 11.3, 3.2 Hz, 1H), 2.80, (bs, 1H), 2.69 (ddd, J = 6.7, 3.3, 3.2 Hz, 1H), 2.40 (bs, 1H), 1.83 (d, J = 2.4 Hz, 3H), 1.07 (m, 21H). ¹³C NMR (CDCl₃) δ 80.7, 75.3, 71.4, 65.1, 64.2, 38.0, 17.9, 11.8, 3.5. Anal. Calcd. for C₁₆H₃₂O₃Si: C, 63.95; H, 10.73. Found: C 63.38, H, 10.95. The spectroscopic data for regioisomers 2a and 6 are essentially identical to the data reported in reference [34,35].

2.3.16. Preparation of (±)-(2R,3R)-2-(prop-1-ynyl)-4-(triisopropylsilyloxy)butane-1,3-diol (2b) and the minor product (±)-(2S,3S)-3-((triisopropylsilyloxy)methyl)hex-4-yne-1,2-diol

Following general procedure E, 384.0 mL of dry toluene (0.3 M), 48.0 mL (115.2 mmol, 6.0 equiv) of n-BuLi (2.40 M in hexane), an excess of propyne gas, and 64.0 mL (115.2 mmol, 6.0 equiv) of Et₂AlCl (1.8 M in toluene) were added to a round bottom flask. Followed by the addition of a previously prepared solution of 5.0 g (19.2 mmol) of the epoxy alcohol (±)-1-trans in 130 mL of toluene (0.15 M) and 8.8 mL (21.1 mmol, 1.1 equiv) of n-BuLi (2.40 M in hexanes). After work up and solvent evaporation, 5.3 g (91%) of neat crude was obtained as a viscous oil. The alkyne diol 2b as an 80:20 mixture of regioisomers was used for the next step without further purification. ¹H NMR (CDCl₃) δ 3.93 (dd, J = 10.0, 2.0 Hz, 2H), 3.81 (dd, J = 10.0, 3.0 Hz, 1H), 3.79 (dd, J = 10.0, 2.0 Hz, 1H), 3.78 (dd, J = 10.0, 1.5 Hz, 1H), 3.72 (ddd, J = 3.5, 2.0, 2.0 Hz), 2.87 (d, J = 5.0 Hz, 1H), 2.82 (t, J = 5.5 Hz, 1H), 2.65 (ddd, J = 3.5, 3.0, 1.5 Hz, 1H), 1.78 (s, 3H), 1.07 (m, 21H). ¹³C NMR (CDCl₃) δ 80.3, 75.8, 73.2, 65.6, 64.4, 37.5, 17.9, 11.8, 3.5. Anal. Calcd. for C₁₆H₃₂O₃Si: C, 63.95; H, 10.73. Found: C 63.66; H, 10.96. The spectroscopic data for mayor regioisomer 2a and its minor regiosisomer are essentially identical to the data reported in reference [34,35].

2.3.17. Preparation of (±)-(2R,3S)-2-((E)-prop-1-enyl)-4-(triisopropylsilyloxy)butane-1,3-diol (3c)

Following general procedure F, liquid ammonia (200 mL), 3.5 g (154.0 mmol) of Na°, 4.6 g (15.4 mmol) of the alkyne 2a in 42.0 mL of THF, and 5.1 mL (62.0 mmol) of t-BuOH were used. After work up, solvent evaporation, and column chromatography (4:1 hexane/ethyl acetate), 2.9 g (62%) of the alkene diol 3c as a viscous oil was obtained for two consecutive steps. ¹H NMR (CDCl₃): δ 5.60 (dq, J = 15.5, 6.1 Hz, 1H), 5.49 (dd, J = 15.5, 10.3 Hz, 1H), 3.82 (ddd, J = 9.0, 5.0, 2.2 Hz, 1H), 3.72 (dd, J = 20.0, 4.0 Hz, 1H), 3.70 (dd, J = 20.0, 2.5 Hz, 1H), 3.67 (dd, J = 15.3, 2.2 Hz, 1H), 3.65 (dd, J = 15.3, 9.0 Hz, 1H), 2.59 (s, 1H), 2.34 (m, J = 10.3, 5.0, 4.0, 2.5 Hz, 1H), 2.24 (t, J = 6.33 Hz, 1H), 1.72 (d, J = 6.0 Hz, 3H), 1.07 (m, 21H). ¹³C NMR (CDCl₃) δ 129.6, 127.2, 73.0, 65.6, 64.6, 47.7, 18.2, 17.9, 11.8. Anal. Calcd for C₁₆H₃₄O₃Si: C, 63.52; H, 11.33. Found: C 63.48; H, 11.33.

2.3.18. Preparation of (±)-(2R,3R)-2-((E)-prop-1-enyl)-4-(triisopropylsilyloxy)butane-1,3-diol (3d)

Following general procedure E, liquid ammonia (220 mL) 10.5 g (456 mmol) of Na°, 5.27 g (17.5 mmol) of the alkyne 2b in 47 mL of THF and 11.6 mL (140.3 mmol) of t-BuOH were added after column chromatography (4:1 hexane/ethyl acetate) to yield 2.81 g (53%) of alkene diol 3d as a viscous oil for three consecutive steps. ¹H NMR (CDCl₃): δ 5.59 (dq, J = 13.0, 6.4 Hz, 1H), 5.20 (dd, J = 13.3, 9.2 Hz, 1H), 3.81 (ddd, J = 6.0, 6.0, 2.0 Hz, 1H), 3.75 (dd, J = 10.0, 2.0 Hz, 1H), 3.66 (dd, J = 10.0, 6.0 Hz, 1H), 3.61 (dd, J = 10.0, 6.0 Hz, 1H), 3.55 (dd, J = 10.0, 8.0 Hz, 1H), 2.88 (d, J = 4.0 Hz, 1H), 2.84 (t, J = 5.0 Hz, 1H), 2.34 (m, J = 9.2, 8.0, 6.0, 6.0 Hz, 1H), 1.67 (d, J = 6.4 Hz, 3H), 1.07 (m, 21H). ¹³C NMR (CDCl₃) δ 129.3, 127.7, 73.7, 65.8, 65.7, 47.6, 18.1, 17.9, 11.8. Anal. Calcd for C₁₆H₃₂O₃Si: C, 63.95; H, 10.73. Found: C 63.66; H, 10.96.

2.3.19. Preparation of (±)-(((4S,5S)-2,2-dimethyl-5-(prop-1-ynyl)-1,3-dioxan-4-yl)methoxy)triisopropylsilane (7)

Following general procedure G, 0.083 g of 2a was reacted with 0.004 g of PPTS and 0.13 mL of 2-methoxy propene in 2.8 mL of CH₂Cl₂ at 0 °C. After work up and solvent evaporation, 0.092 g (97%) of pure six-membered acetonide 7 was obtained as a viscous oil. ¹H NMR (CDCl₃): δ 4.06 (dd, J = 11.4, 2.8 Hz, 1H), 3.95 (ddd, J = 3.5, 2.8, 1.0 Hz, 1H), 3.92 (dd, J = 11.4, 1.0 Hz, 1H), 3.89 (dd, J = 9.0, 8.8 Hz, 1H), 3.72 (dd, J = 9.0, 4.7 Hz, 1H), 2.59 (m, J = 8.8, 4.7, 3.5 Hz, 1H), 1.82 (d, J = 2.1 Hz, 3H), 1.45 (s, 3H), 1.43 (s, 3H), 1.10 (m, 21H). ¹³C NMR (CDCl₃) δ 98.8, 78.1, 76.5, 71.0, 64.5, 64.3, 29.8, 29.4, 19.0, 17.9, 11.9, 3.77.

2.3.20. Preparation of (±)-((R)-2-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)pent-3-ynyloxy)triisopropylsilane (8)

Following general procedure G, 0.02 g of 6 was reacted with 0.001 g of PPTS and 0.04 mL of 2-methoxy propene in 1.0 mL of CH₂Cl₂ at 0 °C. After work up, solvent evaporation, and purification by flash chromatography (40:1 Hex/EtOAc), 0.02 g (76%) of pure five-membered acetonide 8 was obtained as a viscous oil. ¹H NMR (CDCl₃): δ 4.28 (ddd, J = 8.0, 6.0, 4.8 Hz, 1H), 4.05 (dd, J = 8.0, 6.0 Hz, 1H,), 3.85 (dd, J = 8.0, 8.0 Hz, 1H), 3.83 (dd, J = 10.0, 5.1 Hz, 1H), 3.78 (dd, J = 10.0, 9.0 Hz, 1H), 2.63 (ddd, J = 9.0, 5.1, 4.8 Hz, 1H), 1.80 (d, J = 2.3 Hz, 3H), 1.43 (s, 3H), 1.37 (s, 3H), 1.10 (m, 21H). ¹³C NMR (125 MHz, CDCl₃) δ 108.8, 79.1, 70.0, 74.8, 67.9, 64.0, 38.3, 26.5, 25.9, 17.9, 11.9, 3.66.

2.3.21. Preparation of (±)-(((4R,5R)-2,2-dimethyl-5-((Z)-prop-1-enyl)-1,3-dioxan-4-yl)methoxy)triisopropylsilane (9)

Following general procedure G, 0.091 g of 3a was reacted with 0.005 g of PPTS and 0.11 mL of 2-methoxy propene in 3.0 mL of CH₂Cl₂ at 0 °C. After work up, solvent evaporation, and purification by flash chromatography (50:1 hexane/ethyl acetate), 0.073 g (71%) of pure six-membered acetonide 9 was obtained as a viscous oil. ¹H NMR (CDCl₃) δ 5.86 (dd, J = 10.6, 10.6 Hz, 1H), 5.65 (dq, J = 10.6, 6.8 Hz, 1H), 4.18 (dd, J = 11.3, 2.2 Hz, 1H), 4.09 (dd, J = 3.8, 2.2, 1.0 Hz, 1H), 3.65 (dd, J = 11.3, 1.0 Hz, 1H), 3.58 (m, J = 9.7, 5.6 Hz, 1H), 3.55 (m, J = 9.7, 7.5 Hz, 1H), 2.54 (m, J = 10.6, 7.5, 5.6, 3.0, Hz, 1H), 1.61 (d, J = 6.6 Hz, 3H), 1.49 (s, 3H), 1.38 (s, 3H), 1.04 (m, 21H). ¹³C NMR (CDCl₃) δ 126.8, 125.8, 98.7, 72.4, 65.9, 64.4, 33.4, 29.6, 19.0, 17.9, 13.2, 11.9.

2.3.22. Preparation of (±)-(2Z,4S,5R)-4-(triethylsilyloxymethyl)-5-(triethylsilyloxy)-6-(triisopropylsilyloxy)-2-hexene (10)

The alkene diol 3a (0.34 g, 1.13 mmol) was submitted to general procedure H using 0.38 mL (2.71 mmol) of TEA and 0.77 mL (3.39 mmol) of TES-OTf in 3.0 mL of DMF. The reaction was stopped after judged completed by TLC. After work-up and solvent evaporation at reduced pressure, 0.73 g (>100%) of a clean crude compound 10 was obtained as a viscous oil and used for the next step without further purification. ¹H NMR (CDCl₃): δ 5.63 (dq, J = 11.1, 6.7 Hz, 1H), 5.39 (dd, J = 11.1, 9.5 Hz, 1H), 4.07 (ddd, J = 9.0, 5.3, 2.0 Hz, 1H), 3.63 (dd, J = 10.2, 9.2 Hz, 1H), 3.53 (dd, J = 9.5, 5.3 Hz, 1H), 3.48 (dd, J = 9.5, 9.0 Hz, 1H), 3.47 (dd, J = 10.2, 7.0 Hz, 2H), 2.91 (dddd, J = 9.5, 9.2, 7.0, 2.0 Hz, 1H), 1.66 (dd, J = 6.7, 1.6 Hz, 3H), 1.07 (m, 21H), 0.96 (m, 18H), 0.66–0.49 (m, 12H). ¹³C NMR (CDCl₃): δ 127.0, 126.6, 71.2, 65.5, 62.7, 42.1, 18.0, 13.4, 11.9, 6.8 and 6.4, 5.1 and 4.6.

2.3.23. Preparation of (±)-(2S,3R)-2-((Z)-prop-1-enyl)-3-(triethylsilyloxy)-4-(triisopropylsilyloxy)-1-butanol (11)

Following general procedure I, 0.22 g (0.414 mmol) of the bis-TES ether 10 dissolved in 2.1 mL of THF, 0.41 mL of HOAc, and 0.21 mL of water were added. The reaction was refluxed for approximately 3 h. Work up and solvent evaporation yielded 0.19 (>100%) of crude material. The crude was purified by column chromatography (4:1 hexane/ethylacetate) to yield 0.09 g (54%) of pure secondary TES ether 11 as a viscous oil after three consecutive steps. ¹H NMR (CDCl₃): δ 5.72 (dq, J = 11.0, 6.8 Hz, 1H), 5.41 (dd, J = 11.0, 9.6 Hz, 1H), 3.836 (ddd, J = 7.7, 4.9, 3.0 Hz, 1H), 3.69 (dd, J = 10.9, 6.5 Hz, 1H), 3.62 (dd, J = 10.9, 7.6 Hz, 1H), 3.62 (dd, J = 9.8, 4.9 Hz, 1H), 3.56 (dd, J = 9.8, 7.7 Hz), 2.97 (dddd, J = 9.6, 7.6, 6.5, 3.0 Hz, 1H), 2.18 (bs, Hz, 1H), 1.67 (dd, J = 6.8, 1.7 Hz, 3H), 1.06 (m, 21H), 0.94 (m, 9H), 0.63–0.49 (m, 6H). ¹³C NMR (CDCl₃): δ 128.2, 126.6, 73.9, 65.4, 64.3, 42.6, 18.0, 13.5, 11.9, 6.9, 5.0. Anal. Calcd. for C₂₂H₄₈O₃Si₂: C, 63.40; H, 11.61. Found: C 63.77; H, 11.64.

2.3.24. Preparation of (±)-(2R,3R)-2-((2S,3R)-3-methyloxiran-2-yl)-3-(triethylsilyloxy)-4-(triisopropylsilyloxy)butan-1-ol (12)

Following general procedure C, VO(acac)₂ (0.01 g, 0.042 mmol, 0.014 equiv), toluene (36.0 mL, 0.083 M), 1.20 g of alkenol 11 (2.98 mmol), and 0.85 mL of TBHP (3.278 mmol, 1.1 equiv, 3.85 in toluene) were used. The reaction was completed in 13 min. After work up and solvent evaporation, 1.26 g (98%) of crude was obtained with epoxide 12 as a viscous oil. ¹H NMR (CDCl₃): δ 3.97 (dd, J = 10.4, 6.2 Hz, 1H), 3.90 (ddd, J = 7.9, 4.6, 4.3 Hz, 1H), 3.81 (dd, J = 10.4, 6.2 Hz, 1H), 3.69 (dd, J = 10.0, 4.6 Hz), 3.63 (dd, J = 10.0, 7.9 Hz), 3.14 (dd, J = 9.2, 3.9 Hz, 1H), 3.08 (dq, J = 5.3, 3.9 Hz, 1H), 2.75 (bs, 1H), 1.85 (dddd, J = 9.2, 6.2, 5.8, 4.3 Hz, 1H), 1.31 (d, J = 5.3 Hz, 3H), 1.05 (m, 21H) 0.94 (t, J = 7.9 Hz, 9H), 0.59 (q, J = 7.9 Hz, 6H). ¹³C NMR (CDCl₃) δ 72.9, 65.7, 63.4, 56.6, 53.0, 41.9, 18.0, 14.0, 11.9, 6.8, 5.7.

2.3.25. Preparation of (±)-(5S,6R)-5-(hydroxymethyl)-6-(triethylsilyloxy)-3-methyl-7-(triisopropylsilyloxy)-1-(trimethylsilyl)hept-1-yn-3-ol (13)

Following general procedure D, 13.0 mL of dry toluene (0.35 M), 1.7 mL (4.1 mmol, 6.0 equiv) of n-BuLi (2.53 M in hexane), 0.6 mL (4.1 mmol) of trimethylsilyl acetylene, and 2.5 mL (4.1 mmol, 6.0 equiv) of Et₂AlCl (1.8 M in toluene) were added to a round bottom flask. Followed by the addition of a previously prepared solution of 0.30 g (0.69 mmol) of the epoxy alcohol 12 in 4.6 mL of toluene (0.15 M) and 0.3 mL (0.76 mmol, 1.1 equiv) of n-BuLi (2.53 M in hexanes). After work up, solvent evaporation, and purification by flash chromatography (9:1 hexane/ethylacetate), 0.07 g (20%) of the less polar product 13, 0.03 (7%) of mixture, and 0.09 g (23%) of the most polar product 13 were obtained as a viscous oil.

Spectral data for the least polar product 13: ¹H NMR (300 MHz, CDCl₃) δ 3.95 (m, 1H), 3.79–3.60 (m, 4H), 2.30 (m,1H), 1.90 (dd, J = 15.1, 4.0 Hz, 1H), 1.63 (dd, J = 15.1, 5.0 Hz, 1H), 1.50 (s, 3H), 1.07 (m, 21H), 0.95 (t, J = 8.0 Hz, 9H), 0.60 (q, J = 8.0 Hz, 6H), 0.14 (s, 9H). ¹³C NMR (75 MHz, CDCl₃) δ 110.5, 86.8, 73.5, 68.0, 65.6, 64.4, 39.9, 39.3, 30.2, 17.9, 11.9, 6.8, 4.9, −0.1. Anal. Calcd for C₂₇H₅₈O₄Si₃: C, 61.07; H, 11.01. Found: C 61.26; H, 11.02.

Spectral data for the most polar product 13: ¹H NMR (500 MHz, CDCl₃) δ 4.00 (dd, J = 11.1, 5.0 Hz, 1H), 3.90 (dd, J = 11.2, 5.5 Hz, 1H), 3.86 (m, J = 3.9 Hz, 1H), 3.69 (dd, J = 9.5, 7.2 Hz, 2H), 2.31 (m, 1H), 1.85 (m, 2H), 1.53 (s, 3H), 1.11 (m, 21H), 0.99 (t, J = 7.9 Hz, 9H), 0.65 (q, J = 7.9 Hz, 6H), 0.17 (s, 9H). ¹³C NMR (126 MHz, CDCl₃) δ 109.9, 87.2, 75.5, 66.9, 65., 63.4, 42.1, 41.0, 31.7, 18.0, 11.9, 6.8, 4.9, −0.1.

2.3.26. Preparation of (±)-(2E,4R,5S)-4-(triethylsilyloxymethyl)-5-(triethylsilyloxy)-6-(triisopropylsilyloxy)-2-hexene (14)

The alkene diol 3c (3.7 g, 12.2 mmol) was submitted to general procedure H using 5.1 mL (36.7 mmol) of TEA and 8.3 mL (36.7 mmol) of TES-OTf in 35.0 mL of DMF. The reaction was stopped after stirring for 30 min by adding 30.0 mL of water and 30.0 mL of hexane. After work up and solvent evaporation at reduced pressure, 7.1 g (>100%) of a clean crude 14 was obtained as a viscous oil and used for the next step without further purification. ¹H NMR (CDCl₃): δ 5.52 (dq, J = 15.4, 6.3 Hz, 1H), 5.34 (dd, J = 15.4, 9.1 Hz, 1H), 3.95 (ddd, J = 7.7, 5.0, 2.0 Hz, 1H), 3.64 (dd, J = 12.0, 10.0 Hz, 1H), 3.54 (dd, J = 12.1, 2.0 Hz, 1H), 3.52 (dd, J = 12.0, 2.0 Hz, 1H), 3.50 (dd, J = 12.1, 5.0 Hz), 2.47 (dddd, J = 10.0, 9.1, 7.7, 2.0 Hz, 1H), 1.67 (dd, J = 6.3, 1.4 Hz, 3H), 1.05 (m, 21H), 0.98–0.91 (m, 18H), 0.64–0.61 (m, 12H). ¹³C NMR (CDCl₃): δ 128.5, 127.6, 71.6, 65.4, 63.6, 48.1, 18.2, 17.9, 11.8, 6.9, 6.7, 5.0, 4.8.

2.3.27. Preparation of (2S,3R)-2-((E)-prop-1-enyl)-3-(triethylsilyloxy)-4-(triisopropylsilyloxy)-1-butanol (15)

Following general procedure G, 6.35 g (11.96 mmol) of the bis-TES ether 14 dissolved in 61.2 mL of THF, 12.2 mL of HOAc, and 6.1 mL of water were added. The reaction was refluxed for approximately 8 h. Work up and solvent evaporation yielded 5.43 g (>100%) of crude material, which was purified by column chromatography (9:1 hexane/ethylacetate) to yield 2.18 g (44%) of pure secondary TES ether 15 as a viscous oil after four consecutive steps. ¹H NMR (CDCl₃): δ 5.60 (dq, J = 15.0, 6.2 Hz, 1H), 5.45 (dd, J = 15.0, 9.0 Hz, 1H), 3.82 (m, 1H), 3.71–3.61 (m, 4H), 2.54 (m, J = 9.0 Hz, 1H), 1.71 (d, J = 6.2 Hz, 3H), 1.07 (m, 21H), 0.97 (t, J = 7.8 Hz, 9H), 0.62 (q, J = 7.8 Hz, 6H). ¹³C NMR (CDCl₃): δ 129.5, 127.7, 74.3, 65.3, 64.2, 48.7, 18.4, 17.9, 11.8, 6.8, 5.0. Anal. Calcd. for C₂₂H₄₈O₃Si₂: C, 63.40; H, 11.61. Found: C 63.49; H, 11.57.

2.3.28. Preparation of (±)-(2S,3S)-2-((2S,3S)-3-methyloxiran-2-yl)-3-(triethylsilyloxy)-4-(triisopropylsilyloxy)butan-1-ol (16) and the Minor Isomer

Following general procedure C, VO(acac)₂ (0.019 g, 0.073 mmol), toluene (63.0 mL, 0.083 M), 2.18 g of alkenol 15 (5.23 mmol), and 1.5 mL of TBHP (5.75 mmol, 1.1 equiv, 3.85 in toluene) were combined. The reaction was completed in 13 min. After work up, solvent evaporation, and purification by Flash column chromatography (9:1) hexane/ethyl acetate yielded 1.16 g (51%) of a 85:15 mixture of epoxy alcohols 16a and its minor isomer 16b as a viscous oil. ¹H NMR (CDCl₃): δ 3.94 (m, J = 11.0, 3.5 Hz, 1H), 3.94 (m, J = 8.5, 5.9, 5.0 Hz, 1H), 3.79 (dd, J = 11.0, 6.3 Hz, 1H), 3.71 (dd, J = 10.0, 5.0 Hz), 3.61 (dd, J = 10.0, 8.5 Hz), 2.90 (dq, J = 5.2, 2.3 Hz, 1H), 2.85 (dd, J = 8.5, 2.3 Hz, 1H), 2.55 (bs, 1H), 1.67 (dddd, J = 8.5, 6.3, 5.9, 3.5 Hz, 1H), 1.30 (d, J = 5.1 Hz, 3H), 1.05 (m, 21H) 0.94 (t, J = 7.9 Hz, 9H), 0.59 (q, J = 7.8 Hz, 6H). ¹³C NMR (CDCl₃) δ 72.7, 65.3, 63.1, 58.4, 54.4, 46.4, 17.9, 17.5, 11.8, 6.8, 4.9. Anal. Calcd. for C₂₂H₄₈O₄Si₂: C, 61.05; H, 11.18. Found: C 61.36; H, 11.25.

Spectral data for the minor isomer 16b: (±)-(2S,3S)-2-((2R,3R)-3-methyloxiran-2-yl)-3-(triethylsilyloxy)-4-(triisopropylsilyloxy)butan-1-ol: ¹H NMR (CDCl₃) 4.03–3.98 (m, 2H), 3.79 (d, J = 6.1 Hz, 1H), 3.76 (m, 1H), 3.57 (dd, J = 9.9, 6.9 Hz), 2.97–2.85 (m, 2H), 2.85 (dd, J = 8.5, 2.3 Hz, 1H), 1.85 (m, 1H), 1.32 (d, J = 2.0 Hz, 3H), 1.05 (m, 21H), 0.94 (t, J = 7.9 Hz, 9H), 0.59 (q, J = 7.8 Hz, 6H), ¹³C NMR (CDCl₃) δ 73.4, 65.7, 61.4, 58.1, 53.3, 46.6, 17.9, 17.7, 11.8, 6.8, 4.9. Anal. Calcd. for C₂₂H₄₈O₄Si₂: C, 61.05; H, 11.18. Found: C 61.28; H, 11.41.

3. Results and Discussion

The optically active 2,3-epoxy alcohols 1-cis and 1-trans were prepared via Sharpless asymmetric epoxidation (SAE) of the respective allylic alcohols 5-Z and 5-E (

Table 1. Preparation of optically active monoprotected 2,3epoxyalcohols (1) via SAE reaction.

Entry	Allylic Alcohol	Tartrate	Product	${\left[\propto \right]}_{\mathit{D}}^{20}$	ee% a	Yield%
Entry 1	5-Z	L-DIPT	(-)-1-cis	−9.9	80	83
Entry 2		D-DIPT	(+)-1-cis	+8.4	80	80
Entry 3	5-E	L-DIPT	(-)-1-trans	−10.5	94	91
Entry 4		D-DIPT	(+)-1-trans	+13.9	94	80

^a Determined by ³¹P NMR spectroscopy of the Alexakis ester of (-)-1-cis and (+)-1-cis and (-)-1-trans and (+)-1-trans, respectively. ^b Isolated yield.

) [46,47]. We decided to synthesize optically active epoxy alkanols to expand the scope of our second-generation approach and demonstrate the viability of the employment of enantioenriched starting materials. The SAE of allylic alcohol 5-Z required a couple of days to completed, while the reaction with the trans-allylic alcohol 5-E was faster, generally completed in 2 h. The enantiomeric excess (ee) of both enantiomers of 1-cis epoxide was 80%, and for both enantiomers of the 1-trans epoxide was 94%, which were measured using the Alexakis method [44]. The ³¹P NMR spectra of the Alexakis ester of (-)-1-cis and (+)-1-cis are shown in Supporting information.

As previously anticipated, the epoxide-opening reactions in our methodology did not depend on whether racemic or optically active 2,3-epoxy diols were used. Therefore, the studies involving Grignard reagents were conducted using racemic epoxides, which were prepared from the allylic alcohols 5- and 5-E. These precursors were epoxidized with m-CPBA, affording the corresponding epoxides 1-cis and 1-trans, respectively, in good yields, as shown in Scheme 4.

The copper-catalyzed Grignard epoxide cleavage reaction was investigated using second-generation TIPS-protected cis- and trans-epoxy alcohols (1-cis and 1-trans) with various alkenyl Grignard reagents (Scheme 3,

Table 2. Cleavage of second-generation TIPS-protected 2,3-epoxy alcohols 1-cis and 1-trans using Cu-catalyzed alkenyl Grignard reagents.

Entry	Epoxide	Alkenyl Grignard a	Major Product	Regioselectivity b	Z/E Ratio c	% Yield d
entry 1	1-cis		3a	95:5	>95/5	66
entry 2	1-trans		3b	>95:5	>95/5	88
entry 3	1-cis		3c	>95:5	34:66	42
entry 4	1-trans		3d	>95:5	37:63	63
entry 5	1-cis		3e	>95:5	N/A	81
entry 6	1-trans		3f	>95:5	N/A	51
entry 7	1-cis		3g	>95:5	N/A	54
entry 8	1-trans		3h	>95:5	N/A	46

^a The Grignard reagents (6 equiv) were prepared in THF and then transferred to the CuI (1.3 or 0.1 equiv) in ether, −78 °C to rt. ^b No other regioisomer was detected, except for entry 1. ^c The Z/E geometry of the 1-bromopropene starting material was determined by NMR spectroscopy. ^d The yield of major product, except for entries 3 and 4, the yield of the Z/E mixture of isomers.

). The selection of alkenyl Grignard reagents was based on their commercial availability and potential utility in the synthesis of polypropionate fragments within our epoxide cleavage methodology.

Cleavage of epoxides 1-cis and 1-trans with cis-1-propenylmagnesium bromide (entries 1 and 2) proceeded with excellent regioselectivity (95:5), affording the corresponding cis-homoallylic diols: anti-1,3-diol (3a) in 66% yield and syn-1,3-diol (3b) in 88% yield (Table 1: entries 1 and 2). The reaction with trans-1-propenylmagnesium bromide (Table 1: entries 3 and 4) also exhibited excellent regioselectivity (>95:5). Surprisingly, this was accompanied by the formation of a mixture of trans/cis alkenols, resulting in a moderate ~65:35 trans/cis diastereoselectivity and yielding anti,trans-1,3-diol (3c) and syn,trans-1,3-diol (3d) as major products. This concomitant partial double-bond isomerization of trans-1-propenylmagnesium bromide to its cis isomer had been previously reported by our group [38]. Although this isomerization can be minimized by carefully controlling the reagent formation conditions, the reaction is impractical for synthetic purposes due to the inseparability of the resulting isomeric mixture by chromatography.

Cleavage of epoxides 1-cis and 1-trans with vinylmagnesium bromide (entries 5 and 6) proceeded with excellent regioselectivity (>95:5), affording the terminal anti-homoallylic 1,3-diol 3e at 81% yield and the terminal syn-homoallylic 1,3-diol 3f at 51% yield (Table 1: entries 5 and 6). The use of α-(trimethylsilyl)vinylmagnesium bromide (Table 1: entries 7 and 8) also afforded excellent regioselectivity (>95:5), with moderate (46–54%) to good (81%) yields of the corresponding syn/anti-homoallylic 1,3-diols 3g and 3h, respectively (Table 1: entries 7 and 8).

These results highlight the excellent regioselectivity achieved using alkenyl Grignard reagents for the cleavage of TIPS-monoprotected epoxides 1-cis and 1-trans, which surpassed that reported with the Bn-monoprotected cis- and trans-2,3-epoxy alcohols [36,43]. The improved selectivity observed with the second-generation epoxides can be attributed to the bulky TIPS ether, which effectively suppresses nucleophilic attack at the more hindered C3 position. Furthermore, coordination of the Grignard reagent with the hydroxyl group (in its alkoxide form) likely facilitates exclusive attack at the less hindered C2 position to form 1,3-diols in a regioselective and stereoselective manner. These results highlight the role of the free primary alcohol in directing nucleophilic attack at C2.

Although the epoxide cleavage methodology using alkenyl Grignard reagents provides one-step access to syn- and anti-hydroxymethyl 1,3-diols (3a–h) with excellent regioselectivity, the diastereoselective synthesis of trans-homoallylic 1,3-diols (3c and 3d) by this approach remains a challenge. Fortunately, we previously reported an alternative two-step synthesis of trans-homoallylic alcohols 3b and 3c (Scheme 1 and Scheme 4) [34,35]. In this strategy, TIPS-protected epoxy alcohol 1-cis was regioselectively cleaved (90:10) using the diethylpropynyl alanate reagent, affording the corresponding homopropargylic alcohol 2a (Scheme 5). Subsequent sodium/ammonia reduction of the homopropargylic 1,3-diol 2a exclusively produced the trans-homoallylic 1,3-diol 3c in 62% isolated yield for two consecutive steps. Similarly, propynyl alanate cleavage of 1-trans, followed by trans-selective reduction, afforded only the syn-homoallylic 1,3-diol 3d in 53% isolated yield for two consecutive steps. This propynyl alanate–reduction route (Scheme 1 and Scheme 5) complements the alkenyl Grignard methodology (Scheme 3), and together they represent a second-generation strategy that provides access to syn- and anti-hydroxymethyl 1,3-diols (3a–h) with excellent region- and diastereoselectivities.

The stereoselectivity of the propenyl cis/trans geometry in the homoallylic 1,3-diol products (3a-3d) was determined by ¹H and ¹³C NMR spectroscopy. The stereochemistry of the resulting alkenes was established by analyzing the coupling constants of the vinyl protons, with trans isomers displaying larger J_ab values (13–15 Hz) compared to cis isomers (10–11 Hz). The ¹³C NMR spectra showed diagnostic allylic methyl signals at 13.4–13.5 ppm for cis alkenes, and at 18.1–18.2 ppm for the trans isomers. The regioselectivity of the epoxide ring opening of 2,3-epoxy diols 1-cis and 1-trans was determined by ¹H and ¹³C NMR spectroscopy. All 1,3-diols 3a–h exhibited a single diagnostic peak corresponding to the methine C2 carbon atom, and no signals consistent with the C3 methine carbon of the 1,2-diols were observed.

To further validate the regioselectivity of the epoxide cleavage reactions with Grignard and propynyl alanes, acetonides 7, 8, and 9 were formed from the resulting 1,3- and 1,2-diols (Scheme 6). Representative examples are summarized in

Table 3. Selected acetonide syntheses and ¹³C NMR shifts of the ketal and gem-dimethyl carbons.

Entry	Diol	Product	Yield%	13C (ppm) (CDCl3)
				Ketal carbon	Methyl carbons
Entry 1	2a	7	76	98.8	29.4, 19.0
Entry 2	6	8	97 a	108.8	26.5, 25.9
Entry 3	3a	9	71	98.7	29.6, 19.0

^a Crude Yield.

. The formation of six-membered acetonides was observed when nucleophilic attack occurred at the C2 position (Table 2: entries 1 and 3), as expected from reactions involving organoaluminum ate complexes and Grignard reagents. In contrast, formation of a five-membered acetonide confirmed nucleophilic attack at the C3 position (Table 2: entry 2). In general, the ¹³C NMR spectra showed signals at approximately 29 and 19 ppm for the gem-dimethyl carbons of the six-membered acetonides, whereas the five-membered acetonide displayed two signals in the range of 25.9–26.6 ppm.

The conformational models presented in Scheme 7 explain the expected ¹³C NMR chemical shifts for the acetonide gem-dimethyls. The structural differences between the six- (chair) and five-membered acetonide (enveloped) result in significantly different ¹³C NMR spectra of the ketal carbon and associated methyl substituents. The six-membered acetonides adopt two chair conformations which interconvert. The equilibrium between these forms depends on the substituents propensity to occupy the given pseudo axial or pseudo equatorial positions. Therefore, the 1,3-diaxial interactions present in the chair–chair interconversions will provide a more stable and “frozen” chair, thus, the axial and equatorial methyl carbons are not chemically equivalents. The five-membered acetonides are in “conformational flux”, where the methyl group’s chemical shifts are almost equivalents with the rapid interchange.

Table 2 also includes the ¹³C chemical shifts of the ketal carbons, which are consistent with the findings reported [48,49]. Specifically, the six-membered acetonides 7 and 9 exhibited resonances above 98.8–98.9 ppm (Table 3: entries 1 and 3), while the five-membered acetonide 8 appeared around 108.8 ppm (Table 3: entry 2). These diagnostic signals were key in identifying the nature of the acetonides. In addition, the methine protons Ha and Hb in an anti-relationship within six-membered acetonides 7 and 9 displayed coupling constants J_ab = 3.0–4.0 Hz, consistent with an axial–equatorial arrangement (see Scheme 6 and Scheme 7). In contrast, the six-membered acetonide derived from syn-diol 2b confirmed the syn relationship, as evidenced by the larger coupling constants J_ab = 8–10 Hz.

We explored the potential application of this second-generation methodology for the synthesis of polypropionate fragments containing hydroxymethyl 1,3-diol motifs. For this purpose, anti-homoallylic 1,3-diol 3a was used (Scheme 8). Application of the TES diprotection followed by selective TES deprotection afforded homoallylic alcohol 11 with the free primary alcohol. Subsequent microwave-assisted epoxidation using VO(acac)₂/TBHP stereoselectively provided the anti,cis-3,4-epoxy alcohol 12 in >95:5 diastereoselectivity in 13 min with 98% yield (Scheme 8) [35]. Alternatively, epoxidation of 11 at room temperature for 24 h afforded the desired epoxide 12 in good yield (85%). Next, epoxide 12 was subjected to cleavage with a TMS-alkynyl aluminum reagent. However, the major products were tertiary alcohols 13a and 13b, formed as a diastereoselective 65:35 mixture due to alkynyl addition to a rearranged γ-hydroxy ketone intermediate. These unexpected products arose from the Lewis acidic nature of the aluminum reagent, which promotes epoxide-to-ketone rearrangement in susceptible substrates [50,51]. When the reaction was performed without pretreatment of epoxide 12 with n-BuLi, the diastereoselectivity was inverted to 43:57, thus providing a potential complementary method for the preparation of fragments 13a and 13b. Additionally, product 13a was identified as an alternative precursor for the C5–C10 fragment found in the tylosin family because this compound contains the correct stereochemistry and a hydroxymethyl group at C6, which can be further oxidized to form the required aldehyde in the natural compound [3]. Fragment 13a also possesses a tertiary alcohol at C8 adjacent to the deoxygenated C7 carbon. Although this approach does not afford the tertiary alcohol with stereocontrol, isolation of both diastereomers was straightforward, offering a valuable opportunity to assign the relative stereochemistry of each diastereomer—information that has not yet been determined. If the primary hydroxy group is no longer required after serving its role in the synthesis—as is the case for the C5–C10 fragment of mycinamicin I and the polypropionate chain of aldgamacins N/O/J—it can be removed at any stage via tosylation, followed by hydride reduction to yield the C6 methyl group [52].

Recognizing the synthetic opportunities this finding offers for polypropionate synthesis, the anti-hydroxymethyl 1,3-diol 3b motif can serve as a key structural element in target molecules (Scheme 9). For instance, this trans-homoallylic diol appears in the C14–C15 fragment of tylosin, mycinamicins, aldgamacins, tianchimycin, swalpamycin, and the chalcomycin series, all of which also require a C20-primary alcohol. Furthermore, trans-homoallylic alcohol 3b could serve as a precursor to the C11–C14 fragment found in mycinamicins III and IV, since it contains both the anti-1,3-diol stereochemistry and the required trans-alkene [9]. We therefore converted anti-1,3-diol 3b into the corresponding homoallylic alcohol 15, which was subsequently transformed stereoselectively into the anti-syn-trans epoxide 16 with an 85:15 diastereoselectivity using a microwave heating protocol (Scheme 9) [35]. The epoxidation of alkenol 15 was also carried out at room temperature; although a similar yield and diastereoselectivity were obtained, the reaction required 24 h to reach completion. Epoxide 16 mimics the C11–C14 fragment present in mycinamicin I and the aldgamacins—both of which require an anti-hydroxymethyl 1,3-diol trans-epoxide for their construction [9].

4. Summary and Conclusions

In summary, we reported a complementary second-generation methodology for the enantio-, regio- and diastereoselective synthesis of syn- and anti-hydroxymethyl 1,3-diols via copper-catalyzed epoxide cleavage using alkenyl Grignard reagents. The use of cis-propenylmagnesium bromide enabled direct access to cis-homoallylic alcohols with excellent regioselectivity and yield, eliminating the need for a partial hydrogenation step and streamlining the synthetic sequence to two steps. In contrast, the trans-propenylmagnesium bromide reagent resulted in undesired Z/E isomerization, limiting its utility. Complementary use of propynyl alanate addition followed by sodium/ammonia reduction provided a practical route to access trans-homoallylic diols with high selectivity. The success of vinyl Grignard additions also opens new avenues for the synthesis of polypropionate fragments bearing terminal homoallylic 1,3-diols. The - and diastereoselectivity of the epoxide opening reactions were confirmed by detailed spectroscopic analysis of the products, including ¹H and ¹³C NMR, which showed characteristic coupling constants and chemical shift patterns consistent with the assigned stereochemistry. These one-step alkenyl Grignard and two-step alkynyl alane-reduction strategies expand the synthetic toolbox for the efficient construction of polyketide-derived structures—such as those found in tylosin, mycinamicins, and aldgamacins—that require the incorporation of syn- and anti-hydroxymethyl 1,3-diols.