Gold-catalyzed diastereoselective synthesis of 2,6-trans-disubstituted tetrahydropyran derivatives: application for the synthesis of the C1–C13 fragment of bistramide A and B

Abstract

An efficient gold(III)-catalyzed general method for the diastereoselective allylation of six-membered cyclic hemiacetals at room temperature is developed. The present protocol is operationally simple with good functional group tolerance, thus providing easy access to various multifunctionalized 2,6-trans-disubstituted tetrahydropyrans. Since an allyl moiety is readily introduced, the developed strategy is highly versatile and has great potential for further functional group manipulation. Furthermore, a diastereoselective synthesis of the C1–C13 fragment of bistramide A and B has been described highlighting this methodology.

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Introduction

The nucleophilic addition of less reactive allylsilanes to carbonyl compounds¹ or acetals,² known as Hosomi–Sakurai allylation, has been the subject of extensive investigation because of the usefulness of products containing one new carbon–carbon bond along with a new stereogenic center (either formed via substrate or reagent controlled). Many successful examples of the intermolecular C–C bond formation strategies have been developed, in most of the cases employing Lewis or Brønsted acids.^1,2 However, allylation of unsymmetrical cyclic acetal via regioselective C–O bond cleavage is a promising method for the synthesis of oxygen heterocycles such as pyran and furan frameworks, which have served widely as building blocks for complex bioactive molecules.³ Although, there are overwhelming reports for the trapping of oxocarbenium ion generated from the corresponding acetal for the synthesis of trans terahydropyran,⁴ the examples of generation of oxocarbenium ion from a hemiacetal are rare.⁵ Furthermore, the real obstacle to employ the existing strategies is the use stoichiometric amount acid catalysts, low temperature conditions and pre-functionalization via a suitable leaving group (eqn (1), Scheme 1). From the viewpoint of step-economy, the direct allylation of lactol would be more desirable and straightforward. In this basis, we envisaged that Au(III) catalyzed activation of hemiacetal would be superior as it can be used without the concern of air and moisture because of its hard, oxophilic Lewis acidity. The catalysis of organic reactions by gold catalyst has recently been shown to be a powerful tool in organic synthesis and this chemistry is now effectively implementing in the edifice of the complex natural products. Relatively few synthetic protocols using different gold catalysts have been reported on the C-glycosidation and O-glycosidation with leaving group at the anomeric position. In 2006, Hotha and coworkers reported a Au(III)-catalyzed anomeric activation of glycoside anomers with the aid of propargyloxy group.⁶ More recently, Balamurugan et al. demonstrated Au(III) promoted allylation of a pre-functionalized lactol with allyltrimethylsilane assisted by alkyne directing group (Scheme 1a).⁷

Scheme 1 Diastereoselective functionalization of anomeric carbon.

However, the lower yield with a less nucleophilic carbon nucleophile limits the process from synthetic point of view. With our attention initially directed towards the synthesis of pyran containing natural products,⁸ the requisite functionalized pyran core in all of which was concisely realized through tandem C=C bond isomerization and Hosomi–Sakurai allylation of in situ formed silyl acetal from δ-hydroxy-α,β-unsaturated aldehyde,^8b,d,i we anticipated the stereoselective C-allylation of a hemiacetal I via a metallic Lewis acid activation. Considering the recent explosion of interest in gold catalysis to the synthesis of a variety of novel heterocyclic architectures,⁹ particularly our recent entry to alkyne functionalization,¹⁰ we envisaged that a oxophilic gold catalyst (Au-III)¹¹ would facilitate oxocarbenium ion formation and promote the axial approach of allylic nucleophile to furnish the 2,6-trans-disubstituted pyran III (Scheme 1C). Herein, we divulge a diastereoselective intermolecular allylation of a cyclic hemiacetal to generate 2,6-trans-disubstituted pyran via a gold-catalyzed O-silylation reaction.¹²

Results and discussion

Our initial experiments were guided by observations made in our laboratory during the development of efficient protocols for regioselective hydration of alkynoates.¹⁰ Accordingly, the general reactivity feature of lactol was examined with 1 by using 1.5 equiv. of allyltrimethylsilane and various gold catalysts (Table 1). The established catalytic conditions of using 3 mol% of the Au(I) catalyst (PPh₃AuOTf) in anhydrous CH₂Cl₂ at room temperature provided the desired allylation product in only 36% yield (Table 1, entry 1). Similarly, attempts to use other counter ions source such as AgSbF₆, AgBF₄ and AgNTf₂ were also not very successful and proceeded with moderate yield (Table 1, entries 2–4). Allylation with AuCl was also gave lower yield of 38% (Table 1, entry 5). To our satisfaction, change of Au(I) to Au(III) catalyst produced the allylation product 2 in an improved yield of 65% (Table 1, entries 6–8). These results of higher yield accounts for the stronger oxophilicity of Au(III) catalyst towards hemiacetal activation compare to Au(I) catalyst.¹¹ Variation of the solvents (THF, CH₃CN, toluene, DCE) did not perk up the yield of the reaction, but sometimes obtained with lesser yield (Table 1, entries 9–12). As a result of the further optimization, it was found that the reaction carried out with the use of AuCl₃ (5 mol%) in anhydrous CH₂Cl₂ at room temperature for 2.5 h gave the best outcome (Table 1, entry 13) (Scheme 2).

Table 1 Reaction optimization by various gold catalysts^a

Entry^a	Catalyst	Solvent	Time	Yield^b (%)
a Conditions: ^a all reactions are performed were performed with 1a (0.2 mmol) and allyltrimethylsilane (1.5 equiv.) in solvent (1 mL) at room temperature under N2 atmosphere. ^b Products yield were reported after column chromatography. ^c 3 mol% of Au catalyst was used. ^d 5 mol% of catalyst was employed. ^e The diastereoselectivity of the allylated product was determined by HPLC analysis (dr = 99 : 1).
1	PPh3AuCl/AgOTf^c	CH2Cl2	2 h	36
2	PPh3AuCl/AgSbF6^c	CH2Cl2	3 h	24
3	PPh3AuCl/AgNTf2^c	CH2Cl2	3 h	32
4	PPh3AuCl/AgBF4^c	CH2Cl2	3 h	25
5	AuCl^c	CH2Cl2	2 h	38
6	NaAuCl4^c	CH2Cl2	2 h	55
7	AuCl3^c	CH2Cl2	2 h	65
8	AuBr3^c	CH2Cl2	2 h	48
9	AuCl3^c	THF	2 h	42
10	AuCl3^c	CH3CN	1.5 h	35
11	AuCl3^c	Toluene	1.5 h	57
12	AuCl3^c	DCE	2 h	60
13	AuCl3^d,e	CH2Cl2	2.5 h	96

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Scheme 2 Gold-catalyzed allylation of the model substrate 1.

To determine the trans-selectivity of the allylated product 2, where both the pyran attached protons are not well distinguished in ¹H (Scheme 3). So also, the NOESY experiment of the resulting alcohol 4 was not able to clarify the relative orientation. Thus, we thought to subject aldehyde 3 under one pot trans–cis isomerization (NaOMe in MeOH) and reduction conditions (NaBH₄ in MeOH) to obtain alcohol 5.¹³ The assumed strategy was proved to be fruitful and also the relative configuration of 5 was clearly determined by 1D NOESY as cis at C2 and C6 (see ESI†).

Scheme 3 Determination of trans-orientation of C2 and C6 hydrogen.

To rationalize the efficacies of the above optimal reaction conditions (5 mol% of AuCl₃ in CH₂Cl₂), different six-membered cyclic hemiacetals were surveyed (Table 2). Reactions of lactols (1a–h, 1j) bearing different O-protecting groups (Bn, PMB, TBDPS, TBS, acetonide), positioned at the complementary end (at C5) are proceeded efficiently with good to excellent yield (Table 2, entries a–h, j). The current allylation reaction was also effective for the substrate 1i possessing a long chain alkyl moiety at C5 and the desired product 2i was obtained in 93% yield (entry I, Table 2). Furthermore, hemiacetals (1b, 1c, 1g and 1h) with variable substituents at either of the positions of the core ring was transformed smoothly into the corresponding allylated products (2b, 2c, 2g and 2h) indicating that steric bulk did not affect the reactivity notably. It is noteworthy from the examples cited in Table 2 that the stereochemistry of labile protecting groups (OTBS, entry h, Table 2) as well as inert aliphatic groups (methyl/s, entries b, c and g, Table 2) did not alter the stereochemical outcome. Also, the reaction was proceeded smoothly with fully protected carbohydrate hemiacetal (1k) providing the allylated product (2k) in slightly longer time.

Table 2 Scope of allylation of cyclic hemiacetal 1 with allylsilane^a

Entry^a	Substrate (1)	Product (2)	Time (h)	Yield^b	Ratio^c
a Reaction conditions: ^a all reactions were performed following the optimized with 1.0 mmol of 1. ^b Isolated yields after purification on silica gel. ^c Diastereomeric ratio was determined by HPLC.^d Only the major product was isolated and characterized by NMR spectroscopy. nd = dr was not determined.
a			3.0	89%	96 : 4
b			3.5	83%	99 : 1
c			2.5	95%	99 : 1
d			2.0	90%	97 : 3
e			2.0	87%	99 : 1
f			2.5	85%	nd^d
g			2.5	91%	97 : 3
h			4.0	75%	90 : 10
i			3.5	93%	nd^d
j			3.0	83%	nd^d
k			6.0	72%	92 : 8

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The catalytic activation of a six membered hemiacetal by the use of Au(III) catalyst is believed to proceed through a pathway as depicted in Scheme 4. An obvious pathway involves the coordination of OH-group by a more oxophilic Au(III) catalyst to generate the oxocarbenium ion B via in situ formation of silylacetal II.¹² An evidence for the formation of silylacetal intermediate was supported from mass spectral analysis of the reaction mixture. Consequently, the subsequent nucleophilic attack of allyltrimethylsilane to oxocarbenium B provides 2,6-trans-tetrahydropyran III and regenerates the Au-catalyst to complete the catalytic cycle.

Scheme 4 Plausible reaction mechanism for allylation.

Synthetic application of the present protocol to the synthesis of C1–C13 fragment of bistramide A and B

The success of the developed catalytic asymmetric allylation reaction prompted us to apply it for the diastereoselective synthesis of C1–C13 fragment of bistramide A and B (Fig. 1),¹⁴ which were considerably more challenging because of its potent biological activities.¹⁵ Moreover, the unique structural features comprising of a 2,6-trans-tetrahydropyran unit and a spiroketal subunit linked peptidically via a γ-amino acid, have elicited significant interest for total synthesis from the synthetic community.¹⁶

Fig. 1 Structures of bistramide A and B.

Our target to synthesize the C1–C13 fragment of 6 and 7 was to utilize the present allyation strategy to construct the THP-ring 2g from lactol 1g, which in turn could be accessed from 1,3-propanediol by following an asymmetric aldol and a palladium catalyzed isomerization as two key reactions.

As per our strategic plan, the synthesis of the required 2,6-trans-disubstituted tetrahydropyran fragment of bistramide A and B was started from 1,3-propanediol (8). Protection of one of the hydroxyl group of 8 as its p-methoxybenzyl (PMB) ether¹⁷ and oxidation of the remaining hydroxyl group with o-iodoxybenzoic acid (IBX)¹⁸ gave aldehyde 10 in 89% yield. The non-Evans-syn aldol reaction¹⁹ of aldehyde 10 with chiral auxiliary 11 in the presence of TiCl₄ and N,N-diisopropylethylamine (DIPEA) gave 12 in 82% yield (dr 7 : 1, separated by silica gel column chromatography). Silylation of the secondary alcohol²⁰ 12 afforded tert-butyldimethylsilyl (TBS) ether 13 in 95% yield, which on controlled reductive cleavage with diisobutylaluminium hydride (DIBAL-H)²¹ produced aldehyde 13 and two carbon Wittig olefination furnished compound 14 in 71% yield over two steps. Reduction of the ester functionality in 14 by DIBAL-H furnished the corresponding allyl alcohol 15 in 95% yield. Cleavage of secondary TBS-ether in 15 camphorsulfonic acid (CSA) in MeOH followed by a palladium-catalyzed isomerization reaction²² furnished the desired lactol 1g (71% yield, over 2 steps) which set the stage for the catalytic allylation reaction (Scheme 5).

Scheme 5 Synthesis of allylation precursor 1g.

With good quantities of lactol 1g in hand, the allylation reaction was carried out under the optimized conditions (see Table 1, entry 12) to obtain 2,6-trans-tetrahydropyran 2g. Elaboration of the terminal olefinic bond in 2g via Jin's oxidative dihydroxylation–oxidation protocol²³ and standard Barbier allylation²⁴ provided the homoallylic alcohol 18 as a mixture of diastereomers. The diastereomeric alcohols were directly used for the next oxidation–isomerization reaction under Swern conditions (using excess Et₃N)²⁵ to form the enone 19 in 77% yield. The Oxidative cleavage of PMB²⁶ group present in 19 was proceeded smoothly in presence of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) to afford the primary alcohol 20, which on subsequent oxidation using (2,2,6,6-tetramethyl-piperidin-1-yl)oxyl (TEMPO) and (diacetoxyiodo) benzene (BAIB)²⁷ in aqueous CH₂Cl₂ furnished C1–C13 fragment of bistramide A (21). The spectral and analytical data were in good agreement with that of the previous report.^16c Pd/C hydrogenation of the resulting acid 21 led to the formation of the saturated analogue 22, the C1–C13 fragment of bistramide B (Scheme 6).

Scheme 6 Completion of the synthesis of C1–C13 fragment of bistramide A (21) and B (22).

Conclusions

In summary, by taking the advantage of the unique oxophilic property of gold, we have achieved for the first time the gold-(III) catalyzed diastereoselective C–C bond formation of a cyclic hemiacetal with allyltrimethylsilane as a nucleophile via the formation of an oxocarbenium ion intermediate. The protocol offers an operationally simple approach to 2,6-trans-disubstituted tetrahydropyran, and features ambient temperature conditions, good diastereoselectivity and protecting group tolerance. It is worth mentioning that the present allylation strategy proceeds in good to excellent yield without pre-functionalization or via alkyne assistance, in contrast to the previous approaches, with a less nucleophilic carbon. In view of the introduction of easily modifiable alkene functionality, this gold catalyzed allylation can be expected to find wide synthetic applications. Meanwhile one of the applications of the current method was demonstrated in the synthesis of C1–C13 fragment of bistramide A (21) and B (22). Further reactivity studies of various metal catalysts to this allylation as well as other C-nucleophiles are currently underway in our laboratory and will be reported in due course.

Experimental sections

General remarks

General methods. Air and/or moisture sensitive reactions were carried out in anhydrous solvents under an atmosphere of argon in an oven or flame-dried glassware. All anhydrous solvents were distilled prior to use: THF, benzene, toluene, diethyl ether from Na and benzophenone; CH₂Cl₂, DMSO, DMF, hexane from CaH₂; MeOH, EtOH from Mg cake. Commercial reagents were used without purification. Column chromatography was carried out by using silica gel (60–120 mesh). Specific optical rotations [α]_D are given in 10⁻¹ deg cm² g⁻¹. Infrared spectra were recorded in CHCl₃/neat (as mentioned) and reported in wave number (cm⁻¹). TOF analyzer type was used for the HRMS measurement. ¹H and ¹³C NMR chemical shifts are reported in ppm downfield from tetramethylsilane and coupling constants (J) are reported in hertz (Hz). The following abbreviations are used to designate signal multiplicity: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad.

General procedure for cyclization

To a stirred solution of lactol (1.0 mmol) and allyltrimethyl silane (1.5 mmol) in CH₂Cl₂ (5 mL) at room temperature, gold(III) chloride (0.05 mmol) was added and allowed to stir for 2 h to 6 h at room temperature. After completion of the reaction (as indicated by TLC), it was quenched with water (5 mL). The reaction mixture was extracted with CH₂Cl₂ (2 × 10 mL), combined organic layer was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to give a pale yellow oil, which was purified by silica gel column chromatography using 5–7% ethyl acetate/hexane as eluent to obtain 72–96% of isolated yield of the allylated cyclized product.

(2R,6R)-2-Allyl-6-phenethyltetrahydro-2H-pyran (2). Yield: 96%; [α]²⁷_D −78.64 (c 1.5, CHCl₃); IR (neat): ν_max 2934, 2857, 1641, 1447, 1200, 1091, 1041 cm⁻¹; ¹H NMR (CDCl₃, 300 MHz): δ 7.30–7.24 (m, 2H), 7.22–7.14 (m, 3H), 5.85 (m, 1H), 5.12–5.0 (m, 2H), 3.82–3.72 (m, 2H), 2.75 (m, 1H), 2.59 (m, 1H), 2.40 (m, 1H), 2.20 (m, 1H), 2.03 (m, 1H), 1.73–1.58 (m, 5H), 1.40–1.31 (m, 2H) ppm; ¹³C NMR (CDCl₃, 75 MHz) δ 142.4, 135.5, 128.4, 128.2, 125.6, 116.4, 76.5, 70.4, 38.4, 34.8, 32.0, 29.8, 29.6, 18.5 ppm; ESI-HRMS: m/z calcd for C₁₆H₂₃O [M + H]⁺ 231.1743, found 231.1732, HPLC analysis (dr = 99 : 1).

2-((2R,6R)-6-Phenethyltetrahydro-2H-pyran-2-yl)acetaldehyde (3). To a solution of 2 (300 mg, 0.130 mmol) in dioxane and water (3 : 1) (10 mL), 2,6-lutidine (0.55 mL, 0.521 mmol), OsO₄ (0.13 mL, 0.01 mmol, 1 M solution in toluene) followed by NaIO₄ (1.11 g, 0.521 mmol) were sequentially added at room temperature and stirred for 2 h. After the completion of reaction (monitored by TLC), 1,4-dioxane was removed under reduced pressure and the residual aqueous layer was extracted with CH₂Cl₂ (3 × 15 mL). The CH₂Cl₂ layer was quickly washed with 1 N HCl (2 × 30 mL) to remove excess 2,6-lutidine followed by brine (2 × 30 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to get the crude aldehyde which on purification by short flash column chromatography over silica gel (ethyl acetate/hexane = 1 : 9) afforded aldehyde 3 (242 mg, 80%) as a colorless oil which was immediately used for the next step without further characterization.

2-((2R,6R)-6-Phenethyltetrahydro-2H-pyran-2-yl)ethanol (4). To a solution of the aldehyde 3 (100 mg, 0.431 mmol) in MeOH (5 mL) was added sodium borohydride (8.2 mg, 0.215 mmol) portion-wise at 0 °C. The mixture was stirred for 30 min. After complete consumption of the starting material (monitored by TLC), it was quenched with water (5 mL) and methanol was removed under reduced pressure. The aqueous layer was extracted with EtOAc (3 × 10 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na₂SO₄, and concentrated in vacuo. The residue was purified by column chromatography over silica gel (ethyl acetate/hexane = 7 : 3) to afford alcohol 4 (83.7 mg, 83%) as a colourless liquid. [α]²⁷_D −15.6 (c 0.5, CHCl₃); IR (neat): ν_max 3428, 2928, 2858, 1450, 1373, 1244, 1049 cm⁻¹;¹H NMR (CDCl₃, 300 MHz): δ 7.33–7.24 (m, 2H), 7.21–7.14 (m, 3H), 3.95 (m, 1H), 3.89–3.77 (m, 3H), 2.81–2.55 (m, 2H), 2.13 (m, 1H), 1.90 (m, 1H), 1.78–1.53 (m, 6H), 1.46–1.35 (m, 2H); ¹³C NMR (CDCl_3, 75 MHz): δ 142.1, 128.4, 128.3, 125.7, 71.2, 70.5, 61.6, 36.3, 33.8, 32.1, 31.0, 29.3, 18.4; ESI-HRMS: m/z calcd for C₁₅H₂₂O₂Na [M + Na]⁺ 257.1512, found 257.1504.

2-((2S,6R)-6-Phenethyltetrahydro-2H-pyran-2-yl)ethanol (5). To a solution of the aldehyde 3 (100 mg, 0.431 mmol) in MeOH (5 mL) was added NaOMe (3.2 mg, 0.086 mmol) was stirred at room temperature for 5 h. To this solution sodium borohydride (8.2 mg, 0.215 mmol) was added portion-wise at 0 °C. The mixture was stirred for 30 min. After complete consumption of the starting material (monitored by TLC), the solution was evaporated. The residue was diluted with water (5 mL) an ethyl acetate (15 mL). The organic layer was separated and the aqueous layer extracted with ethyl acetate (2 × 15 mL). The combined organic layer was washed with brine (30 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, hexanes/EtOAc, 7/3) to afford alcohol 5 (76 mg, 75%) as colourless oil. [α]²⁷_D +16.0 (c 0.5, CHCl₃); IR (neat): ν_max 3422, 2928, 2855, 1448, 1379, 1327, 1197, 1079, 1046 cm⁻¹; ¹H NMR (CDCl₃, 300 MHz): δ 7.32–7.24 (m, 2H), 7.21–7.13 (m, 3H), 3.87–3.79 (m, 2H), 3.56 (m, 1H), 3.31 (m, 1H), 2.81–2.57 (m, 2H), 1.92–1.64 (m, 6H), 1.62–1.43 (m, 2H), 1.40–1.27 (m, 2H); ¹³C NMR (CDCl_3, 75 MHz): δ 142.0, 128.4, 128.3, 125.7, 78.7, 77.0, 61.8, 38.0, 31.8, 31.6, 31.3, 23.3; ESI-HRMS: m/z calcd for C₁₅H₂₃O₂ [M + H]⁺ 235.1692, found 235.1687.

(2R,6R)-2-Allyl-6-(benzyloxymethyl)tetrahydro-2H-pyran (2a). Yield: 89%; [α]²⁷_D −19.8 (c 0.6, CHCl₃); IR (neat): ν_max 2926, 2856, 1742, 1643, 1454, 1373, 1103, 1042 cm⁻¹; ¹H NMR (CDCl₃, 500 MHz): δ 7.36–7.26 (m, 5H), 5.81 (m, 1H), 5.11–5.02 (m, 2H), 4.56 (AB_q, J = 16.7, 12.2 Hz, 2H), 3.95 (m, 1H), 3.81 (m, 1H), 3.58 (dd, J = 9.9, 6.4 Hz, 2H), 3.45 (dd, J = 9.9, 5.3 Hz, 1H), 2.46 (m, 1H), 2.23 (m, 1H), 1.69–1.59 (m, 4H), 1.42 (m, 1H) ppm; ¹³C NMR (CDCl_3, 75 MHz): δ 135.2, 128.3, 127.6, 127.5, 116.5, 73.1, 71.6, 71.5, 69.9, 37.5, 28.8, 27.0, 18.3 ppm; ESI-HRMS: m/z calcd for C₁₆H₂₂O₂Na [M + Na]⁺ 269.1516, found 269.1512, HPLC analysis (dr = 96 : 4).

(2R,3R,6R)-6-Allyl-2-((4-methoxybenzyloxy)methyl)-3-methyltetra hydro-2H-pyran (2b). Yield: 83%; [α]²⁷_D −19.6 (c 0.5, CHCl₃); IR (neat): ν_max 2929, 2859, 1733, 1612, 1512, 1460, 1247, 1097, 1034, 913 cm⁻¹; ¹H NMR (CDCl₃, 300 MHz): δ 7.27 (d, J = 9.0 Hz, 2H), 6.87 (d, J = 9.0 Hz, 2H), 5.80 (m, 1H), 5.13–4.99 (m, 2H), 4.50 (AB_q, J = 30.2, 12.0 Hz, 2H), 3.90 (m, 1H), 3.81 (s, 3H), 3.54–3.50 (m, 2H), 3.44 (m, 1H), 2.48 (m, 1H), 2.25 (m, 1H), 1.77–1.44 (m, 4H), 1.33 (m, 1H), 0.88 (d, J = 6.04 Hz, 3H) ppm; ¹³C NMR (CDCl_3, 75 MHz): δ 159.0, 135.4, 130.6, 129.2, 116.4, 113.6, 75.4, 72.8, 70.5, 55.2, 36.2, 30.5, 26.9, 26.6, 18.0 ppm; ESI-HRMS: m/z calcd for C₁₈H₂₆O₃Na [M + Na]⁺ 313.1774; found: 313.1777, HPLC analysis (dr = 99 : 1).

(2-((2S,6R)-6-Allyl-3,3-dimethyltetrahydro-2H-pyran-2-yl)ethoxy) (tertbutyl)diphenylsilane (2c). Yield: 95%; [α]²⁷_D −48.2 (c 1.6, CHCl₃); IR (neat): ν_max 2931, 2859, 1742, 1644, 1467, 1430, 1386, 1105 cm⁻¹; ¹H NMR (CDCl₃, 300 MHz): δ 7.74–7.60 (m, 4H), 7.46–7.30 (m, 6H), 5.68 (m, 1H), 5.06–4.82 (m, 2H), 3.82–3.65 (m, 2H), 3.58–3.38 (m, 2H), 2.28 (m, 1H), 2.09 (m, 1H), 1.85–1.58 (m, 2H), 1.44–1.22 (m, 4H), 1.06 (s, 9H), 0.96 (s, 3H), 0.82 (s, 3H) ppm; ¹³C NMR (CDCl₃, 75 MHz): δ 135.6, 135.4, 134.1, 129.4, 127.5, 116.3, 75.9, 69.9, 61.5, 37.9, 33.0, 32.0, 30.9, 27.0, 26.8, 25.9, 23.3, 19.1 ppm; ESI-HRMS: m/z calcd for C₂₈H₄₀O₂SiNa [M + Na]⁺ 459.2689, found 459.2693, HPLC analysis (dr = 99 : 1).

(2S,6S)-2-Allyl-6-(3-(benzyloxy)propyl)tetrahydro-2H-pyran (2d). Yield: 90%; [α]²⁷_D +21 (c 1.5, CHCl₃); IR (neat): ν_max 2935, 2853, 1641, 1451, 1361, 1202, 1099, 1042 cm⁻¹; ¹H NMR (CDCl₃, 300 MHz): δ 7.36–7.23 (m, 5H), 5.81 (m, 1H), 5.14–4.97 (m, 2H), 4.50 (s, 2H), 3.81–3.64 (m, 2H), 3.57–3.41 (m, 2H), 2.40 (m, 1H), 2.16 (m, 1H), 1.80–1.54 (m, 7H), 1.52–1.19 (m, 3H) ppm; ¹³C NMR (CDCl_3, 75 MHz): δ 138.6, 135.4, 128.3, 127.5, 127.4, 116.3, 72.7, 70.8, 70.5, 70.2, 38.0, 30.0, 29.7, 29.4, 26.0, 18.4 ppm; ESI-HRMS: m/z calcd for C₁₈H₂₆O₂Na [M + Na]⁺ 297.1825, found 297.1821, HPLC analysis (dr = 97 : 3).

(2R,6R)-2-Allyl-6-(2-(4-methoxybenzyloxy)ethyl)tetrahydro-2H-pyran (2e). Yield: 87%; [α]²⁷_D −23.1 (c 0.5, CHCl₃); IR (neat): ν_max 2928, 2854, 1641, 1612, 1512, 1246, 1092, 1037 cm⁻¹; ¹H NMR (CDCl₃, 300 MHz): δ 7.26 (d, J = 8.6 Hz, 2H), 6.87 (d, J = 8.6 Hz, 2H), 5.78 (m, 1H), 5.09–5.00 (m, 2H), 4.43 (AB_q, J = 15.7, 11.4 Hz, 2H), 3.90 (m, 1H), 3.80 (s, 3H), 3.74 (m, 1H), 3.54–3.50 (m, 2H), 2.40 (m, 1H), 2.16 (m, 1H), 1.95 (m, 1H), 1.71–1.59 (m, 5H), 1.39–1.31 (m, 2H) ppm; ¹³C NMR (CDCl_3, 75 MHz): δ 159.0, 135.4, 130.6, 129.3, 116.3, 113.7, 72.7, 70.6, 68.1, 66.9, 55.2, 37.0, 33.5, 30.2, 29.5, 29.4, 18.5 ppm; ESI-HRMS: m/z calcd for C₁₈H₂₆O₃Na [M + Na]⁺ 313.1910, found 313.1909. HPLC analysis (dr = 97 : 3).

(((2R,6R)-6-Allyltetrahydro-2H-pyran-2-yl)methoxy)(tert-butyl)dimethylsilane (2f). Yield: 85%; [α]²⁷_D +2.1 (c 0.4, CHCl₃); IR (neat): ν_max 2931, 2857, 1744, 1641, 1465, 1253, 1100, 1044 cm⁻¹; ¹H NMR (CDCl₃, 300 MHz): δ 5.81 (m, 1H), 5.12–5.00 (m, 2H), 3.85–3.64 (m, 3H), 3.59 (m, 1H), 2.45 (m, 1H), 2.19 (m, 1H), 1.73–1.62 (m, 4H), 1.47–1.31 (m, 2H), 0.90 (s, 9H), 0.06 (s, 6H) ppm; ¹³C NMR (CDCl_3, 75 MHz): δ 135.3, 116.4, 71.6, 71.4, 64.8, 37.5, 29.6, 29.0, 26.7, 25.8, 18.2, −5.3; ESI-HRMS: m/z calcd for C₁₅H₃₁O₂Si [M + H]⁺ 271.2087, found 271.2094.

(2S,3S,6R)-6-Allyl-2-(2-(4-methoxybenzyloxy)ethyl)-3-methyl tetrahydro-2H-pyran (2g). Yield: 91%; [α]²⁷_D −42.1 (c 0.5, CHCl₃); IR (neat): ν_max 2928, 2857, 1637, 1513, 1460, 1369, 1247, 1901 cm⁻¹; ¹H NMR (CDCl₃, 300 MHz): δ 7.27 (d, J = 8.7 Hz, 2H), 6.88 (d, J = 8.7 Hz, 2H), 5.77 (m, 1H), 5.12–4.95 (m, 2H), 4.45 (s, 2H), 3.90 (m, 1H), 3.80 (s, 3H), 3.59–3.44 (m, 3H), 2.35–1.81 (m, 3H), 1.72–1.50 (m, 3H), 1.43–1.27 (m, 3H), 0.81 (d, J = 7.0 Hz, 3H) ppm; ¹³C NMR (CDCl_3, 75 MHz): δ 159.0, 135.4, 130.6, 129.3, 116.3, 113.7, 73.7, 72.8, 68.6, 67.3, 55.2, 40.1, 33.0, 30.3, 26.7, 25.7, 16.7 ppm; ESI-HRMS: m/z calcd for C₁₉H₂₈O₃Na [M + Na]⁺ 327.1930, found 327.1936, HPLC analysis (dr = 98 : 2).

((2R,3R,4R,6R)-2-Allyl-6-(3-(benzyloxy)propyl)tetrahydro-2H-pyran-3,4-diyl)bis(oxy)-bis-(tert-butyldimethylsilane) (2h). Yield: 75%; [α]²⁷_D −23.6 (c 1.1, CHCl₃); IR (neat): ν_max 2953, 2928, 2856, 1744, 1662, 1466, 1386, 1361, 1254, 1093 cm⁻¹; ¹H NMR (CDCl₃, 300 MHz): δ 7.37–7.21 (m, 5H), 5.83 (m, 1H), 5.13–4.98 (m, 2H), 4.50 (s, 2H), 3.83–3.72 (m, 2H), 3.64 (t, J = 7.5 Hz, 1H), 3.50–3.38 (m, 2H), 3.34 (m, 1H), 2.68 (m, 1H), 2.47 (m, 1H), 1.93–1.38 (m, 6H), 0.90 (s, 9H), 0.89 (s, 9H), 0.07 (s, 3H), 0.06 (s, 3H), 0.05 (s, 6H) ppm; ¹³C NMR (CDCl₃, 75 MHz): δ 138.6, 136.2, 128.3, 127.6, 127.4, 116.3, 78.3, 72.9, 70.4, 70.3, 70.2, 64.2, 34.9, 34.7, 32.1, 31.9, 25.9, 25.8, 18.0, 17.9, −4.7, −4.9 ppm; ESI-HRMS: m/z calcd for C₃₀H₅₅O₄Si₂ [M + H]⁺ 535.3633, found 535.3635, HPLC analysis (dr = 93 : 7).

(2S,6R)-2-Allyl-6-pentadecyltetrahydro-2H-pyran (2i). Yield: 93%; [α]²⁷_D −8.5 (c 0.4, CHCl₃); IR (neat): ν_max 2925, 2885, 1734, 1657, 1457, 1272, 1037 cm⁻¹; ¹H NMR (CDCl₃, 500 MHz): δ 5.82 (m, 1H), 5.10–5.01 (m, 2H), 3.75 (m, 1H), 3.69 (m, 1H), 2.40 (m, 1H), 2.18 (m, 1H), 1.69–1.60 (m, 6H), 1.38–1.30 (m, 4H), 1.29–1.20 (m, 24H), 0.88 (t, J = 6.8 Hz, 3H) ppm; ¹³C NMR (CDCl_3, 125 MHz): δ 135.5, 116.3, 71.1, 70.5, 38.1, 33.3, 31.9, 29.9, 29.7, 29.6, 29.5, 29.3, 25.8, 22.7, 18.5, 14.1 ppm; ESI-HRMS: m/z calcd for C₂₃H₄₅O [M + H]⁺ 337.3464, found 337.3472.

(2S,6S)-2-Allyl-6-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)tetrahydro-2H-pyran (2j). Yield: 83%; [α]²⁷_D +26.4 (c 0.5, CHCl₃); IR (neat): ν_max 2929, 2885, 1743, 1639, 1443, 1275, 1101, 1042 cm⁻¹; ¹H NMR (CDCl₃, 500 MHz): δ 5.77 (m, 1H), 5.09–5.02 (m, 2H), 4.09–4.01 (m, 2H), 3.85 (m, 1H), 3.80 (m, 1H), 3.51 (m, 1H), 2.45 (m, 1H), 2.16 (m, 1H), 1.72–1.65 (m, 3H), 1.64–1.50 (m, 9H) ppm; ¹³C NMR (CDCl_3, 125 MHz): δ 135.2, 116.6, 109.7, 76.1, 72.2, 72.1, 67.2, 37.0, 28.8, 27.2, 24.0, 23.8, 18.0 ppm; ESI-HRMS: m/z calcd for C₁₃H₂₃O₃ [M + H]⁺ 227.1042, found 227.1041.

(2R,3S,4R,5R,6R)-2-Allyl-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran (2k). Yield: 72%; [α]_D²⁰ +28.8; (c 0.5, CHCl₃); IR (neat): ν_max 3030, 2919, 2863, 1453, 1361, 1209, 1090, 1027 cm⁻¹; ¹H NMR (CDCl₃, 400 MHz): δ 7.36–7.24 (m, 18H), 7.15–7.10 (m, 2H), 5.81 (m, 1H), 5.14–5.03 (m, 2H), 4.93 (d, J = 10.9 Hz, 1H), 4.83–4.78 (m, 2H), 4.71–4.58 (m, 3H), 4.50–4.44 (m, 2H), 4.13 (quint, J = 5.1 Hz, 1H), 3.81–3.57 (m, 6H), 2.54–2.44 (m, 2H) ppm; ¹³C NMR (CDCl_3, 100 MHz): δ 138.7, 138.1, 138.1, 138.0, 134.7, 128.3, 128.2, 128.9, 127.8, 127.8, 127.7, 127.6, 127.5, 127.5, 116.8, 82.3, 80.0, 78.0, 75.4, 75.0, 73.6, 73.4, 73.0, 71.0, 68.8, 29.7 ppm; ESI-HRMS: m/z calcd for C₃₇H₄₁O₅ [M + H]⁺ 565.2949, found 565.2959. HPLC analysis (dr = 92 : 8).

3-(4-Methoxybenzyloxy)propan-1-ol (9). To a stirred solution propane-1,3-diol (10.0 g, 131.4 mmol), p-anisyl alcohol (19.9 g, 114.56 mmol) and catalytic amount (10% w/w, 1 g) of Amberlyst-15 resin in dry CH₂Cl₂ (75 mL) was refluxed. After 6 h, the crude reaction mixture was filtered and the residue was washed with CH₂Cl₂ (2 × 50 mL), dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to give the crude product which on purification by flash column chromatography over silica gel (ethyl acetate/hexane = 3 : 7) furnished the desired alcohol 9 (23.7 g, 92%) as a colorless liquid. IR (neat): ν_max 3402, 2926, 2859, 1613, 1513, 1462, 1364, 1301, 1247, 1176, 1085, 1033 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 7.26 (d, J = 8.3 Hz, 2H), 6.88 (d, J = 8.3 Hz, 2H), 4.45 (s, 2H), 3.82–3.74 (m, 5H), 3.64 (t, J = 6.0 Hz, 2H), 1.85 (p, J = 11.3, 6.0 Hz, 2H) ppm; ¹³C NMR (75 MHz, CDCl₃): δ 159.1, 130.1, 129.2, 113.7, 72.8, 68.8, 61.6, 55.1, 32.0 ppm; ESI-HRMS: m/z calcd for C₁₁H₁₆O₃Na [M + Na]⁺ 219.0994, found 219.0988.

3-(4-Methoxybenzyloxy)propanal (10). To anhydrous dimethyl sulfoxide (50 mL), IBX (25.6 g, 91 mmol) was added and stirred for 40 min at room temperature. To this solution, alcohol 9 (11.9 g, 60.7 mmol) in dry THF (50 mL) was added at 0 °C and stirred for 2 h at room temperature. The reaction mixture was diluted with diethyl ether (100 mL) stirred for 20 min and filtered. The filtrate was washed water (100 mL), brine (100 mL), dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to afford aldehyde 10 (10.5 g, 89%), which was immediately used for the next step without further characterization.

(2R,3S)-1-((S)-4-Benzyl-2-thioxothiazolidin-3-yl)-3-hydroxy-5-(4-methoxybenzyloxy)-2-methyl pentan-1-one (12). To a stirred solution of N-acetylthiazolidinethione 11 (11.8 g, 56.7 mmol) in CH₂Cl₂ (80 mL), TiCl₄ (51.5 mL, 51.5 mmol, 1 M in CH₂Cl₂) was added drop-wise at −20 °C. After stirring for 15 min, triethylamine (7.2 mL, 51.5 mmol) was added to the dark red suspension and the mixture was allowed to stir for further 20 min at −20 °C. A solution of freshly prepared aldehyde 10 (10.0 g, 51.5 mmol) in CH₂Cl₂ (30 mL) was added to the reaction mixture and the resulting mixture was stirred for 1 h at −20 °C. The reaction was quenched with saturated NH₄Cl solution (75 mL) and layers were separated. The aqueous phase was extracted with CH₂Cl₂ (2 × 100 mL), and the combined organic extract was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to give the crude product which on purification by flash column chromatography over silica gel (ethyl acetate/hexane = 1 : 4) furnished the product 12 (19.4 g, 82%) as light yellow liquid. [α]²⁷_D +87.0 (c 3.24, CHCl₃); IR (neat): ν_max 3418, 2940, 2867, 1728, 1612, 1512, 1491, 1363, 1301, 1248, 1035 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 7.38–7.22 (m, 7H), 6.87 (d, J = 8.3 Hz, 2H), 5.38 (m, 1H), 4.72 (m, 1H), 4.45 (s, 2H), 4.26 (br s, 1H), 3.79 (s, 3H), 3.73–3.57 (m, 2H), 3.34 (dd, J = 11.3, 8.3 Hz, 1H), 3.27–3.18 (m, 2H), 3.02 (m, 1H), 2.87 (d, J = 12.0 Hz, 1H), 1.97–1.63 (m, 2H), 1.23 (d, J = 7.5 Hz, 3H) ppm; ¹³C NMR (75 MHz, CDCl₃): δ 201.3, 117.4, 159.1, 136.3, 130.1, 129.3, 129.2, 128.8, 127.1, 113.7, 72.8, 70.0, 68.8, 67.9, 55.2, 43.1, 36.9, 33.5, 31.6, 11.2 ppm; HRMS (ESI): calcd for C₂₄H₂₉NO₄S₂Na [M + Na]⁺ 482.1435; found 482.1419.

(2R,3S)-1-((S)-4-Benzyl-2-thioxothiazolidin-3-yl)-3-(tert-butyldime thylsilyloxy)-5-(4-methoxy benzyloxy)-2-methylpentan-1-one (13). To a stirred solution of 12 (15.0 g, 32.67 mmol) in dry CH₂Cl₂ (120 mL) was added 2,6-lutidine (11.3 mL, 98.03 mmol) and TBSOTf (11.2 mL, 49.0 mmol) sequentially at 0 °C under N₂ atmosphere. After 1 h of stirring at room temperature, the reaction was then quenched with saturated aqueous NaHCO₃ (50 mL). The layers were then separated and the aqueous layer further extracted with CH₂Cl₂ (2 × 100 mL). The crude product was purified by column chromatography over silica gel (ethyl acetate/hexane = 1 : 4) to provide the product 13 (17.7 g, 95%) as bright yellow oil. [α]²⁷_D +35.0 (c 0.4, CHCl₃); IR (neat): ν_max 3029, 2954, 2932, 2890, 2857, 1698, 1612, 1513, 1463, 1363, 1342, 1252 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.35–7.30 (m, 2H), 7.27–7.21 (m, 5H), 6.84 (d, J = 8.9, 2H), 5.30 (m, 1H), 4.75 (m, 1H), 4.39 (ABq, J = 10.8, 8.9 Hz, 2H), 4.23 (m, 1H), 3.79 (s, 3H), 3.60–3.46 (m, 2H), 3.27 (dd, J = 11.8, 7.9 Hz, 1H), 3.12 (dd, J = 13.8, 2.9 Hz, 1H), 2.83–2.73 (m, 2H), 1.95 (m, 1H), 1.88 (m, 1H), 1.22 (d, J = 6.9 Hz, 3H), 0.90 (s, 9H), 0.08 (s, 6H) ppm; ¹³C NMR (75 MHz, CDCl₃): δ 200.7, 176.4, 159.0, 136.7, 130.5, 129.4, 129.3, 128.8, 127.0, 113.6, 72.7, 70.9, 68.9, 66.0, 55.1, 43.8, 36.8, 35.2, 31.3, 25.9, 18.1, 14.6, −4.3, −4.4 ppm; HRMS (ESI): calcd for C₃₀H₄₃NO₄S₂SiNa [M + Na]⁺ 596.2295; found 596.2282.

(4S,5S,E)-Ethyl-5-(tert-butyldimethylsilyloxy)-7-(4-methoxybenzyloxy)-4-methylhept-2-enoate (14). To a stirred solution of 13 (14.6 g, 25.4 mmol) in dry CH₂Cl₂ (100 mL) at −78 °C, was added DIBAL-H (17.2 mL, 1.76 M in hexane, 30.4 mmol). The solution was stirred until the yellow colour faded and then quenched by addition of saturated sodium potassium tartrate solution (60 mL) at −78 °C. The solution was warmed to room temperature, diluted with CH₂Cl₂ (50 mL) and stirred until two clear layers were observed. The layers were separated and the aqueous layer extracted with CH₂Cl₂ (2 × 50 mL). The combined organic layer was dried over anhydrous Na₂SO₄ and solvent was evaporated. The crude oil was dissolved in toluene and was added stable two-carbon Wittig yield (Ph₃PCHCO₂Et) (9.8 g, 28.6 mmol). The reaction mixture was refluxed for 3 h and then allowed to cool to room temperature. The solvent was removed under reduced pressure and the compound was purified by column chromatography over silica gel (ethyl acetate/hexane = 1 : 4) to obtain 14 (7.8 g, 71%) as pale yellow liquid. [α]²⁷_D −34.7 (c 0.5, CHCl₃); IR (neat): ν_max 3430, 2955, 2932, 2857, 1719, 1651, 1613, 1513, 1465, 1366, 1251, 1179 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 7.25 (d, J = 8.3 Hz, 2H), 7.03 (dd, J = 15.8, 6.7 Hz, 1H), 6.88 (d, J = 8.3 Hz, 2H), 5.78 (d, J = 15.8 Hz, 1H), 4.40 (ABq, J = 18.8, 12.0 Hz, 2H), 4.19 (q, J = 6.8 Hz, 2H), 3.86–3.78 (m, 4H), 3.52–3.44 (m, 2H), 2.46 (m, 1H), 1.81–1.61 (m, 2H), 1.29 (t, J = 6.8, 3H), 1.01 (d, J = 6.8 Hz, 3H), 0.88 (s, 9H), 0.04 (s, 6H) ppm; ¹³C NMR (75 MHz, CDCl₃): δ 116.4, 159.0, 151.3, 130.3, 129.1, 120.9, 113.6, 72.5, 72.1, 66.3, 59.9, 55.0, 41.8, 33.7, 25.7, 17.9, 14.1, 13.8, −4.6, −4.7 ppm; HRMS (ESI): calcd for C₂₄H₄₀O₅SiNa [M + Na]⁺ 459.2537; found 459.2518.

(4S,5S,E)-5-(tert-Butyldimethylsilyloxy)-7-(4-methoxybenzyloxy)-4-methylhept-2-en-1-ol (15). To a solution of compound 14 (5.5 g, 12.6 mmol) in CH₂Cl₂ (40 mL) at 0 °C, was added DIBAL-H (22.2 mL, 1.76 M in hexane, 31.5 mmol). The solution was stirred for 30 min and quenched by addition of saturated sodium potassium tartrate solution (40 mL). The solution was brought to room temperature, diluted with CH₂Cl₂ (40 mL) and stirred for 4 h until two clear layers were observed. The layers were separated and the aqueous layer further extracted with CH₂Cl₂ (2 × 75 mL). The combined organic layer was dried with Na₂SO₄ and solvent was evaporated under reduced pressure. The residue was purified by column chromatography (10–15% EtOAc/hexane) to afford allylic alcohol 15 (4.47 g, 95%) as colorless oil. [α]²⁷_D −37.9 (c 1.4, CHCl₃); IR (neat): ν_max 3445, 2954, 2930, 2857, 1613, 1512, 1464, 1249 cm⁻¹; ¹H NMR (CDCl₃, 300 MHz): δ 7.19 (d, J = 8.0 Hz, 2H), 6.81 (d, J = 8.0 Hz, 2H), 5.68 (m, 1H), 5.57 (m, 1H), 4.36 (AB_q, J = 28.0, 11.0 Hz, 2H), 4.05 (d, J = 5.0 Hz, 2H), 3.78 (s, 3H), 3.70 (m, 1H), 3.43 (t, J = 7.0 Hz, 2H), 2.29 (m, 1H), 1.70 (m, 1H), 1.59 (m, 1H), 0.96 (d, J = 7.0 Hz, 3H), 0.88 (s, 9H), 0.03 (s, 3H), 0.02 (s, 3H), ppm; ¹³C NMR (75 MHz, CDCl₃): δ 158.9, 134.8, 130.4, 129.2, 128.8, 113.6, 72.9, 72.5, 66.7, 63.7, 55.1, 41.7, 33.3, 25.8, 18.0, 15.2, −4.4, −4.7 ppm; ESI-HRMS: m/z calcd for C₂₂H₃₈O₄SiNa [M + Na]⁺ 417.2431, found 417.2414.

(4S,5S,E)-7-(4-Methoxybenzyloxy)-4-methylhept-2-ene-1,5-diol (16). To a solution of compound 15 (2.63 g, 6.67 mmol) in MeOH (30 mL), was added camphor sulfonic acid (775 mg, 3.3 mmol) at 0 °C. The reaction was allowed to stir for 0.5 h at room temperature and quenched with Et₃N (1.2 mL, 8.5 mmol). The solvent was removed under reduced pressure and purified on silica gel column chromatography (ethyl acetate/hexane = 1 : 1) to afford the product 16 (1.5 g, 80%) as a colorless viscous liquid. [α]²⁷_D −10.6 (c 1.8, CHCl₃); IR (neat): ν_max 3425, 2929, 2862, 1614, 1513, 1247, 1085, 1034 cm⁻¹; ¹H NMR (CDCl₃, 300 MHz): δ 7.24 (d, J = 8.4 Hz, 2H), 6.87 (d, J = 8.4 Hz, 2H), 5.69–5.61 (m, 2H), 4.44 (s, 2H), 4.12–4.04 (m, 2H), 3.80 (s, 3H), 3.74–3.54 (m, 3H), 3.08 (br s, 1H), 2.27 (m, 1H), 1.79 (br s, 1H), 1.75–1.66 (m, 2H), 1.04 (d, J = 6.7 Hz, 3H) ppm; ¹³C NMR (75 MHz, CDCl₃): δ 159.1, 134.5, 129.9, 129.5, 129.2, 113.7, 74.1, 72.8, 68.7, 63.1, 55.1, 42.1, 33.2, 14.8 ppm; ESI-HRMS: m/z calcd for C₁₆H₂₄O₄Na [M + Na]⁺ 303.1566, found 303.1558.

(5S,6S)-6-(2-(4-Methoxybenzyloxy)ethyl)-5-methyltetrahydro-2H-pyran-2-ol (1g). A 50 mL two-neck round-bottomed flask was charged with of 10 wt% of Pd(OH)₂/C (46 mg) and toluene (10 mL) was added. H₂ gas was passed via a balloon for 30 min (for the activation of catalyst). The H₂ gas supply was stopped and stirring continued for 10 min after which a solution of allylic alcohol 16 (456 mg, 1.628 mmol) in toluene (5 mL) was added. The reaction mixture was stirred for another 30 min. After completion of the reaction (as indicated by TLC), the reaction mixture was filtered through a small Celite pad and washed with ethyl acetate (10 mL). The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane = 3 : 7) to obtain the desired lactol 1g (405 mg, 89%) as a colorless oil. [α]²⁷_D +53.2 (c 1.7, CHCl₃) IR (neat): ν_max 3448, 2928, 2854, 1641, 1612, 1512, 1246, 1092, 1037 cm⁻¹; ¹H NMR (CDCl₃, 300 MHz): δ 7.29–7.22 (m, 2H), 6.90–6.85 (m, 2H), 5.19 (m, 0.3H), 4.66 (m, 0.7H), 4.48–4.39 (m, 2H), 4.22 (m, 0.3H), 3.80 (s, 3H), 3.70 (m, 0.7H), 3.60–3.46 (m, 2H), 2.07 (m, 1H), 1.86–1.42 (m, 6H), 0.96–0.91 (m, 3H) ppm; ¹³C NMR (CDCl_3, 75 MHz): δ 159.0, 130.4, 129.2, 113.6, 96.8, 91.5, 74.9, 72.4, 72.3, 67.6, 66.5, 66.4, 55.2, 36.5, 34.4, 33.0, 32.5, 30.5, 30.1, 24.9, 24.8, 11.6, 11.3 ppm; ESI-HRMS: m/z calcd for C₁₆H₂₄O₄Na [M + Na]⁺ 303.1566, found 303.1560.

(2S,3S,6R)-6-Allyl-2-(2-(4-methoxybenzyloxy)ethyl)-3-methyltetra hydro-2H-pyran (2g). To a stirred solution of lactol 9a (300 mg, 1.071 mmol) and allyltrimethylsilane (0.18 mL, 1.607 mmol) in CH₂Cl₂ (15 mL), was added AuCl₃ (16 mg, 0.054 mmol) at room temperature and allowed to stir for 2.5 h. After completion of the reaction (monitored by TLC), it was quenched with H₂O (15 mL). The organic layer was separated the aqueous layer extracted with CH₂Cl₂ (2 × 20 mL). The combined organic layer was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to give a pale yellow oil which was purified by column chromatography (ethyl acetate/hexane = 1 : 9) to furnish the desired compound 2g (293 mg, 91%).

2-((2R,5S,6S)-6-(2-(4-Methoxybenzyloxy)ethyl)-5-methyltetra hydro-2H-pyran-2-yl)acetaldehyde (17). To a solution of 2g (175 mg, 0.576 mmol) in dioxane and water (3 : 1) (8 mL), 2,6-lutidine (0.26 mL, 2.30 mmol), OsO₄ (57.6 μL, 0.05 mmol, 1 M solution in toluene) followed by NaIO₄ (492 mg, 2.30 mmol) were sequentially added at room temperature and stirred for 2 h. After the completion of reaction (monitored by TLC), 1,4-dioxane was removed under reduced pressure and the residual aqueous layer was extracted with CH₂Cl₂ (3 × 10 mL). The CH₂Cl₂ layer was quickly washed with 1 N HCl (2 × 20 mL) to remove excess 2,6-lutidine followed by brine (2 × 20 mL), dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to get the crude aldehyde which on purification by short flash column chromatography over silica gel (ethyl acetate/hexane = 2 : 5) afforded aldehyde 17 (145 mg, 82%) as a colorless liquid which was immediately used for the next step without further characterization.

1-((2R,5S,6S)-6-(2-(4-Methoxybenzyloxy)ethyl)-5-methyltetra hydro-2H-pyran-2-yl)pent-4-en-2-ol (18). Allyl bromide (0.1 mL, 1.18 mmol) and zinc powder (8 mg, 1.18 mmol) were added to the aldehyde 17 (145 mg, 0.473 mmol) in THF/saturated NH₄Cl solution (2 : 1, 5 mL) at 0 °C. The reaction mixture was stirred for 1.5 h at room temperature. After complete consumption of the starting material (monitored by TLC), the reaction mixture was diluted with ethyl acetate (10 mL). The organic layer was separated and the aqueous layer extracted with ethyl acetate (3 × 10 mL). The combined organic layer was washed with brine (25 mL) and dried over Na₂SO₄. The organic layer was concentrated under reduced pressure to obtain the crude mass which on purification by silica gel column chromatography (ethyl acetate/hexane = 1 : 4) furnished the desired alcohol 18 (140 mg, 85%) as a colorless liquid. [α]²⁷_D −28.2 (c 3.0, CHCl₃); IR (neat): ν_max 3449, 2926, 2859, 1615, 1512, 1246, 1089, 1036 cm⁻¹; ¹H NMR (CDCl₃, 300 MHz): δ 7.33–7.22 (m, 2H), 6.88 (d, J = 9.0 Hz, 2H), 5.80 (m, 1H), 5.16–5.0 (m, 2H), 4.47 (d, J = 3.0 Hz, 2H), 4.08–3.72 (m, 6H), 3.70–3.46 (m, 2H), 3.21 (br s, 1H), 2.34–2.14 (m, 2H), 2.12–1.23 (m, 8H), 0.80 (d, J = 6.8, 3H) ppm; ¹³C NMR (CDCl_3, 75 MHz) δ 159.0, 134.8, 134.6, 130.3, 129.5, 128.8, 117.5, 117.3, 113.7, 75.2, 74.8, 72.8, 72.7, 71.9, 70.2, 67.8, 67.4, 67.1, 65.9, 55.2, 41.9, 41.7, 41.2, 33.2, 33.0, 32.0, 31.1, 29.6, 26.7, 26.3, 24.8, 24.6, 17.3, 17.2 ppm; ESI-HRMS: m/z calcd for C₂₁H₃₂O₄Na [M + Na]⁺ 371.2192, found 371.2185.

(E)-1-((2R,5S,6S)-6-(2-(4-Methoxybenzyloxy)ethyl)-5-methyltetra hydro-2H-pyran-2-yl)pent-3-en-2-one (19). Dry DMSO (63.7 μL, 0.897 mmol) was added to a solution of oxalyl chloride (46 μL, 0.538 mmol) in anhydrous CH₂Cl₂ (5 mL) cooled at −78 °C and the reaction mixture was stirred for 30 min. A solution of alcohol 18 (125 mg, 0.359 mmol) in anhydrous CH₂Cl₂ (4 mL) was added to the reaction mixture at −78 °C and stirred for a further 30 min at that temperature. A solution of freshly distilled Et₃N (2 mL, 14.37 mmol) in anhydrous CH₂Cl₂ (2 mL) was added dropwise to the reaction mixture, allowed to warm to room temperature and stirred for 24 h. The reaction mixture was diluted with CH₂Cl₂ (15 mL) and washed with saturated aqueous solutions of NaHCO₃ (15 mL), NH₄Cl (15 mL) and NaCl (15 mL). The aqueous layer was extracted with CH₂Cl₂ (2 × 15 mL). The combined organic layer was dried over NaSO₄ and concentrated under reduced pressure. The crude residue was purified by flash column chromatography on silica gel (ethyl acetate/hexane = 1 : 4) to yield compound 19 (96 mg, 77%) as a colorless oil. [α]²⁷_D −88.7 (c 1.5, CHCl₃); IR (neat): ν_max 3181, 2928, 2858, 1720, 1612, 1513, 1466, 1249, 1090 cm⁻¹; ¹H NMR (CDCl₃, 500 MHz): δ 7.26 (d, J = 7.9 Hz, 2H), 6.90–6.78 (m, 3H), 6.13 (d, J = 15.9 Hz, 1H), 4.42 (d, J = 4.99 Hz, 2H), 4.03 (m, 1H), 3.89 (m, 1H), 3.79 (s, 3H), 3.62–3.45 (m, 2H), 2.78 (m, 1H), 2.46 (m, 1H), 2.01 (m, 1H), 1.88 (d, J = 5.9 Hz, 3H), 1.74–1.49 (m, 4H), 1.48–1.23 (m, 2H), 0.81 (d, J = 6.9 Hz, 3H) ppm; ¹³C NMR (CDCl₃, 75 MHz) δ 198.5, 159.0, 143.0, 132.5, 130.8, 129.3, 113.6, 73.9, 72.8, 67.0, 65.7, 55.2, 45.8, 32.9, 30.9, 26.7, 25.5, 18.2, 16.8 ppm; ESI-HRMS: m/z calcd for C₂₁H₃₀O₄Na [M + Na]⁺ 369.2036, found 369.2040.

(E)-1-((2R,5S,6S)-6-(2-Hydroxyethyl)-5-methyltetrahydro-2H-pyran-2-yl)pent-3-en-2-one (20). To a stirred solution of compound 19 (59 mg, 0.169 mmol) in CH₂Cl₂ (5 mL) and water (0.5 mL) at 0 °C, was added DDQ (96 mg, 0.423 mmol) in one portion. The reaction mixture was stirred at 25 °C for 1 h, quenched with saturated aqueous NaHCO₃ (5 mL), diluted with water (5 mL) and CH₂Cl₂ (10 mL). The resulting mixture was stirred vigorously for 2 h. The layers were separated and the aqueous layer extracted with CH₂Cl₂ (2 × 15 mL). The combined organic layer was washed with brine (30 mL), dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane = 2 : 3) to afford alcohol 20 (35 mg, 92%) as a colorless oil. [α]²⁷_D −30.2 (c 0.8, CHCl₃); IR (neat): ν_max 3445, 2929, 1670, 1630, 1441, 1380, 1292, 1085, 1056 cm⁻¹; ¹H NMR (CDCl₃, 300 MHz): δ 6.89 (dq, J = 15.9, 6.8 Hz, 1H), 6.15 (dd, J = 15.9, 1.5 Hz, 1H), 4.18 (m, 1H), 3.93 (m, 1H), 3.75 (t, J = 6.0, 2H), 2.87 (dd, J = 15.9, 8.3 Hz, 1H), 2.53 (dd, J = 15.9, 3.8 Hz, 1H), 1.91 (dd, J = 6.8, 2.3 Hz, 3H), 1.79–1.60 (m, 3H), 1.52–1.29 (m, 4H), 0.84 (d, J = 6.8 Hz, 3H) ppm; ¹³C NMR (CDCl_3, 75 MHz) δ 198.7, 143.6, 132.0, 75.3, 65.9, 60.4, 45.4, 32.9, 30.1, 28.4, 26.4, 18.2, 16.4 ppm; ESI-HRMS: m/z calcd for C₁₃H₂₃O₃ [M + H]⁺ 227.1641, found 227.1641.

2-((2S,3S,6R)-3-Methyl-6-((E)-2-oxopent-3-enyl)tetrahydro-2H-pyran-2-yl)acetic acid (21). To a stirred solution of alcohol 20 (21 mg, 0.092 mmol) and iodosobenzene diacetate (59 mg, 0.184 mmol) in CH₂Cl₂ (2 mL) and H₂O (2 mL), TEMPO (2.8 mg, 0.018 mmol) was added at room temperature. After complete consumption of the starting material (monitored by TLC), the reaction mixture was diluted with CH₂Cl₂ (10 mL) and water (5 mL). The organic layer was separated and the aqueous layer extracted with CH₂Cl₂ (2 × 10 mL). The combined organic layers were washed with aqueous 1 N HCl (15 mL). The aqueous layer was extracted with CH₂Cl₂ (15 mL). The combined layer was dried over Na₂SO₄ and the solvent was evaporated under reduced pressure. The crude material was purified by silica gel column chromatography (ethyl acetate/hexane = 1 : 1) to furnish the desired acid 21 (20 mg, 90%) as a colorless liquid. [α]²⁷_D −54.1 (c 0.5, CHCl₃); IR (neat): ν_max 3447, 2927, 1716, 1670, 1630, 1439, 1381, 1292, 1191, 1072 cm⁻¹; ¹H NMR (CDCl_3, 300 MHz): δ 6.87 (dq, J = 15.9, 6.8 Hz, 1H), 6.12 (dd, J = 15.9, 1.5 Hz, 1H), 4.26 (m, 1H), 4.14 (m, 1H), 2.90–2.73 (m, 2H), 2.57 (dd, J = 15.9, 5.2 Hz, 1H), 2.39 (dd, J = 15.1, 3.8 Hz, 1H), 1.97 (m, 1H), 1.90 (dd, J = 6.7, 1.5 Hz, 3H), 1.81–1.59 (m, 2H), 1.48–1.23 (m, 2H), 0.85 (d, J = 6.7 Hz, 3H) ppm; ¹³C NMR (CDCl₃, 75 MHz): δ 198.4, 176.6, 143.8, 132.1, 73.9, 66.4, 45.4, 32.6, 32.2, 30.3, 26.3, 18.3, 16.6 ppm; ESI-HRMS calcd for C₁₃H₂₁O₄ [M + H]⁺ 241.1432, found 241.1434.

2-((2S,3S,6R)-3-Methyl-6-(2-oxopentyl)tetrahydro-2H-pyran-2-yl)acetic acid (22). To a stirred solution of the compound 21 (15 mg, 0.06 mmol) in ethyl acetate (2 mL), Pd/C (10%) (2.0 mg) was added. The mixture was stirred for 2 h at room temperature under hydrogen atmosphere. After complete consumption of the starting material (monitored by TLC), the black reaction mass was filtered through a small pad of Celite and then thoroughly washed with ethyl acetate (3 × 5 mL). The filtrate was concentrated under reduced pressure and purification of the crude product by silica gel column chromatography (ethyl acetate/hexane = 1 : 1) furnished the desired acid 22 (14 mg, 95%) as a colorless liquid. [α]²⁷_D −84.8 (c 0.4, CHCl₃); IR (neat): ν_max 3423, 2960, 2930, 2877, 1711, 1459, 1379, 1289, 1192, 1075 cm⁻¹; ¹H NMR (CDCl_3, 500 MHz): δ 4.26 (m, 1H), 4.10 (m, 1H), 2.78 (dd, J = 10.5, 15.1 Hz, 1H), 2.68 (dd, J = 7.6, 16.0 Hz, 1H), 2.47–2.36 (m, 4H), 1.95 (m, 1H), 1.76–1.62 (m, 2H), 1.62–1.53 (m, 2H), 1.42–1.23 (m, 2H), 0.90 (t, J = 7.4 Hz, 3H), 0.85 (d, J = 7.0 Hz, 3H) ppm; ¹³C NMR (CDCl₃, 75 MHz): δ 209.6, 176.2, 73.8, 66.3, 48.2, 45.5, 32.5, 32.3, 30.2, 26.3, 16.9, 16.6, 13.6 ppm; ESI-HRMS calcd for C₁₃H₂₂O₄Na [M + Na]⁺ 265.1410, found 265.1409.

Acknowledgements

The authors thank Council of Scientific and Industrial Research (CSIR), New Delhi for financial support as part of XII Five Year plan programme under title ORIGIN (CSC-0108). B. P. and D. S. R. thank CSIR and University Grants Commission (UGC), New Delhi, India, for financial assistance in the form of fellowships.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Scanned copy of ¹H and ¹³C NMR, NOESY spectrum of compound 4 and 5. See DOI: 10.1039/c5ra17646h

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