First total synthesis of cryptopyranmoscatone A2 from D-ribose

Abstract

The first total synthesis of a naturally occurring styryl lactone, cryptopyranmoscatone A2 has been achieved from inexpensive and highly abundant D-ribose. The key features of the synthetic strategy are the utilization of oxa-Michael addition, asymmetric allylation and metathesis reactions.

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Naturally occurring styryl lactones are reported to possess significant cytotoxicity toward human tumor cell lines.¹ They have been traditionally used for the treatment of edema and rheumatism.² Other applications include their use as painkillers³ and mosquito repellants.⁴ Cryptopyranmoscatones A1, A2, A3, B1, B2 and B4 (Fig. 1, 1–6),⁵ a series of styryl lactones along with other Cryptocarya pyrones were isolated from the branch and stem bark of Cryptocarya moschata, Lauraceae, a tree growing up to 30–40 m high, found in the Atlantic Forest, mainly in the Southeastern region of Brazil. The structures of these compounds were established by spectroscopic studies. Some of these Cryptocarya pyrones possessed biological activities. For example, cryptomoscatone D2 has been identified as a highly efficacious inhibitor of the G2 check point,⁶ which can enhance killing of cancer cells by ionizing radiation and DNA-damaging chemotherapeutic agents, particularly in cells lacking p53 function. This styryl lactone also displayed high dose- and time dependent antiproliferative activity against HeLa, SiHa, C33A and MRC-5 cell lines.⁷ Cryptofolione^5,8 displayed activity towards Trypanosoma cruzi, trypomastigotes, reducing their number by 77% at 250 μg mL⁻¹. Cryptocarya species showed outstanding equipotent activity towards COX-1 and COX-2.⁹ C. moschata is recognized as an important alimentary food source for primates such as Brachyteles arachnoides. The striking structural motif of cryptopyranmoscatones, coupled with their scarcity, prompted us to pursue their syntheses, and rendering them readily available for biological investigations. Karlotoxin-2,¹⁰ a marine cytotoxic polyketide also possess a similar tetrahydropyran core.

Fig. 1 Structures of natural cryptopyranmoscatones 1–6.

As part of our program on the synthesis of biologically active natural lactones,¹¹ our group reported the first total syntheses of cryptopyranmoscatone B1 (ref. 12) and A1 (ref. 13) in 2010 and 2011 respectively. Now, we herein disclose our first stereoselective total synthesis of cryptopyranmoscatone A2 from readily available D-ribose using oxa-Michael, ring-closing metathesis (RCM) and cross-metathesis (CM) reactions as key steps.

Results and discussion

Our retrosynthetic strategy for cryptopyranmoscatone A2 is depicted in Scheme 1. We envisaged that cryptopyranmoscatone A2 could be obtained from an intermediate 7 through oxa-Michael addition reaction (Scheme 1). Cryptopyranmoscatone A2 (2) could be prepared by first elaborating the right side and then to the left side of the oxa-Michael product, 2,6-trans-tetrahydropyran 9, performing RCM and cross-metathesis reactions as the key steps. In turn, the intermediate 7 could be accessible from D-ribose via lactone 10 (Scheme 1).

Scheme 1 A retrosynthetic approach for cryptopyranmoscatone A2 (2).

The synthesis of 2,6-trans-tetrahydropyran core of 2 is illustrated in Scheme 2. It was initiated from compound 11, which was synthesized in two steps from commercially available D-ribose following a known protocol.¹⁴ The primary alcohol 11 was protected with TBSCl/imidazole to give silyl ether 12 in 95% yield. Hydroboration¹⁵ of 12 with BH₃·Me₂S followed by oxidative workup afforded 1,5-diol 13 in 80% yield. Oxidative cyclization of diol 13 with 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) and [bis(acetoxy)iodo]benzene [(PhI(OAc)₂) (BAIB)]¹⁶ produced the desired δ-lactone 10 in 86% yield. The intermediate 7 could be made from 10 by lactone opening. Thus, lactone 10 was reduced to lactol using DIBAL-H and subjected to Wittig olefination using stabilized ylide to furnish α,β-unsaturated ester 7 in 85% overall yield (Scheme 2).

Scheme 2 Synthesis of trans-tetrahydropyran core (9).

Cis- or trans-2,6-tetrahydropyran core can be synthesized from an intermediate 7 based on different reaction conditions. Since, we need a trans-tetrahydropyran unit, the hydroxy ester 7 was subjected to intramolecular oxa-conjugate cyclization (oxa-Michael reaction)¹⁷ by exposure to KO^t-Bu in THF at −78 °C for 30 min, which gave rise to 2,6-trans-tetrahydropyran (trans-9) in 95% yield with high diastereoselectivity (dr = 20 : 1) (Scheme 2).

This trans-stereochemistry of the newly generated ring-junction of tetrahydropyran 9 was assigned based on ¹H NMR (600 MHz, CDCl₃) data and assignments were made with the aid of TOCSY and NOESY experiments (Fig. 2). The medium NOE between C₂H/C₆H suggested that both the protons are anti to each other (trans related). This was further supported by NOE correlation between C₂H/Me-a, C₄H/C₆H, C₂H/C₅H and C₃H/C₄H, confirming the structure. The energy minimized structure is also shown in Fig. 3.

Fig. 2 NOESY spectrum showing the characteristic NOE correlations of compound 9.

Fig. 3 Chemical and energy-minimized structure of 9.

Completion of the total synthesis of cryptopyranmoscatone A2 (2) is illustrated in Scheme 3. Diisobutylaluminium hydride (DIBAL-H) reduction of ester in trans-9 furnished an aldehyde, which was subjected to Brown asymmetric allylation¹⁸ with (+)-Ipc₂B-allyl at −100 °C to give homoallyl alcohol 14 in 80% yield. Stereochemical assignment at the newly created hydroxy bearing center was confirmed at the later stage after converting into ester. Acylation of 14 with cinnamic acid under DCC–DMAP conditions provided compound 8 in 83% yield with dr 99 : 1 (by HPLC).¹⁹ Treatment of 8 with second-generation Grubbs' catalyst²⁰ (10 mol%) in CH₂Cl₂ at reflux temperatures afforded lactone 15 in 90% yield. Removal of the TBS group with TBAF in THF gave primary alcohol 16. Alcohol 16 was oxidized under Swern conditions to give an aldehyde, which was subjected to Wittig olefination to give an olefinic lactone 17 in 60% yield over two steps. The cross-metathesis reaction of olefin 17 with styrene 18 using Grubbs' second generation carbene catalyst²⁰ in CH₂Cl₂ under reflux conditions for 4 h afforded 19 in 90% yield. Finally deprotection of the acetonide group in compound 19 using conc TiCl₄ (ref. 21) completed the first total synthesis of cryptomoscatone A2 (2) in 80% yield. Spectral and analytical data of our synthetic compound were all in good agreement with those of the natural cryptomoscatone A2 (2).⁵

Scheme 3 Total synthesis of cryptopyranmoscatone A2 (2).

Conclusions

In conclusion, we have achieved the first total synthesis of cryptopyranmoscatone A2. D-Ribose has been used as the starting material. The key steps in the synthesis involved are oxa-Michael, asymmetric allylation and metathesis reactions.

Experimental section

General

All reactions were performed under inert atmosphere. All glassware apparatus used for reactions are perfectly oven/flame dried. Anhydrous solvents were distilled prior to use: THF from Na and benzophenone; CH₂Cl₂, DMSO from CaH₂; MeOH from Mg cake. Commercial reagents were used without purification. Column chromatography was carried out by using silica gel (60–120 mesh) unless otherwise mentioned. Analytical thin layer chromatography (TLC) was run on silica gel 60 F254 pre-coated plates (250 μm thickness). Optical rotations [α]_D were measured on a polarimeter and given in 10⁻¹ deg cm² g⁻¹. Infrared spectra were recorded in CHCl₃/KBr (as mentioned) and reported in wave number (cm⁻¹). Mass spectral data were obtained using MS (EI) ESI, HRMS mass spectrometers. High resolution mass spectra (HRMS) [ESI+] were obtained using either a TOF or a double focusing spectrometer. ¹H NMR spectra were recorded at 300, 400, 500 and ¹³C NMR spectra 75 MHz in CDCl₃ solution unless otherwise mentioned, chemical shifts are 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.

(R)-2-((tert-Butyldimethylsilyl)oxy)-1-((4R,5S)-2,2-dimethyl-5-vinyl-1,3-dioxolan-4-yl)ethanol (12)

To a stirred solution of diol 11 (5.0 g, 16.50 mmol) and imidazole (3.6 g, 52.87 mmol) in dry CH₂Cl₂ (30 mL) was added TBDMS-Cl (3.6 g, 24.0 mmol) portion wise at 0 °C. The reaction mixture was stirred at the same temperature for 2 h. The reaction mixture was quenched with a saturated aqueous solution of NH₄Cl and extracted with CH₂Cl₂. The extract was washed with water and brine, dried over anhydrous Na₂SO₄, the solvent was removed in vacuo and the residue was purified by silica gel column chromatography (hexane/EtOAc, 9 : 1) to furnish pure compound 12 (7.6 g, 95% yield) as a colorless liquid. [α]²⁵_D: −12.6 (c = 0.08, CHCl₃); ¹H NMR (CDCl₃, 500 MHz): δ 6.09–5.96 (m, 1H), 5.41 (dt, J = 16.9, 1.5 Hz, 1H), 5.28 (dt, J = 10.3, 1.3 Hz, 1H), 4.68 (tt, J = 1.3, 7.7 Hz, 1H), 4.05 (dd, J = 6.4, 8.8 Hz, 1H), 3.80 (dd, J = 3.0, 9.8 Hz, 2H), 3.71–3.59 (m, 2H), 2.53 (d, J = 5.2 Hz, 1H), 1.46 (s, 3H), 1.35 (s, 3H), 0.91 (s, 9H), 0.08 (s, 6H); ¹³C NMR (CDCl₃, 75 MHz): δ 134.0, 117.4, 108.6, 78.6, 77.3, 69.4, 64.3, 27.7, 25.8, 25.3, 18.2, −5.4, −5.5; IR (neat): 3480, 2954, 2930, 1463, 1381, 1255, 1059, 837, 779 cm⁻¹; HRMS (ESI) for C₁₅H₃₀O₄SiNa [M + Na]⁺ found 325.1811 calcd 325.1806.

(R)-2-((tert-Butyldimethylsilyl)oxy)-1-((4R,5S)-5-(2-hydroxyethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)ethanol (13)

To compound 12 (7.5 g, 23.40 mmol) in dry THF (50 mL) was added BH₃·Me₂S (12.4 mL, 2 M solution in THF) for over a period of 10 min maintaining the temperature at 0 °C. The reaction mixture was brought to rt and stirred for a period of 8 h. This was then treated with a very slow addition of 3 N NaOH until the reaction mixture was basic at 0 °C. To this was added H₂O₂ (30% solution in H₂O, 50 mL) and the reaction mixture was stirred for over a period of 3 h and then extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na₂SO₄, concentrated and purified by column chromatography (hexane/EtOAc, 8 : 2) to furnish the diol 13 (6.3 g, 80% yield) as colorless liquid. [α]²⁵_D: −1.58 (c = 0.12, CHCl₃); ¹H NMR (CDCl₃, 500 MHz): δ 4.41–4.35 (m, 1H), 3.98 (dd, J = 5.6, 9.0 Hz, 1H), 3.90–3.75 (m, 3H), 3.71–3.63 (m, 2H), 2.79 (br.s, 1H), 2.10–2.04 (m, 1H), 1.93–1.85 (m, 1H), 1.42 (s, 3H), 1.32 (s, 3H), 0.91 (s, 9H), 0.09 (s, 6H); ¹³C NMR (CDCl₃, 75 MHz): δ 108.1, 77.7, 77.1, 68.9, 64.3, 61.4, 31.5, 28.1, 25.8, 25.6, −5.4, −5.5; IR (neat): 3486, 2988, 2927, 1372, 1230, 1086, 835, 768 cm⁻¹; HRMS (ESI) for C₁₅H₃₂O₅SiNa [M + Na]⁺ found 343.1916 calcd 343.1904.

(3aS,4R,7aS)-4-(((tert-Butyldimethylsilyl)oxy)methyl)-2,2-dimethyldihydro-3aH-[1,3]dioxolo[4,5-c]pyran-6(4H)-one (10)

BAIB (6.6 g, 20.4 mmol) was added to a solution of diol 13 (6.0 g, 18.9 mmol) and TEMPO (0.29 g, 1.85 mmol) in 20 mL of CH₂Cl₂. The reaction mixture was stirred until the alcohol was no longer detectable (TLC), and then it was diluted with CH₂Cl₂ (20 mL). The mixture was washed with a saturated aqueous solution of Na₂S₂O₃ (20 mL) and extracted with CH₂Cl₂ (4 × 20 mL). The combined organic extracts were washed with aqueous NaHCO₃ (30 mL) and brine (30 mL), dried (Na₂SO₄), and concentrated under reduced pressure and purified by silica gel column chromatography (hexane/EtOAc = 7 : 3) to afford 10 as a light yellow coloured liquid (5.0 g, 86%) [α]²⁵_D: +33.9 (c = 0.2, CHCl₃); ¹H NMR (CDCl₃, 500 MHz): δ 4.64–4.55 (m, 1H), 4.39–4.33 (m, 1H), 4.31–4.25 (m, 1H), 3.99 (dd, J = 2.6, 11.3 Hz, 1H), 3.87 (dd, J = 3.7, 11.3 Hz, 1H), 3.06 (dd, J = 6.0, 15.8 Hz, 1H), 2.67 (dd, J = 5.2, 15.8 Hz, 1H), 1.48 (s, 3H), 1.37 (s, 3H), 0.90 (s, 9H), 0.10 (s, 6H); ¹³C NMR (CDCl₃, 75 MHz): δ 169.5, 110.2, 80.2, 71.2, 70.7, 63.0, 34.9, 26.8, 25.8, 24.5, 18.3, −5.5, −5.6; IR (neat): 3488, 2932, 2858, 1756, 1256, 1067, 838, 779 cm⁻¹; HRMS (ESI) for C₁₅H₂₈O₅SiNa [M + Na]⁺ found 339.1604 calcd 339.1615.

(E)-Ethyl 4-((4S,5R)-5-((R)-2-((tert-butyldimethylsilyl)oxy)-1-hydroxyethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)but-2-enoate (7)

A stirred solution of lactone 10 (4.8 g, 12.3 mmol) in CH₂Cl₂ (30 mL) was cooled to −78 °C, then DIBAL-H (23.4 mL, 1.6 M solution in toluene) was added slowly. After 1 h, the reaction was quenched with methanol (10 mL) and potassium sodium tartrate (15 mL), and stirred at room temperature for 0.5 h. The layers were separated and the aqueous layer was extracted with CH₂Cl₂ (3 × 50 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo to afford the crude lactol. This was used for the next step without further purification. To a solution of the above lactol in C₆H₆ (30 mL) was added Ph₃P=CHCOOEt (7.9 g, 22.7 mmol) and the reaction mixture was stirred for 4 h at reflux condition. After completion of the reaction, monitored by TLC, C₆H₆ was removed under reduced pressure, residue was dissolved in ether, and petroleum ether was added to it. The triphenylphosphineoxide crystallized out was filtered off and the filtrate was concentrated to dryness. The crude product was purified by column chromatography (hexane/EtOAc, 7 : 3) to afford the pure α,β-unsaturated ester 7 (4.9 g, 85%) as a colorless oil. [α]²⁵_D: −38.9 (c = 0.2, CHCl₃); ¹H NMR (CDCl₃, 500 MHz): δ 7.05 (dt, J = 7.1, 15.7 Hz, 1H), 5.93 (dt, J = 1.3, 15.7 Hz, 1H), 4.32–4.27 (m, 1H), 4.19 (q, J = 7.0, 14.2 Hz, 2H), 3.99 (dd, J = 5.7, 9.1 Hz, 1H), 3.86–3.81 (m, 1H), 3.70–3.64 (m, 2H), 2.74–2.68 (m, 1H), 2.62 (br.s, 1H), 2.51–2.43 (m, 1H), 1.42 (s, 3H), 1.32 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H), 0.92 (s, 9H), 0.10 (s, 6H); ¹³C NMR (CDCl₃, 75 MHz): δ 169.5, 110.2, 80.2, 71.2, 70.7, 63.0, 34.8, 26.8, 25.7, 24.5, 18.2, −5.5, −5.6; IR (neat): 3490, 2927, 2882, 1698, 1383, 1256, 1218, 1046, 759 cm⁻¹; HRMS (ESI) for C₁₉H₃₆O₆SiNa [M + Na]⁺ found 411.2175 calcd 411.2168.

Ethyl 2-((3aS,4R,6S,7aS)-4-(((tert-butyldimethylsilyl)oxy)methyl)-2,2-dimethyltetrahydro-3aH-[1,3]dioxolo[4,5-c]pyran-6-yl)acetate (9)

To a solution of alcohol 7 (4.6 g, 11.8 mmol) in THF (20 mL) at −78 °C was added t-BuOK (1.46 g, 13.02 mmol). After 0.5 h stirring at −78 °C, a saturated solution of NH₄Cl (10 mL) was added and the mixture warmed up to rt. Extraction was carried out with Et₂O (3 × 20 mL). The organic phase was dried over MgSO₄, filtered and concentrated in vacuo. The purification of the residue by flash column chromatography (hexane/EtOAc, 8 : 2) furnished cyclic compound 9 (4.3 g, 95%) as a colorless oil. [α]²⁵_D: +39.5 (c = 0.23, CHCl₃); ¹H NMR (CDCl₃, 500 MHz): δ 4.39–4.32 (m, 1H), 4.13 (q, J = 6.8 Hz, 2H), 4.09–4.0 (m, 1H), 3.84 (dd, J = 4.5, 9.0 Hz, 1H), 3.80 (dd, J = 1.5, 11.3 Hz, 1H), 3.63 (dd, J = 5.3, 11.3 Hz, 1H), 3.38–3.31 (m, 1H), 2.53 (dd, J = 7.5, 15.1 Hz, 1H), 2.37 (dd, J = 5.3, 15.1 Hz, 1H), 2.13 (dt, J = 2.2, 15.1 Hz, 1H), 1.77–1.65 (m, 1H), 1.48 (s, 3H), 1.35 (s, 3H), 1.25 (t, J = 7.5 Hz, 3H), 0.87 (s, 9H), 0.03 (s, 6H); ¹³C NMR (CDCl₃, 75 MHz): δ 170.7, 108.7, 78.8, 71.8, 70.3, 68.9, 63.4, 60.3, 40.7, 325, 28.2, 26.1, 25.8, 18.3, 14.0, −5.3; IR (neat): 3445, 2933, 1731, 1382, 1254, 1098, 837, 759 cm⁻¹; HRMS (ESI) for C₁₉H₃₆O₆SiNa [M + Na]⁺ found 411.2211 calcd 406.2195.

(R)-1-((3aS,4R,6R,7aS)-4-(((tert-Butyldimethylsilyl)oxy)methyl)-2,2-dimethyltetrahydro-3aH-[1,3]dioxolo[4,5-c]pyran-6-yl)pent-4-en-2-ol (14)

To a stirred solution of acetonide protected ester trans-9 (4.0 g, 10.3 mmol) in dry CH₂Cl₂ (20 mL) was added DIBAL-H (7.7 mL, 1.6 M solution in toluene) dropwise over a period of 10 min under nitrogen atmosphere at −78 °C. After stirring for 2 h at the same temperature, dry methanol (10 mL) was added and the reaction mixture was allowed to warm to room temperature. Saturated aqueous solution of sodium potassium tartarate (10 mL) was added and the resulting mixture was stirred vigorously until the two layers were separated. The organic layer was separated and the aqueous layer was extracted with additional CH₂Cl₂ (2 × 40 mL). The combined organic filtrates were washed with H₂O (2 × 10 mL) and brine (2 × 10 mL), dried (Na₂SO₄), and concentrated in vacuo to afford the crude aldehyde. This was used for the next step without further purification.

To a solution of (+)-IPC₂B(allyl) (1.0 M in pentane, 12.4 mL) in diethyl ether (10 mL) was cooled to −100 °C and a solution of above crude aldehyde in 10 mL of diethyl ether was added slowly. The mixture was stirred at −100 °C for 2 h and then warmed to 0 °C. The reaction was quenched by the dropwise addition of 3 mL of 30% H₂O₂ (aq.) and 3 mL of 1 N NaOH. The mixture was diluted with 20 mL of ethyl acetate and the layers were separated. The aqueous layer was extracted with (3 × 10 mL) ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude reaction mixture was further purified by silica gel column chromatography (hexane/EtOAc, 7 : 3) to give homoallyl alcohol 14 (3.1 g, 80%) as a clear liquid. [α]²⁵_D: +24.0 (c = 0.15, CHCl₃); ¹H NMR (CDCl₃, 500 MHz): δ 5.92–5.75 (m, 1H), 5.15–5.04 (m, 2H), 4.41–4.34 (m, 1H), 3.97–3.86 (m, 2H), 3.82 (dd, J = 1.8, 11.1 Hz, 1H), 3.77 (dd, J = 4.9, 9.2 Hz, 1H), 3.59 (dd, J = 6.6, 11.1 Hz, 1H), 3.36 (dd, J = 2.0, 9.0 Hz, 1H), 2.78 (br.s, 1H), 2.32–2.22 (m, 1H), 2.08–1.99 (m, 1H), 1.84–1.60 (m, 4H), 1.51 (s, 3H), 1.36 (s, 3H), 0.89 (s, 9H), 0.06 (s, 6H); ¹³C NMR (CDCl₃, 75 MHz): δ 135.1, 117.3, 108.9, 79.0, 72.0, 70.9, 69.9, 68.3, 63.7, 41.7, 40.8, 33.2, 28.3, 26.3, 25.9, 18.3; IR (neat): 3453, 2929, 1640, 1381, 1251, 1086, 835, 778 cm⁻¹; HRMS (ESI) for C₂₀H₃₈O₅SiNa [M + Na]⁺ found 409.2378 calcd 409.2382.

(R)-1-((3aS,4R,6R,7aS)-4-(((tert-Butyldimethylsilyl)oxy)methyl)-2,2-dimethyltetrahydro-3aH-[1,3]dioxolo[4,5-c]pyran-6-yl)pent-4-en-2-yl cinnamate (8)

Cinnamic acid (1.72 mL, 8.7 mmol) was added dropwise under N₂ to a solution of 14 (3.0 g, 5.8 mmol), DCC (3.20 g, 11.6 mmol) in CH₂Cl₂ (15 mL), and catalytic amount of DMAP was added to it. The mixture was stirred at 0 °C for 0.5 h. After completion, the mixture was poured into brine (5 mL), and extracted with CH₂Cl₂ (2 × 10 mL). The organic phase was washed with 1 M aq. HCl, dried (Na₂SO₄), and concentrated. The crude product purified by column chromatography (hexane/EtOAc, 8 : 2) to afford the corresponding acrylic ester 8 (3.3 g, 83%) as a colorless oil. [α]²⁵_D: −32.7 (c = 0.11, CHCl₃); ¹H NMR (CDCl₃, 500 MHz): δ 7.66 (d, J = 16.0 Hz, 1H), 7.56–7.49 (m, 2H), 7.42–7.36 (m, 3H), 6.42 (d, J = 15.8 Hz, 1H), 5.87–5.72 (m, 1H), 5.33–5.23 (m, 1H), 5.14–5.03 (m, 2H), 4.40–4.34 (m, 1H), 3.91 (dd, J = 5.1, 9.4 Hz, 1H), 3.83 (dd, J = 2.0, 11.5 Hz, 1H), 3.66 (dd, J = 5.1, 11.5 Hz, 2H), 3.29–3.21 (m, 1H), 2.4–2.38 (m, 2H), 2.05 (dt, J = 2.4, 14.9 Hz, 1H), 1.77–1.63 (m, 3H), 1.45 (s, 3H), 1.34 (s, 3H), 0.90 (s, 9H), 0.07 (s, 6H); ¹³C NMR (CDCl₃, 75 MHz): δ 166.3, 144.5, 134.4, 133.5, 130.1, 128.8, 128.0, 118.4, 117.8, 108.7, 78.6, 72.2, 70.7, 70.5, 69.0, 63.4, 39.7, 39.1, 33.5, 28.3, 26.3, 25.94, 18.5, −5.2; IR (neat): 3443, 2928, 1714, 1638, 1252, 1170, 835, 768 cm⁻¹; HRMS (ESI) for C₂₉H₄₄O₆SiNa [M + Na]⁺ found 539.2812 calcd 539.2799.

(R)-6-(((3aS,4R,6R,7aS)-4-(((tert-Butyldimethylsilyl)oxy)methyl)-2,2-dimethyltetrahydro-3aH-[1,3]dioxolo[4,5-c]pyran-6-yl)methyl)-5,6-dihydro-2H-pyran-2-one (15)

A solution of Grubbs' second-generation catalyst G-II (0.033 g, 0.0419 mmol, 10 mol%) in CH₂Cl₂ (10 mL) was added dropwise to a solution of acrylic ester 8 (0.250 g, 0.419 mmol) in CH₂Cl₂ (60 mL) at rt, and stirring was continued for 5 h at reflux condition. The solvent was evaporated and the crude product purified by column chromatography (hexane/EtOAc, 75 : 25) to give lactone 15 (0.219 g, 92% yield) as a pale yellow oil. [α]²⁵_D: +70.6 (c = 0.15, CHCl₃); ¹H NMR (CDCl₃, 500 MHz): δ 6.86 (qd, J = 2.4, 9.6 Hz, 1H), 6.01 (dd, J = 2.4, 9.6 Hz, 1H), 4.76–4.65 (m, 1H), 4.39–4.33 (m, 1H), 3.97–3.86 (m, 1H), 3.82 (dd, J = 2.1, 11.7 Hz, 1H), 3.74 (dd, J = 5.1, 9.6 Hz, 1H), 3.58 (dd, J = 6.8, 11.5 Hz, 1H), 3.36 (dd, J = 2.0, 9.0 Hz, 1H), 2.50–2.39 (m, 1H), 2.38–2.29 (m, 1H), 2.08 (dt, J = 1.9, 14.5 Hz, 1H), 1.95–1.86 (m, 1H), 1.77–1.66 (m, 2H), 1.50 (s, 3H), 1.35 (s, 3H), 0.88 (s, 9H), 0.04 (s, 6H); ¹³C NMR (CDCl₃, 75 MHz): δ 169.5, 145.0, 117.6, 110.2, 80.2, 74.4, 71.2, 70.7, 69.2, 63.0, 34.9, 26.8, 29.4, 25.7, 24.5, −5.5, −5.6; IR (neat): 3437, 2932, 1694, 1638, 1377, 1218, 1053, 835, 756 cm⁻¹; HRMS (ESI) for C₂₁H₃₆O₆SiNa [M + Na]⁺ found 430.2632 calcd 430.2619.

(R)-6-(((3aS,4R,6R,7aS)-4-(Hydroxymethyl)-2,2-dimethyltetrahydro-3aH-[1,3]dioxolo[4,5-c]pyran-6-yl)methyl)-5,6-dihydro-2H-pyran-2-one (16)

To a solution of 15 (3.0 g, 7.2 mmol) in anhydrous THF (15 mL) was added TBAF (7.2 mL, 7.2 mmol, 1 M soln in THF) dropwise at 0 °C, and the mixture was stirred for 30 min. H₂O (2 mL) was added, and the mixture was extracted with EtOAc. The org. extracts were washed with brine and dried over anhydrous Na₂SO₄. After evaporation of the solvent, the residue was purified by column chromatography (hexane/EtOAc 6 : 4) to furnish the alcohol 16 (2.1 g, 90% yield) as colorless liquid. [α]²⁵_D: +30.4 (c = 0.1, CHCl₃); ¹H NMR (CDCl₃, 500 MHz): δ 6.91–6.86 (m, 1H), 6.04–6.0 (m, 1H), 4.76–4.66 (m, 1H), 4.40–4.36 (m, 1H), 4.22–3.95 (m, 3H), 3.86–3.75 (m, 1H), 3.64–3.51 (m, 1H), 2.45–2.32 (m, 2H), 2.15–2.09 (m, 1H), 1.96–1.89 (m, 1H), 1.76–1.65 (m, 2H), 1.53 (s, 3H), 1.39 (s, 3H); ¹³C NMR (CDCl₃, 75 MHz): δ 170.7, 146.5, 115.7, 109.2, 78.3, 75.3, 72.0, 71.7, 70.9, 63.1, 38.6, 32.7, 30.3, 28.2, 26.2; IR (neat): 3498, 2925, 1705, 1637, 1249, 1173, 1055, 767 cm⁻¹; HRMS (ESI) for C₁₅H₂₂O₆Na [M + Na]⁺ found 321.1317 calcd 321.1321.

(R)-6-(((3aS,4R,6R,7aS)-2,2-Dimethyl-4-vinyltetrahydro-3aH-[1,3]dioxolo[4,5-c]pyran-6-yl)methyl)-5,6-dihydro-2H-pyran-2-one (17)

A solution of oxalyl chloride (0.8 mL, 13.4 mmol) in 10 mL of freshly distilled CH₂Cl₂ was cooled to −78 °C, and anhydrous DMSO (1.4 mL, 26.8 mmol) was added dropwise. The mixture was stirred 30 min at −78 °C upon which alcohol 16 (2.0 g, 6.7 mmol) in 10 mL CH₂Cl₂ was added dropwise. The reaction was stirred 45 min at −78 °C then triethylamine (neat, 4.0 mL, 40.2 mmol) was added dropwise. The mixture was stirred 30 min at −78 °C then washed with 10 mL for each of H₂O, 1 N HCl, saturated sodium bicarbonate, then brine. Each wash was back-extracted with CH₂Cl₂ (2 × 20 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was used for the next step without further purification.

In a reaction flask, a 2.5 M solution of n-BuLi in hexane (8.1 mL, 20.1 mmol) was added under N₂ atmosphere to a stirred suspension of methyltriphenylphosphonium iodide (8.3 g, 20.1 mmol) in dry THF (100 mL) at −78 °C. The mixture was allowed to warm to room temperature, stirred for 1 h, and cooled to −78 °C again. To this mixture a solution of above crude aldehyde in dry THF (10 mL) was added dropwise, and the resulting mixture was stirred at room temperature for 2 h, quenched with aqueous NH₄Cl, and extracted with EtOAc (2 × 30 mL). The combined organic extracts were dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by column chromatography (hexane/EtOAc 8 : 2) to give compound 17 (0.8 g, 60% over 2 steps) as liquid. [α]²⁵_D: +62.7 (c = 0.16, CHCl₃); ¹H NMR (CDCl₃, 500 MHz): δ 6.89–6.85 (m, 1H), 6.02 (dd, J = 1.6, 9.9 Hz, 1H), 5.92–5.82 (m, 1H), 5.33 (dt, J = 1.3, 17.3 Hz, 1H), 5.22 (dt, J = 1.5, 10.6 Hz, 1H), 4.73–4.66 (m, 1H), 4.40–4.34 (m, 1H), 4.02–3.97 (m, 1H), 3.81 (dd, J = 5.3, 9.1 Hz, 1H), 3.72 (dd, J = 4.7, 9.3 Hz, 1H), 2.44–2.29 (m, 2H), 2.11 (dt, J = 1.8, 14.9 Hz, 1H), 1.95–1.89 (m, 1H), 1.76–1.67 (m, 2H), 1.52 (s, 3H), 1.37 (s, 3H); ¹³C NMR (CDCl₃, 75 MHz): δ 164.3, 145.0, 135.9, 121.4, 116.4, 109.1, 77.9, 74.8, 74.6, 72.0, 68.2, 41.2, 33.4, 29.9, 28.3, 26.2; IR (neat): 3432, 2986, 1696, 1357, 1254, 1073, 839, 756 cm⁻¹; HRMS (ESI) for C₁₆H₂₂O₅Na [M + Na]⁺ found 295.1538 calcd 295.1529.

(R)-6-(((3aS,4R,6R,7aS)-2,2-Dimethyl-4-((E)-styryl)tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyran-6-yl)methyl)-5,6-dihydro-2H-pyran-2-one (19)

A solution of Grubbs' second-generation catalyst G-II (86 mg, 0.10 mmol, 10 mol%) in CH₂Cl₂ (1 mL) was added dropwise to a solution compound 17 (300 mg, 1.01 mmol) and the styrene 18 (320 mg, 3.03 mmol) in CH₂Cl₂ (10 mL) at rt, and the mixture was refluxed for 5 h. The solvent was evaporated and the crude product purified by column chromatography (hexane/EtOAc, 7 : 3) to give lactone 19 (0.3 g, 90% yield) as a pale yellow oil. [α]²⁵_D: +36.7 (c = 0.23, CHCl₃); ¹H NMR (CDCl₃, 500 MHz): δ 7.42–7.38 (m, 2H), 7.32–7.26 (m, 2H), 7.24–7.20 (m, 1H), 6.88 (dq, J = 2.1, 9.6 Hz, 1H), 6.65 (d, J = 16.0 Hz, 1H), 6.24 (dd, J = 5.6, 16.1 Hz, 1H), 6.03 (dd, J = 1.6, 9.7 Hz, 1H), 4.78–4.71 (m, 1H), 4.43–4.39 (m, 1H), 4.09–4.03 (m, 1H), 4.0 (dd, J = 5.6, 9.1 Hz, 1H), 3.82 (dd, J = 4.8, 9.3 Hz, 1H), 2.46–2.30 (m, 2H), 2.15 (dt, J = 2.1, 15.1 Hz, 1H), 1.95 (ddd, J = 2.3, 9.3, 14.6 Hz, 1H), 1.79–1.71 (m, 2H), 1.56 (s, 3H), 1.39 (s, 3H); ¹³C NMR (CDCl₃, 75 MHz): δ 164.2, 145.0, 136.6, 131.3, 128.4, 127.6, 127.2, 126.5, 121.4, 109.2, 77.8, 75.1, 74.6, 72.1, 68.3, 41.2, 33.4, 29.9, 28.3, 26.2; IR (neat): 3442, 2985, 2927, 1721, 1378, 1247, 1046, 968, 749 cm⁻¹; HRMS (ESI) for C₂₂H₂₆O₅Na [M + Na]⁺ found 393.1668 calcd 393.1659.

(R)-6-(((2S,4S,5S,6R)-4,5-Dihydroxy-6-((E)-styryl)tetrahydro-2H-pyran-2-yl)methyl)-5,6-dihydro-2H-pyran-2-one [cryptopyranmoscatone A2 (1)]

To a stirred solution of compound 19 (100 mg, 0.25 mmol) in anhydrous CH₂Cl₂ (5 mL), TiCl₄ (0.03 mL, 0.25 mmol) was added at 0 °C and the reaction mixture was stirred at the same temperature for 1 h. The reaction mixture was quenched with solid NaHCO₃ and filtered. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (50% EtOAc/hexane) to afford 2 (48 mg, 80%) as a colourless oil. [α]²⁵_D: +9.5 (c = 0.26, CHCl₃); ¹H NMR (CDCl₃, 500 MHz): δ 7.44–7.39 (m, 2H), 7.37–7.31 (m, 2H), 7.27–7.25 (m, 1H), 6.86 (dq, J = 2.4, 9.6 Hz, 1H), 6.71 (d, J = 16.0 Hz, 1H), 6.21 (dd, J = 16.0, 7.3 Hz, 1H), 6.01 (dd, J = 2.5, 9.7 Hz, 1H), 4.75–4.67 (m, 1H), 4.23–4.19 (m, 3H), 3.42 (dd, J = 9.6, 2.8 Hz, 1H), 2.44–2.31 (m, 2H), 1.97–1.92 (m, 1H), 1.79–1.50 (m, 3H); ¹³C NMR (CDCl₃, 75 MHz): δ 164.4, 145.1, 136.1, 133.8, 128.6, 128.0, 126.8, 126.6, 121.4, 76.5, 74.9, 71.3, 67.0, 66.8, 41.0, 38.0, 29.9; IR (neat): 3420, 2924, 2854, ss1719, 1384, 1253, 1071, 755 cm⁻¹; HRMS (ESI) for C₁₉H₂₂O₅Na [M + Na]⁺ found 353.1365 calcd 353.1358.

Acknowledgements

AMR thank CSIR, New Delhi, India for financial assistance in the form of fellowship. All the authors thank CSIR, New Delhi for financial support as part of XII Five Year plan programme under title ORIGIN (CSC-0108).

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Footnote

† Electronic supplementary information (ESI) available: Spectral data of all compounds and copies of ¹H and ¹³C NMR spectra of all compounds. See DOI: 10.1039/c5ra03706a

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