First total synthesis of cryptomoscatone F1

Abstract

The total synthesis of cryptomoscatone F1 has been accomplished for the first time. The strategy involves chelation-controlled allylation, the addition of alkylzinc to an aldehyde and olefin cross-metathesis reactions as key steps. a new route to a vinyl lactone was explored.

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Styryl lactones such as cryptomoscatones D1,¹ D2, E1, E2 (cryptofolione), E3, and F1 ² (Fig. 1) were isolated from branch and stem bark of Cryptocarya mandiocanna, and C. moschata Lauraceae. Their structures were established by spectroscopic methods. C moschata Nees is an arboreal species that is widespread in the Atlantic forests of Brazil. It is recognised as an important food source for primates such as Brachyteles arachnoids (E. Geoffroy, 1806). Cryptocarya is one of the largest pantropical genera in Lauraceae. The genus includes about 350 species, and lactones isolated from these species have been shown to exhibit several biological activities.³ Cryptomoscatone D2 possesses high dose-dependent and time-dependent cytotoxicity in HeLa, SiHa, C33A, and MRC-5 cell lines.⁴ Cryptofolione showed activity towards Trypanosoma cruzi trypomastigotes, reducing their number by 77% at 250 μg mL⁻¹.⁵

Thus, interesting biological activities of cryptomoscatones, along with limited availability from natural sources, impelled us to undertake a total synthesis of cryptomoscatone F1. We have reported the synthesis of cryptomoscatone D2 ^6a and cryptofolione.⁷ Recently, similar cryptomoscatones^6b,c,d have attracted the attention of other synthetic research groups. Now, we describe herein the first total synthesis of cryptomoscatone F1 (6). It was proposed a threo relationship between OH-4′ and OH-6′ and erythro relationship between OH-6′ and OH-8′.

Our synthetic plan toward 6 is summarized in Scheme 1. We envisaged that F1 could be derived from the triol 7 and the vinyl lactone 8 via olefin cross-metathesis (CM). While vinyl lactone 8 could be prepared from commercially available (R)-2,3-O-cyclohexylidene glyceraldehyde⁸ by a new synthetic route.

Scheme 1 Retrosynthetic analysis for 6.

Fig. 1 Natural cryptomoscatones 1–6.

Results and discussion

The synthesis of triol 7, depicted in Scheme 2, started with protection of 12 [(S)-enantiomer] (prepared as reported for its known R-enantiomer)⁹ as its benzyl ether using benzyl trichloroacetimidate and CSA in CH₂Cl₂ to give 14 in 84% yield. To establish the second stereogenic center with the required stereochemistry, it was thought worthwhile to adopt a chelation-controlled stereoselective allylation reaction occurring through 1,3-induction. Accordingly, oxidative cleavage of the olefin in compound 14 under Jin's one-pot conditions¹⁰ using OsO₄–NaIO₄ and 2,6-lutidine in dioxane–water (3 : 1) furnished the corresponding aldehyde, which was immediately treated with allyltrimethylsilane in the presence of MgBr₂·OEt₂ ¹¹ in CH₂Cl₂ at 0 °C to afford homoallyl alcohol 15 in 86% yield with a diastereomeric ratio of 20 : 1. The benzyl group was deprotected with Li/naphthalene in dry THF to give diol 16, which was subsequently transformed into isopropylidene derivative 17 with dimethoxypropane and a catalytic amount of PPTS in 90% yield. The TBDPS group in compound 17 was removed with TBAF in THF and the anti geometry was assigned to 1,3-diol group in compound 11 by Rychnovsky method.¹² In the ¹³C NMR spectrum of 11, the resonance arising from the acetonide methyl groups appeared at δ = 24.64 and 24.75 ppm and that of the quaternary carbon atom at δ = 100.29 ppm, indicating a 1,3-anti relationship.

Scheme 2 Synthesis of triol 7. reagents (a) BNOC(NH)CCl₃, CSA, CH₂Cl₂, rt, 12 h, 84%; (b) (i) OsO₄, NaIO₄, 2,6-lutidine, 1,4-dioxane/H₂O, rt, 2 h; (ii) allylSiMe₃, MgBr₂·Et₂O, CH₂Cl₂, 0 °C, 12 h, 76% (over 2 steps); (c) Li/naphthalene, dry THF, 1 h, −10 °C, 85%; (d) 2,2-DMP, PPTS, 0 °C rt, 10 h, 94%; (e) TBAF, THF, 0 °C, 3 h, 90%; (f) IBX, AcCN, reflux, 1 h (ii) phenylacetylene, Et₂Zn, (S)-BINOL, Ti(OⁱPr)₄, toluene, dry CH₂Cl₂, 6 h, 74% (over 2 steps); (g) Red-Al, THF, 0 °C, 3 h, 93%; (h) CuCl₂·2H₂O, AcCN, 0 °C, 1 h, 90%.

After confirming the stereocenters, compound 11 on oxidation with IBX in CH₃CN gave an aldehyde. Next, we planned to introduce C8′ chiral center by asymmetric alkynylzinc addition reaction to aldehyde.¹³ Thus, addition of phenylacetylene to an aldehyde in the presence of diethylzinc, (S)-BINOL, and Ti(OⁱPr)₄ generated chiral propargyl alcohol with dr 95 : 5.¹⁴

Stereochemical assignment at the newly created hydroxy bearing center in 9 (C8′-OH in target molecule) was established as R by preparing R and S-mandelic esters. A reduction of the triple bond in compound 9 to the corresponding double bond was accomplished using Red-Al to give 18 in 92% yield. The acetonide group was removed upon treatment with CuCl₂·2H₂O in CH₃CN at 0 °C to afford triol compound 7 in 90% yield.

The synthesis of vinyl lactone, other synthon was initiated from (R)-2,3-O-isopropylidene glyceraldehyde, which was subjected to 1,2-chelation-controlled allylation¹⁵ in the presence of MgBr₂·(OEt)₂, allyltributyltin to afford syn homoallylic alcohol 13 in 86% yield and dr 97 : 3.¹⁶ The diastereomeric ratio was determined by chiral HPLC column in the next step after conversion of homoallylic alcohol 13 into cinnamoyl ester. Thus, esterification of homoallylic alcohol 13 with cinnamoyl chloride furnished the corresponding ester, which was subjected to ring-closing metathesis (RCM) using Grubbs Ist generation catalyst to afford unsaturated lactone. The cyclohexylidene protecting group was easily removed with 80% TFA in CH₂Cl₂ to obtain diol, which on treatment with PPh₃–imidazole–iodine¹⁷ in refluxing toluene converted to the terminal olefin affording vinyl lactone (8) (Scheme 3).

Scheme 3 Synthesis of vinyl lactone 8. Reagents: (a) allyltributyltin, MgBr₂·Et₂O, CH₂Cl₂, −78 °C to −20 °C, 16 h, 86%; (b) (E)-cinnamoyl chloride, Et₃N, DMAP, CH₂Cl₂, 0 °C, 12 h, 85%; (c) G-I catalyst, dry CH₂Cl₂, reflux, 24 h, 92%; (d) (i) 80% TFA, CH₂Cl₂, 0 °C, 2 h, (ii) PPh₃, Im, I₂, toluene, reflux, 3 h, 68% (over 2 steps).

Having both fragments 7 and 8 in hand, we proceeded for olefin cross-metathesis reaction. Thus, triol 7 was subjected to cross-metathesis coupling with vinyl lactone 8 in the presence of Grubbs' second generation catalyst¹⁸ in refluxing CH₂Cl₂ for 1 h to afford the target, cryptomoscatone F1 in 89% yield (Scheme 4). The ¹H and ¹³C NMR of our synthetic 6 are in full agreement with the reported spectra of natural product. NOESY experiment was also performed in order to confirm the E configuration of the double bonds in compound 6 (Fig. 2).

Scheme 4 Synthesis of cryptomoscatone F1. Reagents (a) G-II catalyst, CH₂Cl₂, reflux, 1 h, 89%.

Fig. 2 NOESY characteristic NOE correlations of compound 6.

Determining the E-configuration of C1′=C2′ and C9′=C10′ double bonds based on ¹H NMR (500 MHz, CDCl₃) data and assignments were made with the aid of NOESY experiments (Fig. 3). The medium NOE correlation observed between C1′H/C5H, C1′H/C3′H determining the E-configuration of C1′=C2′ double bond. The medium NOE correlation observed between C9′H/C7′H, and strong NOE correlation between C9′H/PhH, C10′H/PhH determining the E-configuration of C9′=C10′ double bond (Fig. 2). Since the remaining double bond geometry was deduced by ¹H–¹H coupling constants (J_H-3,H-4 = 9.9 Hz (Z)-configuration).

This was further supported by ¹H–¹H coupling constants.

J_H-3,H-4 = 9.9 Hz (Z)-configuration,

J_{H-1′, H-2′} = 15.5 Hz (E)-configuration,

J_{H-9′, H-10′} = 15.8 Hz (E)-configuration

Fig. 3 NOESY spectrum showing the characteristic NOE correlations of compound 6.

Conclusions

In conclusion, we have accomplished the first total synthesis of cryptomoscatone F1 (6) in 13 steps with an overall yield of 11.57%.

Comparative data for the natural and synthetic compound was provided in Table 1.

Table 1 Comparative data of natural product² and synthetic compound (6)

^1H NMR				^13C NMR
H	Natural product	Synthetic product	C	Natural product	Synthetic product
3	6.00 (dt, J = 10, 1 Hz)	6.03 (dt, J = 9.9, 1.6 Hz)	2	164.1	164.2
4	6.80 (dt, J = 10, 4 Hz)	6.91–6.85 m	3	121.4	121.3
5	2.40 m	2.47–2.39 m	4	144.8	144.9
6	4.90 (br q, J = 6 Hz)	4.93–4.86 m	5	29.7	29.6
1^1	5.70 (dd, J = 16, 6 Hz)	5.69 (dd, J = 15.5, 6.5 Hz)	6	77.9	77.9
2^1	5.90 (dt, J = 16, 7 Hz)	5.92–5.84 m	1^1	129.7	129.5
3^1	2.30 (t, J = 7 Hz)	2.35–2.22 m	2^1	131.4	131.4
4^1	4.00 m	4.08–4.01 m	3^1	40.3	40.2
5^1	1.70 m	1.92–1.82 m, 1H	4^1	68.1	67.9
6^1	4.30 m	4.33–4.24 m	5^1	42.3	42.4
7^1	1.70 m	1.75–1.60 m, 3H	6^1	70.0	69.6
8^1	4.60 m	4.62–4.56 m	7^1	42.9	42.9
9^1	6.20 (dd, J = 16, 6 Hz)	6.23 (dd, J = 15.8, 6.5 Hz)	8^1	73.6	73.3
10^1	6.60 (d, J = 16 Hz)	6.60 (d, J = 15.8 Hz)	9^1	130.2	130.0
Ph	7.30 m	7.41–7.22 m, 5H	10^1	131.6	131.6
			1^11	136.5	136.5
			2^11/6^11	126.5	126.4
			3^11/5^11	128.6	128.5
			4^11	127.8	127.6

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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, 500 and ¹³C NMR spectra 75 125 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)-1-((R)-1,4-Dioxaspiro[4.5]decan-2-yl)but-3-en-1-ol (13). To a solution of crude aldehyde (0.8 g, 4.7 mmol) in dry CH₂Cl₂ (8 mL) was added MgBr₂·Et₂O (1.46 g, 5.64 mmol). After stirring for 15 min and cooling to −78 °C allyl tributyl tin (1.6 mL, 5.17 mmol) was added; stirring was continued for 16 h while the temperature slowly rose to −20 °C. The mixture was poured into 10% aq HCl (10 mL). The water phase was extracted with CH₂Cl₂ (3 × 10 mL). The combined organic extracts were washed with sat. aq NaHCO₃ (10 mL) and brine, dried, the solvent was evaporated and the residue purified by column chromatography (30% hexane/EtOAc) to give 13 (0.858 g, 86%) as a colorless liquid. [α]²⁵_D: +1.72 (c 1.2, CHCl₃). IR (neat) ν_max: 3435, 2935, 2860, 1640, 1163, 1100, 1044 cm⁻¹. ¹H NMR (300 MHz, CDCl₃): δ 5.91–5.75 (m, 1H), 5.20–5.09 (m, 2H), 4.05–3.87 (m, 3H), 3.83–3.73 (m, 1H), 2.38–2.12 (m, 2H), 1.69–1.49 (m, 6H), 1.45–1.22 (m, 4H). ¹³C NMR (CDCl₃, 125 MHz): δ 133.9, 118.1, 109.5, 77.6, 70.3, 64.7, 37.5, 36.1, 34.7, 25.0, 23.9, 23.7. HRMS (ESI) for C₁₂H₂₀O₃Na [M + Na]⁺ found 235.1345 calcd 235.1340.

(R)-1-((R)-1,4-Dioxaspiro[4.5]decan-2-yl)but-3-en-1-yl cinnamate (19). To the solution of alcohol 13 (0.76 g, 3.58 mmol) was dissolved in 10 mL of CH₂Cl₂ and cooled to 0 °C and (0.895 mg, 5.37 mmol) of cinnamoyl chloride, (1 mL, 7.16 mmol) of Et₃N, and (35 mg, 0.29 mmol) DMAP were added, warmed to room temperature and stirred overnight. The mixture was then poured into brine and extracted with CH₂Cl₂ (2 × 10 mL). The organic phases were washed with 1 M aq HCl (5 mL) and brine (8 mL), dried over Na₂SO₄. The solvent was removed under aspirator vacuum, and the crude product was purified by column chromatography silica gel (20% hexane/EtOAc), to obtain 0.999 g (85%) of 19. [α]²⁵_D: +8.09 (c 0.8, CHCl₃). IR (neat) ν_max: 3081, 2936, 2861, 1714, 1638, 1449, 1202, 1166, 1100, 767 cm⁻¹. ¹H NMR (500 MHz, CDCl₃): 7.69 (d, J = 16.0 Hz, 1H), 7.55–7.50 (m, 2H), 7.41–7.36 (m, 3H), 6.44 (d, J = 16.0 Hz, 1H), 5.86–5.77 (m, 1H), 5.18–5.06 (m, 3H), 4.24–4.19 (m, 1H), 4.09–4.04 (m, 1H), 3.89–3.84 (m, 1H), 2.56–2.49 (m, 1H), 2.47–2.39 (m, 1H), 1.65–1.53 (m, 6H), 1.44–1.23 (m, 4H). ¹³C NMR (CDCl₃, 75 MHz): δ 166.1, 145.2, 134.2, 131.1, 130.3, 128.8, 128, 118, 117.7, 110.1, 75.8, 73, 65.8, 36, 35.3, 34.8, 25.1, 23.9, 23.7. HRMS (ESI) for C₂₁H₂₆O₄Na [M + Na]⁺ found 365.1728 calcd 365.1721.

(R)-6-((R)-1,4-Dioxaspiro[4.5]decan-2-yl)-5,6-dihydro-2H-pyran-2-one (20). Grubbs' first-generation catalyst (0.225 g, 0.27 mmol) was added to a solution of 19 (0.9 g, 2.74 mmol) in dry CH₂Cl₂ (100 mL) at reflux, over 24 h. After completion of the reaction (TLC), the solvent was removed under reduced pressure and the residue was purified by column chromatography (40% hexane/EtOAc) to give 20 (0.6 g, 92%) as a colorless liquid. [α]²⁵_D: +15.8 (c 1.3, CHCl₃). IR (neat) ν_max: 2935, 2860, 1738, 1247, 1099, 1054, 816 cm⁻¹. ¹H NMR (300 MHz, CDCl₃): δ 6.96–6.86 (m, 1H), 6.01 (dd, J = 9.8, 1.7 Hz, 1H), 4.31–3.98 (m, 4H), 2.67–2.55 (m, 1H), 2.52–2.38 (m, 1H), 1.64–1.49 (m, 8H), 1.48–1.27 (m, 2H). ¹³C NMR (CDCl₃, 75 MHz): δ 163, 144.9, 121.1, 110.4, 78, 75.6, 66.5, 36.4, 34.4, 26.2, 24.9, 23.9, 23.6. HRMS (ESI) for C₁₃H₁₈O₄Na [M + Na]⁺ found 261.1097 calcd 261.1096.

(R)-6-Vinyl-5,6-dihydro-2H-pyran-2-one (8). Compound 20 (0.545 g, 2.28 mmol) was dissolved in 80% aq CF₃COOH (1 mL) at 0 °C and the mixture was stirred at the same temperature for 2 h. The reaction mixture was then extracted with CH₂Cl₂ (3 × 5 mL). The collected organic layers were combined, washed with 10% NaHCO₃ (3 × 5 mL), water, and brine, dried over Na₂SO₄, and concentrated in vacuo. The crude product was taken as such for the next step without further purification. To a solution of crude diol (0.3 g, 1.89 mmol) in dry toluene (5 mL) was added triphenylphosphine (1.989 g, 7.59 mmol) followed by imidazole (0.517 g, 7.59 mmol) and stirred vigorously. To the resulting solution was added iodine (0.722 g, 5.69 mmol) and the mixture was refluxed at 110 °C for 3 h. The reaction mixture, after bringing to room temperature, was decanted into excess sat. aq Na₂S₂O₃ (5 mL) and sat. aq NaHCO₃ (5 mL) in a separatory funnel. The residue in the reaction flask was extracted with EtOAc (3 × 5 mL). These extracts were combined with the material in the separatory funnel and shaken until the iodine was consumed. The organic phase was washed with H₂O (1 × 5 mL), dried, and concentrated. The crude residue was chromatography (30% hexane/EtOAc), to obtain 8 (0.193 g, 68% (over 2 steps) as liquid. [α]²⁵_D: +80.6 (c 0.9, CHCl₃). IR (neat) ν_max: 1723, 1385, 1248, 1033, 817 cm⁻¹. ¹H NMR (500 MHz, CDCl₃): δ 6.88 (ddd, J = 9.7, 5.4, 3.0 Hz, 1H), 6.04 (td, J = 9.7, 1.2 Hz, 1H), 5.94 (ddd, J = 17.0, 10.6, 5.7 Hz, 1H), 5.40 (dd, J = 17.2, 0.9 Hz, 1H), 5.29 (dd, J = 10.5, 0.9 Hz, 1H), 4.95–4.90 (m, 1H), 2.51–2.38 (m, 2H). ¹³C NMR (CDCl₃, 75 MHz): δ 163.3, 144.0, 134.2, 120.9, 117.3, 76.1, 28.7. HRMS (ESI) for C₇H₈O₂Na [M + Na]⁺ found 147.0422 calcd 147.0422.

(R)-((3-(Benzyloxy)hex-5-en-1-yl)oxy)(tert-butyl)diphenylsilane (14). To a stirring solution of alcohol 12 (2 g, 5.64 mmol), freshly prepared benzyl trichloroacetimidate (2.14 g, 8.47 mmol), and CH₂Cl₂ (10 mL) in a 50 mL round bottom flask, under an atmosphere of N₂, was added (±)-camphor-10-sulfonic acid (131 mg, 0.56 mmol) in one portion. The reaction was allowed to proceed for 12 h at rt, after which time TLC analysis indicated essentially complete consumption of starting material. The reaction mixture was concentrated under reduced pressure, diluted with 20% hexane/EtOAc (30 mL), filtered over a pad of celite, and concentrated under reduced pressure to give a red slurry. Purification was accomplished by column chromatography (5% hexane/EtOAc), collecting 8 mL fractions. The product containing fractions were combined and concentrated under reduced pressure to give benzyl ether 14 (2.1 g, 84% yield) as colorless oil. [α]²⁵_D: +13.8 (c 1.5, CHCl₃). IR (neat) ν_max: 3069, 2956, 2932, 2891, 1639, 1427, 1109, 735, 701 cm⁻¹. ¹H NMR (500 MHz, CDCl₃): δ 7.72–7.69 (m, 4H), 7.44–7.33 (m, 11H), 5.88–5.79 (m, 1H), 5.10–5.04 (m, 2H), 4.78 (s, 2H), 3.86–3.78 (m, 1H), 3.77–3.70 (m, 2H), 2.36–2.31 (m, 2H), 1.80–1.75 (m, 2H), 1.10 (s, 9H). ¹³C NMR (CDCl₃, 75 MHz): δ 138.4, 135.8, 135.1, 134.7, 134.5, 129.6, 129.5, 127.6, 127.5, 127.4, 127.3, 72.6, 70.2, 66.8, 41.5, 36.0, 26.5, 18.9. HRMS (ESI) for C₂₉H₃₆O₂SiNa [M + Na]⁺ found 467.2376 calcd 467.2373.

(4S,6S)-6-(Benzyloxy)-8-((tert-butyldiphenylsilyl)oxy)oct-1-en-4-ol (15). To a solution of 14 (2.01 g, 4.52 mmol) in 1,4-dioxane/water (3 : 1; 12 mL), 2,6-lutidine (1.1 mL, 9.05 mmol), OsO₄ (4.6 mL, 0.09 mmol) followed by NaIO₄ (3.87 g, 18.1 mmol) were sequentially added at room temperature, and the mixture was stirred for 2 h. After completion of the reaction (monitored by TLC), 1,4-dioxane was removed under reduced pressure, and the residue was diluted with CH₂Cl₂ (20 mL). The organic layer was separated and the aqueous layer extracted with CH₂Cl₂ (2 × 10 mL). The combined organic layers were quickly washed with 1 N HCl (2 × 5 mL) to remove excess 2,6-lutidine followed by brine (2 × 5 mL), dried with anhydrous Na₂SO₄, and concentrated under reduced pressure to give the crude aldehyde. To a solution of crude aldehyde (1.8 g, 4.03 mmol) in CH₂Cl₂ (15 mL) at 0 °C were added MgBr₂·OEt₂ (2.08 g, 8.07 mmol), and allyltrimethylsilane (3.2 mL, 20.17 mmol). The resultant mixture was stirred at 0 °C overnight before being quenched with 1 N aq HCl solution. The resultant mixture was warmed to room temperature and extracted with EtOAc. The organic layer was washed successively with sat. aq NaHCO₃ solution and brine. The organic layer was dried (Na₂SO₄), filtered, and concentrated under reduced pressure. Purification of the residue by column chromatography silica gel (20% hexane/EtOAc) to give homoallylic alcohol 15 (1.693 g, 76.5% (over 2 steps) as a colorless oil. [α]²⁵_D: +25.6 (c 1.3, CHCl₃). IR (neat) ν_max: 3432, 3069, 2932, 2857, 1639, 1427, 1108, 702 cm⁻¹. ¹H NMR (500 MHz, CDCl₃): δ 7.68–7.63 (m, 4H), 7.45–7.25 (m, 1H), 5.85–5.75 (m, 1H), 5.12–5.06 (m, 2H), 4.5 (s, 2H), 4.00–3.89 (m, 2H), 3.83–3.69 (m, 2H), 2.23–2.16 (m, 2H), 2.00–1.92 (m, 1H), 1.80–1.70 (m, 1H), 1.63–1.57 (m, 2H), 1.05 (s, 3H). ¹³C NMR (CDCl₃, 75 MHz): δ 138.1, 135.5, 134.8, 134.7, 133.6, 129.6, 128.3, 127.8, 127.6, 117.4, 74.2, 71.4, 67.7, 60.4, 42.1, 39.5, 36.5, 26.8, 19.1. HRMS (ESI) for C₃₁H₄₀O₃ SiNa [M + Na]⁺ found 511.2638 calcd 511.2623.

(3S,5S)-1-((tert-Butyldiphenylsilyl)oxy)oct-7-ene-3,5-diol (16). To a stirred solution of naphthalene (2.6 g, 20.28 mmol) in THF (10 mL) were added lithium granules (165 mg, 23.66 mmol) at room temperature, and the solution was allowed to stir at room temperature for 30 min to generate Li naphthalenide. To the resulting dark green solution was added benzyl ether 15 (1.65 g, 3.38 mmol) at −10 °C, and the mixture was allowed to stir at the same temperature for 30 min, quenched with aqueous NH₄Cl, extracted into EtOAc (3 × 50 mL), dried over Na₂SO₄, concentrated, and purified on silica gel (40% hexane/EtOAc) to give diol 16 (1.143 g, 85%) as a colorless liquid. [α]²⁵_D: −14.9 (c 1.2, CHCl₃). IR (neat) ν_max: 3416, 2931, 2857, 1428, 1109, 1083, 740, 704 cm⁻¹. ¹H NMR (500 MHz, CDCl₃): δ 7.69–7.65 (m, 4H), 7.47–7.37 (m, 6H), 5.89–5.79 (m, 1H), 5.16–5.09 (m, 2H), 4.30–4.22 (m, 1H), 4.05–3.98 (m, 1H), 3.90–3.85 (m, 2H), 3.78 (br.s, 1H), 2.30–2.25 (m, 2H), 1.92–1.78 (m, 1H), 1.70–1.56 (m, 3H), 1.05 (s, 9H). ¹³C NMR (CDCl₃, 75 MHz): δ 135.4, 134.8, 132.8, 132.6, 129.8, 127.7, 117.6, 69.5, 67.9, 63.6, 42.2, 42, 38.1, 26.7, 18.9. HRMS (ESI) for C₂₄H₃₄O₃SiNa [M + Na]⁺ found 421.2169 calcd 421.2158.

(2-((4S,6S)-6-Allyl-2,2-dimethyl-1,3-dioxan-4-yl)ethoxy)(tert-butyl)diphenylsilane (17). 2,2-Dimethoxypropane (0.7 mL, 5.52 mmol) and catalytic PPTS (83 mg, 0.33 mmol) were added successively to a solution of diol 16 (1.1 g, 2.76 mmol) in a CH₂Cl₂ (8 mL). The solution was stirred for 10 h at room temperature and then quenched with solid NaHCO₃. The crude compound was concentrated in vacuo and purified by column chromatography (15% hexane/EtOAc) to afford the acetonide product 17 (1.137 g, 94%) as a colorless liquid. [α]²⁵_D: +27.8 (c 0.8, CHCl₃). IR (neat) ν_max: 2934, 2858, 1379, 1223, 1110, 739, 704 cm⁻¹. ¹H NMR (500 MHz, CDCl₃): δ 7.69–7.63 (m, 4H), 7.44–7.35 (m, 6H), 5.84–5.75 (m, 1H), 5.13–5.02 (m, 2H), 4.13–4.05 (m, 1H), 3.89–3.75 (m, 2H), 3.72–3.66 (m, 1H), 2.36–2.88 (m, 1H), 2.22–2.15 (m, 1H), 1.77–1.54 (m, 4H), 1.35 (s, 3H), 1.33 (s, 3H), 1.04 (s, 9H). ¹³C NMR (CDCl₃, 75 MHz): δ 135.4, 134.4, 133.8, 129.5, 127.5, 116.7, 100.1, 66.1, 63.3, 60, 40.1, 38.8, 38, 26.8, 24.8, 19.1. HRMS (ESI) for C₂₇H₃₈O₃SiNa [M + Na]⁺ found 461.2482 calcd 461.2471.

2-((4S,6S)-6-Allyl-2,2-dimethyl-1,3-dioxan-4-yl)ethanol (11). A 1 M solution of TBAF in THF (4.56 mL, 4.56 mmol) was added to a solution of compound 17 (1 g, 2.28 mmol) in dry THF (5 mL) at 0 °C. The mixture was stirred at room temperature for 3 h. After completion of the reaction, the mixture was diluted with EtOAc (15 mL). The combined organic layers were washed with brine, and the mixture was extracted with EtOAc (3 × 10 mL), dried over Na₂SO₄. The solvent was removed under reduced pressure, and the mixture was purified by column chromatography (20% hexane/EtOAc) to afford 11 (410 mg, 90%) as a colorless liquid. [α]²⁵_D: +40.6 (c 1.6, CHCl₃). IR (neat) ν_max: 3422, 2987, 2939, 1643, 1308, 1224, 1168, 1054, 761 cm⁻¹. ¹H NMR (500 MHz, CDCl₃): δ 5.83–5.73 (m, 1H), 5.12–5.03 (m, 2H), 4.08–4.01 (m, 1H), 3.91–3.84 (m, 1H), 3.78–3.72 (m, 2H), 2.55 (br.s, 1H), 2.34–2.77 (m, 1H), 2.23–2.16 (m, 1H), 1.77–1.70 (m, 2H), 1.69–1.61 (m, 2H), 1.37 (s, 3H), 1.35 (s, 3H). ¹³C NMR (CDCl₃, 75 MHz): δ 134.2, 117, 100.4, 66.5, 66.1, 40, 37.6 (2C), 24.8, 24.7. HRMS (ESI) for C₁₁H₂₀O₃Na [M + Na]⁺ found 223.1312 calcd 223.1310.

(R)-1-((4S,6S)-6-Allyl-2,2-dimethyl-1,3-dioxan-4-yl)-4-phenylbut-3-yn-2-ol (9). To the solution of alcohol 11 (0.3 g, 1.50 mmol) in anhydrous CH₃CN (5 mL) IBX (0.63 g, 2.25 mmol) was added and the resulting suspension was vigorously stirred at reflux condition for 1 h, and the reaction was allowed to cool to rt, filtered through celite. The residue was washed with EtOAc (3 × 5 mL) and the combined filtrate was concentrated to give the crude aldehyde, which was directly used for the next reaction without further purification. In 25 mL flask, 1 mL toluene solution of phenylacetylene (0.56 mL, 5.09 mmol) and diethylzinc (5.1 mL, 5.09 mmol) was refluxed for 1 hour under nitrogen. After the solution was cooled to room temperature, (S)-BINOL (360 mg, 1.27 mmol), diethyl ether (8 mL) and Ti(OⁱPr)₄ (0.37 mL, 1.27 mmol) were added sequentially. The solution was stirred for another 1 h, and aldehyde (252 mg, 1.27 mmol) was added. After additional 4 h, the reaction was quenched with saturated ammonium chloride. The resulting mixture was extracted with CH₂Cl₂ and concentrated under vacuum. Purification of the residue by passing through a short silica gel column (20% hexane/EtOAc) afforded the pure propargylic alcohol product 9 (335 mg, 74.8%, over 2 steps) as a colorless liquid. [α]²⁵_D: +9.1 (c 0.6, CHCl₃). IR (neat) ν_max: 3412, 3078, 2986, 2926, 1638, 1490, 1381, 1223, 1025, 756 cm⁻¹. ¹H NMR (500 MHz, CDCl₃): δ 7.44–7.41 (m, 2H), 7.33–7.28 (m, 3H), 5.84–5.75 (m, 1H), 5.13–5.04 (m, 2H), 4.48–4.79 (m, 1H), 4.18–4.11 (m, 1H), 3.90 (qt, J = 14.1, 7.0 Hz, 1H), 2.98 (d, J = 2.7 Hz, 1H), 2.35–2.28 (m, 1H), 2.24–2.17 (m, 1H), 2.10–2.02 (m, 1H), 1.97–1.91 (m, 1H), 1.70 (t, 2H), 1.40 (s, 3H), 1.37 (s, 3H). ¹³C NMR (CDCl₃, 75 MHz): δ 134.2, 131.6, 128.3, 128.2, 117, 100.6 (2C), 89.3, 66.1, 66, 43.2, 40, 37.8, 24.9, 24.6. HRMS (ESI) for C₁₉H₂₄O₃Na [M + Na]⁺ found 323.1623 calcd 323.1621.

(R)-(R,E)-1-((4R,6S)-6-Allyl-2,2-dimethyl-1,3-dioxan-4-yl)-4-phenylbut-3-en-2-yl-2-methoxy-2-phenylacetate. To a solution of propargylic alcohol 9 (12 mg, 0.066 mmol) in dry CH₂Cl₂ (5 mL), DMAP catalytic, (R)-O-methylmandelic acid (9 mg, 0.079 mmol) and DCC (12 mg, 0.099 mmol) were added and the mixture was stirred at room temperature for 60 minutes under argon. The reaction was diluted with DCM and filtered through celite. The filtrate was concentrated under reduced pressure and purified by column chromatography (5–10% hexane/ethyl acetate) to afford O-methylmandelate as a colorless oil (15 mg, 85%). ¹H NMR (500 MHz, CDCl₃): δ 7.49–7.43 (m, 2H), 7.38–7.26 (m, 8H), 5.82–5.74 (m, 1H), 5.11–5.03 (m, 2H), 4.81 (s, 1H), 4.13–4.06 (m, 1H), 3.89–3.82 (m, 1H), 3.45 (s, 3H), 3.44–3.40 (m, 1H), 2.33–2.25 (m, 1H), 2.21–2.14 (m, 1H), 2.07–1.92 (m, 2H), 1.66–1.58 (m, 2H), 1.35 (s, 3H), 1.33 (s, 3H).

(S)-(R,E)-1-((4R,6S)-6-Allyl-2,2-dimethyl-1,3-dioxan-4-yl)-4-phenylbut-3-en-2-yl-2-methoxy-2-phenylacetate. To a solution of propargylic alcohol 9 (10 mg, 0.066 mmol) in dry CH₂Cl₂ (5 mL), DMAP catalytic, (S)-O-methylmandelic acid (6 mg, 0.079 mmol) and DCC (10 mg, 0.099 mmol) were added and the mixture was stirred at room temperature for 60 minutes under argon. The reaction was diluted with DCM and filtered through celite. The filtrate was concentrated under reduced pressure and purified by column chromatography (5–10% hexane/ethyl acetate) to afford O-methylmandelate as a colorless oil (13 mg, 87%). ¹H NMR (500 MHz, CDCl₃): δ 7.50–7.27 (m, 10H), 5.79–5.70 (m, 1H), 5.10–5.01 (m, 2H), 4.81 (s, 1H), 4.17–4.07 (m, 1H), 4.02–3.95 (m, 1H), 3.82–3.76 (m, 1H), 3.43 (s, 3H), 2.34–2.32 (m, 1H), 2.17–2.10 (m, 1H), 1.92–1.8 (m, 1H), 1.65–1.50 (m, 3H), 1.30 (s, 3H), 1.29 (s, 3H).

(R,E)-1-((4S,6S)-6-Allyl-2,2-dimethyl-1,3-dioxan-4-yl)-4-phenylbut-3-en-2-ol (18). To a cold (0 °C) solution of propargylic alcohol 9 (0.2 g, 0.66 mmol) in THF (5 mL) was added Red-Al (0.32 mL, 70 wt% in toluene, 0.99 mmol) dropwise. After 3 h at 0 °C, the reaction mixture was quenched carefully by dropwise addition of saturated aqueous sodium sulphate (Caution: vigorous evolution of H₂ may result). EtOAc was added and the mixture was allowed to warm to rt. The organic layer was washed with brine and the combined aqueous layer was extracted several times with EtOAc. The combined organic extracts were dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel (30% hexane/EtOAc) to provide (187 mg, 93% yield) of allylic alcohol 18 as a colorless oil. [α]²⁵_D: +24.5 (c 0.9, CHCl₃). IR (neat) ν_max: 3437, 3026, 2986, 2937, 1641, 1449, 1380, 1223, 1166, 1123, 968, 749 cm⁻¹. ¹H NMR (300 MHz, CDCl₃): δ 7.42–7.18 (m, 5H), 6.61 (d, J = 15.8 Hz, 1H), 6.18 (dd, J = 15.8, 6.4 Hz, 1H), 5.87–5.71 (m, 1H), 5.14–5.02 (m, 2H), 4.53–4.44 (m, 1H), 4.16–4.03 (m, 1H), 3.95–3.84 (m, 1H), 3.43 (br.s, 1H), 2.37–2.14 (m, 2H), 1.83–1.57 (m, 4H), 1.41 (s, 3H), 1.38 (s, 3H). ¹³C NMR (CDCl₃, 75 MHz): δ 136.7, 134.1, 131.6, 129.8, 128.4, 127.4, 126.3, 117, 100.6, 72.2, 66.9, 66, 42.7, 39.9, 38, 24.9, 24.6. HRMS (ESI) for C₁₉H₂₆O₃Na [M + Na]⁺ found 325.1779 calcd 235.1770.

(3R,5R,7S,E)-1-Phenyldeca-1,9-diene-3,5,7-triol (7). To a solution that was cooled in an ice bath of compound 18 (0.1 g, 0.33 mmol) in CH₃CN (5 mL) was added CuCl₂·2H₂O (112 mg, 0.66 mmol) as a solid. The reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was quenched with solid NaHCO₃ (2 g), and the resulting mixture was filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (60% hexane/EtOAc) to afford triol 7 (78 mg, 90%) as a colorless oil. [α]²⁵_D: +42.7 (c 0.5, CHCl₃). IR (neat) ν_max: 3369, 3080, 3027, 2939, 1640, 1433, 1070, 967, 749 cm⁻¹. ¹H NMR (300 MHz, CDCl₃): δ 7.43–7.16 (m, 5H), 6.60 (d, J = 15.8 Hz, 1H), 6.22 (dd, J = 15.8, 6.7 Hz, 1H), 5.89–5.73 (m, 1H), 5.20–5.08 (m, 2H), 4.63–4.53 (m, 1H), 4.35–4.23 (m, 1H), 4.02 (qt, J = 12.8, 6.7 Hz, 1H), 2.32–2.22 (m, 2H), 1.90–1.59 (m, 4H). ¹³C NMR (CDCl₃, 75 MHz): δ 136.5, 134.5, 131.6, 129.8, 128.5, 127.6, 126.4, 117.9, 73, 69.4, 67.7, 43.1, 42.4, 42. HRMS (ESI) for C₁₆H₂₂O₃Na [M + Na]⁺ found 285.1461 calcd 285.1461.

(R)-6-((1E,4S,6R,8R,9E)-4,6,8-Trihydroxy-10-phenyldeca-1,9-dien-1-yl)-5,6-dihydro-2H-pyran-2-one (6) (cryptomoscatone F1). A solution of Grubbs II catalyst (3 mg, 0.003 mmol) in CH₂Cl₂ (1 mL) was added dropwise to a solution of the triol 7 (16 mg, 0.061 mmol) and vinyl lactone 8 (11 mg, 0.091 mmol) in CH₂Cl₂ (1 mL) at rt, and the mixture was refluxed for 1 h. The solvent was removed under reduced pressure and the crude product was purified by column chromatography (80% hexane/EtOAc) to give viscous liquid (19 mg, 89%). [α]²⁵_D: +35.0 (c 1.0, CHCl₃). IR (neat) ν_max: 3405, 2925, 2854, 1713, 1384, 1250, 1054, 753 cm⁻¹. ¹H NMR (500 MHz, CDCl₃): δ 7.41–7.22 (m, 5H), 6.91–6.85 (m, 1H), 6.60 (d, J = 15.8 Hz, 1H), 6.23 (dd, J = 15.8, 6.7 Hz, 1H), 6.03 (dt, J = 9.9, 1.6 Hz, 1H), 5.92–5.84 (m, 1H), 5.69 (dd, J = 15.5, 6.5 Hz, 1H), 4.93–4.86 (m, 1H), 4.62–4.56 (m, 1H), 4.33–4.24 (m, 1H), 4.08–4.01 (m, 1H), 2.47–2.39 (m, 2H), 2.35–2.22 (m, 2H), 1.92–1.82 (m, 1H), 1.75–1.60 (m, 3H).¹³C NMR (CDCl₃, 125 MHz): δ 164.2, 144.9, 136.5, 131.6, 131.4, 130, 129.5, 128.5, 127.6, 126.4, 121.3, 77.9, 73.3, 69.6, 67.9, 42.9, 42.4, 40.2, 29.6. HRMS: calcd for C₂₁H₂₆O₅Na [M + NH₄]⁺: 381.1678: found: 381.1674.

Acknowledgements

AR thank UGC, New Delhi for the award 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/c5ra03693c

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