Diastereoselective vinylalumination for the synthesis of pericosine A, B and C

Abstract

The vinylalumination of α-substituted aldehydes gave anti- and syn-adducts with moderate diastereoselectivity. The diastereomeric ratio was inverted by the addition of lithium or sodium perchlorates. Thus, both anti- and syn-adducts were isolated and transformed into the biologically active conduritols, pericosine B and C, respectively. Formal synthesis of pericosine A was achieved with the anti-adduct. The rationales for the different diastereoselectivity are discussed.

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Introduction

[α-(Alkoxycarbonyl)vinyl]diisobutylaluminum (1), generated in situ from alkyl propiolate and diisobutylaluminum hydride in tetrahydrofuran/hexamethylphosphoramide (THF/HMPA), was introduced by Tsuda, Saegusa and colleagues in 1987 (eqn (1)).¹ The reaction of the nucleophilic aluminium reagents 1 and aldehydes/ketones provided alkyl α-(1-hydroxyalkyl)acrylates, the same products furnished by the Morita–Baylis–Hillman reaction.² This vinylalumination process circumvented the common drawbacks of the Morita–Baylis–Hillman reaction, such as slow reaction rates and the low reactivity of ketones and β-substituted acrylates. Vinylalumination is also applicable to other electrophiles, including allyl bromides,^1a oxiranes and sulfinimines.³ Recently, Ramachandran's group improved the preparation of 1 by replacing the hazardous HMPA with environmentally benign 4-methylmorpholine N-oxide (NMO) increasing the applicability of this vinylalumination.⁴ Here, we report the application of this method to synthesize pericosine A, B and C (2a–c), which are cytotoxic metabolites of the sea hare-derived fungus Periconia byssoides OUPS-N133 reported in 1997 and 2007 by Numata and colleagues.⁵ It is interesting to note that both enantiomers of pericosine C were found in nature with a slight preference for the (−)-isomer.^5b

Pericosines belong to the family of conduritols and display a variety of biological activities including antitumour activity against some human cancer cell lines, inhibitory activity against epidermal growth factor receptor (EGFR), topoisomerase II and P388 leukaemia cells in mice;⁶ therefore, these compounds attract considerable attention from synthetic chemists (Fig. 1).⁷ Conventional approaches to access the six-membered cyclitol structure of pericosines include the use of shikimic acid, quinic acid and 3,5-cyclohexadiene-cis-1,2-diols prepared by the chemoenzymatic modification of substituted benzenes.^8–10 Recently, both Chen's and Vankar's groups utilized ring-closing metathesis (RCM) to generate the cyclitol skeletons of pericosines, where the required dienes for RCM were prepared by the Nozaki–Hiyama–Kishi and Morita–Baylis–Hillman reactions, respectively (Scheme 1).^11,12 We envisioned that the vinylalumination of the corresponding aldehydes could be a new method to synthesize the substrates for RCM, and the manipulation of the diastereoselectivity in this process could lead to the synthesis of both pericosine B and C. To our knowledge, the stereochemistry of the vinylalumination with α-substituted aldehydes has not been previously addressed.¹³

Fig. 1 Pericosine A–E.

Scheme 1 Strategy for the synthesis of pericosines via RCM.

Results and discussion

D-Ribose was converted to the diol 3 according to the reported procedures.¹⁴ The terminal hydroxyl group was differentiated by the formation of tert-butyldimethylsilyl ether 4¹⁵ or pivalate 8. The remaining, secondary hydroxyl group was further protected as p-methoxybenzyl ether 5 or tert-butyldimethylsilyl ether 9, and the desired aldehydes 7a and 7b were prepared after the sequence of deprotection and Swern oxidation (Schemes 2 and 3).¹⁶

Scheme 2

Scheme 3

The vinylalumination of aldehyde 7 is summarized in Table 1. Consistent with previous reports, no product could be found when the additive was absent (entry 1).^1a In the presence of HMPA, the reactions of 7a generated the two diastereomers 11a and 12a with a moderate diastereoselectivity (4 : 1) and reasonable yields (entry 2). The two diastereomers were separable and isolated by column chromatography. Although our attempt to determine their stereochemistry by NMR analysis was inconclusive at this stage, this stereochemical outcome was later validated by further syntheses to pericosine B and C, respectively (vide infra). When the TBS-protected aldehyde 7b was used, the diastereoselectivity diminished to 1.2 : 1 (entry 3), this ratio is close to that observed in the Morita–Baylis–Hillman reaction (1 : 1) promoted by DABCO.¹¹ Several Lewis acids were screened to improve the diastereoselectivity of this vinylalumination, and we found that alkali perchlorates had a strong influence on the reactions of 7a. As the equivalence of LiClO₄ increased, the major product of the vinylalumination gradually shifted from 11a toward 12a (entries 4–6). The same trend was also observed when sodium perchlorate was applied (entries 7 and 8). The effect of KClO₄ was negligible due to the much lower solubility of this salt in organic solvents (entry 9).¹⁷ The addition of LiClO₄ has little effect on the vinylalumination of the TBS-protected aldehyde 7b (entry 10). Other Lewis acids, such as Mg(ClO₄)₂, Ca(ClO₄)₂, ZnBr₂, MgBr₂(OEt₂) and AlMeCl₂, did not generate the desired product, and the starting material 7a was recovered. The vinylalumination became very sluggish when a lower reaction temperature (0 °C) was applied.

Table 1 Vinylalumination of aldehyde 7^a

Entry	Substrate	Additive	11 : 12^b	Yield^c (%)
a The reactions were stirred in THF for 14 h at rt with 3 equiv. of 1a, prepared from the addition of methyl propiolate to the solution of DIBALH, HMPA and THF at 0 °C. b Ratios were determined by ^1H NMR of crude reaction mixtures. c Isolated yields. d The exact stereochemistry of 11b and 12b was not determined as they were inseparable. e Most KClO4 was insoluble.
1	7a	—	—	0
2	7a	HMPA	4 : 1	60
3	7b	HMPA	1.2 : 1^d	28
4	7a	HMPA, LiClO4 (1 equiv.)	5 : 4	64
5	7a	HMPA, LiClO4 (4 equiv.)	1 : 2	60
6	7a	HMPA, LiClO4 (10 equiv.)	1 : 3	61
7	7a	HMPA, NaClO4 (4 equiv.)	1 : 2	58
8	7a	HMPA, NaClO4 (10 equiv.)	1 : 4	37
9	7a	HMPA, KClO4 (4 equiv.)^e	2 : 1	55
10	7b	HMPA LiClO4 (4 equiv.)	1.4 : 1^d	27

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The vinylalumination adducts, 11a and 12a, were methylated to give 13 and 14, respectively. The following cyclisation by RCM and the removal of the acid labile protecting groups by TFA gave pericosine B (2b) and C (2c).¹⁸ The NMR spectra and optical rotation values of the synthetic 2b and 2c were consistent with the reported data,^9b,5b which allowed us to confirm the stereochemical assignment of the vinylalumination adducts, 11a and 12a (Scheme 4).

Scheme 4 Synthesis of pericosine B and C.

Direct RCM of 11a gave the cyclohexenyl alcohol 17, and the following deprotection provided the tetraol 18, which was the key intermediate for the synthesis of pericosine A by Stevenson's group (Scheme 5).^9b

Scheme 5 Formal synthesis of pericosine A.

The stereochemistry of this vinylalumination merits further discussion. In the absence of LiClO₄, the addition of 1 to 7a gave the 3,4-anti11a as the major product. This result is consistent with previous reports, where the addition of lithium enolate or allyl zinc to 2-O-benzyl-3,4-O-isopropylidene-erythrose, a truncated stereochemical analogue of 7a, also gave the anti-adducts as the major product,¹⁹ in accord with the Felkin–Ahn model.²⁰ On the other hand, the formation of the 3,4-syn-adduct 12a from 7a is unusual.²¹ We propose that the excess amount of lithium or sodium cation enforced chelation control to generate the syn-adduct (Scheme 6) as the major product.²² However, the moderate diastereoselectivity (dr = 4) also suggested that the facial discrimination induced by this chelation control is mild. The insignificant effect of LiClO₄ on the reaction of the highly sterically demanding, TBS-protected 7b supports the explanation of chelation control (Table 1, entries 3 and 10).²³

Scheme 6 Chelation control for the formation of 11b.

Conclusions

Diastereoselective vinylalumination using α-substituted aldehydes was achieved to provide α-methylene-β-hydroxy-γ-alkoxy-esters, such as 11 and 12. Therefore, the vinylalumination could be an alternative and stereoselective method to generate the same adducts as the Morita–Baylis–Hillman reaction. The addition of alkali perchlorates allowed us to manipulate the ratio of the two diastereomers (the 3,4-anti versus 3,4-syn) from the original 4 : 1 to 1 : 4. Three further steps transformed the anti- and syn-adducts to the conduritols, pericosine B and C, respectively. Formal synthesis of pericosine A was also achieved via RCM and deprotection of the anti-adduct. Further study utilizing this stereoselective vinylalumination for natural product synthesis is ongoing.

Experimental section

tert-Butyl((R)-2-((4S,5S)-2,2-dimethyl-5-vinyl-1,3-dioxolan-4-yl)-2-((4-methoxybenzyl)oxy)ethoxy)dimethylsilane (5)

A solution of 4 (2.0 g, 6.62 mmol), 4-methoxybenzyl chloride (2.07 g, 13.24 mmol) and THF (5 mL) was added to the suspension of sodium hydride (0.63 g, 26.47 mmol) and THF (20 mL) 0 °C. The reaction mixture was stirred at rt for 20 h, quenched with sat. NH₄Cl_(aq) (2 mL), concentrated, diluted with water (30 mL) and extracted with ethyl acetate (25 mL × 3). The organic layers were combined, dried over Na₂SO₄, filtered and concentrated. The crude product was further purified by column chromatography (SiO₂, EtOAc–hexanes, 1 : 12; R_f 0.50) to give 5 (1.92 g, 4.56 mmol, 69%) as a colourless oil. [α]_D²⁰ −21.9 (c 0.69, CHCl₃); ¹H NMR (CDCl₃, 300 MHz) δ 0.07 (s, 6H), 0.91 (s, 9H), 1.33 (s, 3H), 1.46 (s, 3H), 3.46–3.52 (m, 1H), 3.71–3.77 (m, 1H), 3.78 (s, 3H), 3.99 (d, J = 11.1 Hz, 1H), 4.16–4.22 (m, 1H), 4.37 (d, J = 10.6 Hz, 1H), 4.65 (dt, J = 6.4 Hz, J = 0.9 Hz, 1H), 4.75 (d, J = 10.6 Hz, 1H), 5.22 (dd, J = 10.6 Hz, J = 1.5 Hz, 1H), 5.36 (dd, J = 17.1 Hz, J = 1.5 Hz, 1H), 5.93 (ddd, J = 6.7 Hz, J = 10.4 Hz, J = 18.2 Hz, 1H), 6.84 (d, J = 8.3 Hz, 2H), 7.23 (d, J = 8.3 Hz, 2H); ¹³C NMR (CDCl₃, 75 MHz) δ 159.1, 134.5, 130.7, 129.3, 117.0, 113.7, 108.4, 78.7, 78.2, 76.6, 71.7, 63.8, 55.2, 27.8, 25.9, 25.3, 18.3, −5.4; IR (neat): 2987, 2931, 2857, 1614, 1513, 1463, 1377, 1249, 1087, 1037, 836, 777 cm⁻¹; HRMS (ESI) calcd for [M + Na]⁺ (C₂₃H₃₈O₅SiNa) 445.2386, found 445.2384.

(R)-2-((4S,5S)-2,2-Dimethyl-5-vinyl-1,3-dioxolan-4-yl)-2-((4-methoxybenzyl)oxy)ethanol (6)

Tetrabutylammonium fluoride trihydrate (821 mg, 2.61 mmol) was added to the solution of 5 (1.0 g, 2.37 mmol) and THF (20 mL). The reaction mixture was stirred at rt for 2 h and concentrated. The crude product was further purified by column chromatography (SiO₂, EtOAc–hexanes, 1 : 2; R_f 0.30) to give 6 (599 mg, 1.95 mmol, 82%) as a colourless oil. [α]_D²⁰ −17.5 (c 1.2, CHCl₃); ¹H NMR (CDCl₃, 300 MHz) δ 1.35 (s, 3H), 1.46 (s, 3H), 2.08 (br, 1H), 3.46 (m, 1H), 3.78 (s, 3H), 3.80–3.88 (m, 2H), 4.24 (dd, J = 9.0 Hz, J = 8.7 Hz, 1H), 4.36 (d, J = 10.5 Hz, 1H), 4.47 (d, J = 10.5 Hz, 1H), 4.70 (dd, J = 6.4 Hz, J = 6.4 Hz, 1H), 5.25 (dd, J = 10.6 Hz, J = 1.4 Hz, 1H), 5.39 (dd, J = 17.1 Hz, J = 1.4 Hz, 1H), 5.91 (ddd, J = 6.5 Hz, J = 10.5 Hz, J = 17.0 Hz, 1H), 6.85 (d, J = 8.6 Hz, 2H), 7.21 (d, J = 8.6 Hz, 2H); ¹³C NMR (CDCl₃, 75 MHz) δ 159.4, 133.9, 129.9, 129.4, 117.2, 113.9, 108.6, 78.5, 77.4, 77.1, 71.0, 61.3, 55.3, 27.7, 25.3; IR (neat): 3471, 2987, 2935, 1612, 1513, 1461, 1378, 1249, 1072, 1035, 873, 823, 514 cm⁻¹. HRMS (MALDI) calcd for [M + Na]⁺ (C₁₇H₂₄O₅Na) 331.1522, found 331.1536.

(5R,6R)-8,8,9,9-Tetramethyl-5-((R)-oxiran-2-yl)-6-vinyl-2,4,7-trioxa-8-siladecane (7a)

Dimethyl sulfoxide (126 μL, 1.62 mmol) was added to the solution of oxalyl chloride (67 μL, 0.81 mmol) and dichloromethane (3 mL) at −78 °C. The reaction mixture was stirred at −78 °C for 30 min, then added to a solution of 6 (100 mg, 0.324 mmol) and dichloromethane (0.5 mL), stirred for another 40 min at −78 °C and added with triethylamine (489 μL). The mixture was warmed up to rt, diluted with CH₂Cl₂ (25 mL) and washed with water (5 mL × 3). The organic layer was separated, dried over Na₂SO₄, filtered and concentrated. The crude product was further purified by column chromatography (SiO₂, EtOAc–hexanes, 1 : 2; R_f 0.60) to give 7a (80 mg, 0.26 mmol, 80%) as a light yellow oil. [α]_D²⁰ 13.3 (c 0.87, CHCl₃); ¹H NMR (CDCl₃, 300 MHz) δ 1.33 (s, 3H), 1.47 (s, 3H), 3.74 (dd, J = 7.8 Hz, J = 2.8 Hz, 1H), 3.78 (s, 3H), 4.32–4.37 (m, 2H), 4.45 (d, J = 10.5 Hz, 1H), 4.72 (t, J = 6.2 Hz, J = 6.2 Hz, 1H), 5.25 (dd, J = 10.5 Hz, J = 1.4 Hz, 1H), 5.42 (dd, J = 17.1 Hz, J = 1.4 Hz, 1H), 5.89 (ddd, J = 6.2 Hz, J = 10.6 Hz, J = 16.9 Hz, 1H), 6.85 (d, J = 8.6 Hz, 2H), 7.23 (d, J = 8.4 Hz, 2H), 9.61 (d, J = 2.8 Hz, 1H); ¹³C NMR (CDCl₃, 75 MHz) δ 200.9, 159.6, 132.7, 130.1, 128.9, 118.0, 113.9, 109.6, 81.5, 78.3, 77.0, 72.4, 55.3, 27.4, 25.2; IR (neat): 2987, 2935, 2838, 1733, 1610, 1513, 1461, 1378, 1251, 1074, 1035, 871, 825, 514 cm⁻¹. HRMS (MALDI) calcd for [M + Na]⁺ (C₁₇H₂₂O₅Na) 329.1365, found 329.1552.

(R)-2-((tert-Butyldimethylsilyl)oxy)-2-((4S,5S)-2,2-dimethyl-5-vinyl-1,3-dioxolan-4-yl)ethyl pivalate (9)

Tert-butyldimethylsilyl chloride (872 mg, 5.78 mmol) was added to the solution of 8²⁴ (1.05 g, 3.85 mmol), imidazole (393 mg, 5.78 mmol), 4-(dimethylamino)pyridine (47 mg, 0.38 mmol) and dichloromethane (25 mL). The reaction mixture was stirred at 40 °C for 14 h and concentrated. The crude product was further purified by column chromatography (SiO₂, EtOAc–hexanes, 1 : 9; R_f 0.70) to give 9 (1.12 g, 2.89 mmol, 75%) as a colourless liquid. [α]_D²⁰ −10.75 (c 0.9, CHCl₃); ¹H NMR (CDCl₃, 300 MHz) δ 0.03 (s, 3H), 0.04 (s, 3H), 0.84 (s, 9H), 1.19 (s, 9H), 1.31 (s, 3H), 1.42 (s, 3H), 3.91 (m, 1H), 4.07–4.21 (m, 3H), 4.57 (t, J = 6.9 Hz, J = 6.9 Hz, 1H), 5.22 (d, J = 10.4 Hz, 1H), 5.34 (d, J = 17.1 Hz, 1H), 5.92 (ddd, J = 7.5 Hz, J = 10.2 Hz, J = 17.4 Hz, 1H); ¹³C NMR (CDCl₃, 75 MHz) δ 178.3, 134.3, 118.3, 108.4, 78.7, 77.8, 69.4, 66.1, 38.9, 27.8, 27.2, 25.8, 25.3, 18.0, −3.9, −4.6. HRMS (ESI) calcd for [M + Na]⁺ (C₂₀H₃₈O₅SiNa) 409.2386, found 409.2393.

(R)-2-((tert-Butyldimethylsilyl)oxy)-2-((4S,5S)-2,2-dimethyl-5-vinyl-1,3-dioxolan-4-yl)ethanol (10)

Diisobutylaluminium hydride (1.1 M in cyclohexane, 2.93 mL, 3.23 mmol) was added dropwise to the solution of 9 (500 mg, 1.29 mmol) and dichloromethane (20 mL) at −78 °C. The reaction mixture was stirred at −78 °C for another 2 h, warmed up to rt, quenched with methanol (3 mL) and citric acid_(aq) (w/w, 10%, 5 mL), concentrated. The residue was added with water (10 mL) and extracted with dichloromethane (12 mL × 3). The organic layers were combined, dried over Na₂SO₄, filtered and concentrated. The crude product was further purified by column chromatography (SiO₂, EtOAc–hexanes, 1 : 7; R_f 0.33) to give 10 (308 mg, 1.02 mmol, 79%) as a colourless liquid. [α]_D²⁰ −24.2 (c 1.1, CHCl₃); ¹H NMR (CDCl₃, 300 MHz) δ 0.04 (s, 3H), 0.07 (s, 3H), 0.85 (s, 9H), 1.34 (s, 3H), 1.44 (s, 3H), 2.16 (br, 1H), 3.68–3.81 (m, 3H), 4.16 (t, J = 13.8 Hz, J = 13.8 Hz, 1H), 4.59 (t, J = 6.6 Hz, J = 6.6 Hz, 1H), 5.22 (d, J = 10.7 Hz, 1H), 5.34 (d, J = 17.1 Hz, 1H), 5.90 (ddd, J = 7.2 Hz, J = 10.2 Hz, J = 17.2 Hz, 1H); ¹³C NMR (CDCl₃, 75 MHz) δ 134.1, 118.4, 108.5, 79.5, 78.8, 70.8, 65.0, 27.8, 25.9, 25.4, 18.1, −3.7, −4.4. HRMS (ESI) calcd for [M + Na]⁺ (C₁₅H₃₀O₄SiNa) 325.1811, found 325.1807.

(S)-2-((tert-Butyldimethylsilyl)oxy)-2-((4S,5S)-2,2-dimethyl-5-vinyl-1,3-dioxolan-4-yl)acetaldehyde (7b)

Dimethyl sulfoxide (89 μL, 1.15 mmol) was added to the solution of oxalyl chloride (47 μL, 0.58 mmol) and dichloromethane (3 mL) at −78 °C. The reaction mixture was stirred at −78 °C for 30 min, then added with a solution of 10 (87 mg, 0.29 mmol) and dichloromethane (0.5 mL), stirred for another 40 min at −78 °C and added with triethylamine (400 μL). The mixture was warmed up to rt, diluted with CH₂Cl₂ (20 mL) and washed with water (5 mL × 3). The organic layer was separated, dried over Na₂SO₄, filtered and concentrated. The crude product was further purified by column chromatography (SiO₂, EtOAc–hexanes, 1 : 7; R_f 0.65) to give 7b (77 mg, 0.26 mmol, 90%) as a colourless oil. [α]_D²⁰ 0.5 (c 0.6, CHCl₃); ¹H NMR (CDCl₃, 300 MHz) δ 0.03 (s, 3H), 0.07 (s, 3H), 0.88 (s, 9H), 1.31 (s, 3H), 1.45 (s, 3H), 4.08 (m, 1H), 4.35 (t, J = 6.8 Hz, J = 6.8 Hz, 1H), 4.64 (t, J = 6.8 Hz, J = 6.8 Hz, 1H), 5.23 (dd, J = 10.4 Hz, J = 1.2 Hz, 1H), 5.32 (dd, J = 17.2 Hz, J = 1.2 Hz, 1H), 5.98 (ddd, J = 7.3 Hz, J = 10.2 Hz, J = 17.4 Hz, 1H), 9.57 (s, 1H); ¹³C NMR (CDCl₃, 75 MHz) δ 201.8, 134.0, 119.2, 109.2, 79.3, 78.6, 76.7, 27.1, 25.8, 24.9, 18.1, −4.3, −4.7. HRMS (ESI) calcd for [M + H]⁺ (C₁₅H₂₉O₄Si) 301.1835, found 301.1831.

General procedure for the vinylalumination of aldehydes

Methyl propiolate (204 μL, 3.23 mmol) was added to the solution of diisobutylaluminum hydride (1.1 M in cyclohexane, 2.67 mL, 2.94 mmol), HMPA (766 μL, 4.41 mmol) and THF 10 mL at 0 °C. After being stirred at 0 °C for 1 h, the reaction mixture became a yellow solution and was warmed up to rt in 20 min. A solution of 7a (300 mg, 0.98 mmol) and THF (4 mL) was added to the above solution of [α-(methoxycarbonyl)vinyl]diisobutylaluminum (1a). The resulting mixture was stirred for another 14 h at rt, quenched with methanol (3 mL), added with citric acid_(aq) (10%, w/w), stirred for 3 min, concentrated to remove THF and extracted with diethyl ether (10 mL × 3). The organic layers were separated, dried over Na₂SO₄, filtered and concentrated. The crude product was further purified by column chromatography (SiO₂, EtOAc–hexanes, 1 : 3; 11a, R_f 0.30; 12a, R_f 0.25) to give 11a (184 mg, 0.47 mmol, 49%) and 12a (46.3 mg, 0.12 mmol, 12%) as colourless oils.

11a . [α]_D²⁰ −26.9 (c 1.02, CHCl₃); ¹H NMR (CDCl₃, 300 MHz) δ 1.29 (s, 3H), 1.43 (s, 3H), 3.67 (s, 3H), 3.77 (s, 3H), 3.78–3.82 (m, 1H), 4.14 (dd, J = 8.0 Hz, J = 6.7 Hz, 1H), 4.42 (d, J = 10.5 Hz, 1H), 4.60–4.64 (m, 2H), 4.78 (dd, J = 5.1 Hz, J = 3.9 Hz, 1H), 5.24 (dd, J = 10.9 Hz, J = 1.2 Hz, 1H), 5.34 (dd, J = 17.2 Hz, J = 1.2 Hz, 1H), 5.90–6.02 (m, 2H), 6.24 (d, J = 0.9 Hz, 1H), 6.83 (d, J = 8.7 Hz, 2H), 7.17 (d, J = 8.7 Hz, 2H); ¹³C NMR (CDCl₃, 75 MHz) δ 167.6, 159.2, 138.3, 134.7, 130.1, 129.4, 126.3, 117.7, 113.7, 108.6, 79.6, 79.1, 77.4, 72.9, 72.8, 55.3, 51.8, 27.9, 25.3; IR (neat): 3482, 2987, 2937, 1718, 1614, 1513, 1440, 1378, 1249, 1079, 1035, 871, 819, 516 cm⁻¹; HRMS (MALDI) calcd for [M + Na]⁺ (C₂₁H₂₈O₇Na) 415.1733, found 415.1744.

12a . [α]_D²⁰ −26.51 (c 1.2, CHCl₃); ¹H NMR (CDCl₃, 300 MHz) δ 1.36 (s, 3H), 1.54 (s, 3H), 3.06 (br, 1H, OH), 3.72 (s, 3H), 3.77 (s, 3H), 3.78 (m, 1H), 4.23 (dd, J = 8.7 Hz, J = 6.0 Hz, 1H), 4.32 (d, J = 9.9 Hz, 1H), 4.42 (d, J = 9.9 Hz, 1H), 4.69 (t, J = 6.1 Hz, J = 6.1 Hz, 1H), 4.94 (d, J = 1.3 Hz, 1H), 5.25 (dd, J = 10.6 Hz, J = 1.5 Hz, 1H), 5.40 (dd, J = 17.2 Hz, J = 1.5 Hz, 1H), 5.89–5.98 (m, 1H), 6.00 (t, J = 1.3 Hz, J = 1.3 Hz, 1H), 6.34 (t, J = 1.3 Hz, 1H), 6.82 (d, J = 8.7 Hz, 2H), 7.12 (d, J = 8.7 Hz, 2H); ¹³C NMR (CDCl₃, 75 MHz) δ 166.7, 159.3, 141.4, 133.8, 129.8, 129.4, 125.6, 117.3, 113.8, 108.9, 78.6, 77.2, 72.8, 72.5, 69.3, 55.3, 51.9, 27.8, 25.5; IR (neat): 3498, 2989, 2950, 1720, 1612, 1513, 1440, 1378, 1249, 1179, 1079, 1035, 871, 821, 514 cm⁻¹; HRMS (ESI) calcd for [M + Na]⁺ (C₂₁H₂₈O₇Na) 415.1733, found 415.1731.

General procedure for the vinylalumination of aldehydes with alkali perchlorates

The premixed solution of 7a (300 mg, 0.98 mmol), lithium perchlorate (417 mg, 3.92 mmol, 4 equiv.) and THF (6 mL) was added to the solution of 1a, prepared from methyl propiolate (272 μL, 4.31 mmol), DIBALH (1.1 M in cyclohexane, 3.56 mL, 3.92 mmol), HMPA (1.02 mL, 5.88 mmol) and THF (12 mL), as describe above. The reaction mixture was stirred at rt for 14 h, and the same work-up procedure was followed to give 11a (77 mg, 0.19 mmol, 20%) and 12a (154 mg, 0.39 mmol, 40%).

11b and 12b. The procedure used to prepare 11a and 12a was followed. Starting with 7b (294 mg, 0.98 mmol), methyl propiolate (204 μL, 3.23 mmol), HMPA (766 μL, 4.41 mmol) and diisobutylaluminium hydride (1.1 M in cyclohexane, 2.67 mL, 2.94 mmol), the inseparable mixture of 11b and 12b (106 mg, 0.27 mmol, 28%) was produced after column chromatography (SiO₂, EtOAc–hexanes, 1 : 8; R_f 0.45) as a colourless oil. HRMS (ESI) calcd for [M + H]⁺ (C₁₉H₃₅O₆Si) 387.2197, found 387.2200.

(3R,4R)-Methyl 4-((4S,5S)-2,2-dimethyl-5-vinyl-1,3-dioxolan-4-yl)-3-methoxy-4-((4-methoxybenzyl)oxy)-2-methylenebutanoate (13)

A solution of 11a (50 mg, 0.13 mmol), iodomethane (25 μL, 0.38 mmol) and THF (1 mL) was added to the suspension of potassium hydride (15 mg, 0.38 mmol) and THF (2.5 mL) at 0 °C. The reaction mixture was stirred for another 20 min, quenched with sat. NH₄Cl_(aq) (7 mL), concentrated to remove THF and extracted with ethyl acetate (5 mL × 3). The combined organic layers were dried over Na₂SO₄, filtered and concentrated. The crude product was further purified by column chromatography (SiO₂, EtOAc–hexanes, 1 : 3; R_f 0.50) to give 13 (32 mg, 0.079 mmol, 62%) as a colourless oil. [α]_D²⁰ −16.6 (c 0.7, CHCl₃); ¹H NMR (CDCl₃, 300 MHz) δ 1.30 (s, 3H), 1.43 (s, 3H), 3.32 (s, 3H), 3.67–3.71 (m, 1H), 3.68 (s, 3H), 3.77 (s, 3H), 4.17 (dd, J = 8.6 Hz, J = 6.2 Hz, 1H), 4.36 (d, J = 10.5 Hz, 1H), 4.50 (d, J = 2.4 Hz, 1H), 4.59 (t, J = 6.5 Hz, J = 6.5 Hz, 1H), 4.65 (d, J = 10.5 Hz, 1H), 5.19 (ddd, J = 10.4 Hz, J = 1.8 Hz, J = 1.5 Hz, 1H), 5.33 (ddd, J = 17.2 Hz, J = 1.8 Hz, J = 1.5 Hz, 1H), 5.89–6.01 (m, 2H), 6.36 (d, J = 1.4 Hz, 1H), 6.81 (d, J = 8.7 Hz, 2H), 7.17 (d, J = 8.7 Hz, 2H); ¹³C NMR (CDCl₃, 75 MHz) δ 167.2, 159.1, 137.4, 134.6, 130.5, 129.4, 126.9, 116.9, 113.6, 108.4, 80.8, 79.4, 78.9, 77.19, 72.7, 57.7, 55.3, 51.7, 27.9, 25.4; IR (neat): 2987, 2935, 1718, 1612, 1513, 1440, 1371, 1247, 1081, 1035, 873, 821, 514 cm⁻¹; HRMS (ESI) calcd for [M + Na]⁺ (C₂₂H₃₀O₇Na) 429.1889, found 429.1888.

(3S,4R)-Methyl 4-((4S,5S)-2,2-dimethyl-5-vinyl-1,3-dioxolan-4-yl)-3-methoxy-4-((4-methoxybenzyl)oxy)-2-methylenebutanoate (14)

The procedure used to prepare 13 was followed. Starting with 12a (50 mg, 0.13 mmol), iodomethane (25 μL, 0.38 mmol) and potassium hydride (15 mg, 0.38 mmol), compound 14 (32 mg, 0.079 mmol, 62%) was produced after column chromatography (SiO₂, EtOAc–hexanes, 1 : 3; R_f 0.40) as a colourless oil. [α]_D²⁰ −30.3 (c 0.55, CHCl₃); ¹H NMR (CDCl₃, 300 MHz) δ 1.36 (s, 3H), 1.51 (s, 3H), 3.32 (s, 3H), 3.67–3.71 (m, 1H), 3.75 (s, 3H), 3.78 (s, 3H), 4.27–4.40 (m, 4H), 4.66 (t, J = 6.6 Hz, J = 6.6 Hz, 1H), 5.21 (dd, J = 10.6 Hz, J = 1.5 Hz, 1H), 5.37 (dd, J = 17.1 Hz, J = 1.5 Hz, 1H), 5.96 (ddd, J = 6.6 Hz, J = 10.5 Hz, J = 17.1 Hz, 1H), 6.06 (d, J = 1.1 Hz, 1H), 6.42 (d, J = 1.1 Hz, 1H), 6.78 (d, J = 8.6 Hz, 2H), 7.09 (d, J = 8.6 Hz, 2H); ¹³C NMR (CDCl₃, 75 MHz) δ 166.8, 159.1, 137.3, 134.3, 130.3, 129.1, 127.2, 117.1, 113.6, 108.4, 79.6, 78.7, 77.6, 77.4, 72.3, 57.9, 55.3, 51.9, 28.1, 25.8; IR (neat): 2987, 2935, 1722, 1612, 1513, 1440, 1378, 1249, 1087, 1035, 873, 821, 514 cm⁻¹; HRMS (FAB) calcd for [M + H]⁺ (C₂₂H₃₁O₇) 407.2070, found 407.2068.

(3aS,6R,7R,7aS)-Methyl 6-methoxy-7-((4-methoxybenzyl)oxy)-2,2-dimethyl-3a,6,7,7a-tetrahydrobenzo[d][1,3]dioxole-5-carboxylate (15)

The second generation Grubbs catalyst (10.4 mg, 0.012 mmol) was added to the solution of 13 (50 mg, 0.12 mmol) and toluene (12.8 mL), and the resulting solution was refluxed for 14 h under an atmosphere of nitrogen and concentrated. The crude product was further purified by column chromatography (SiO₂, EtOAc–hexanes, 1 : 2; R_f 0.35) to give 15 (32.3 mg, 0.088 mmol, 74%) as a light brown oil. [α]_D²⁰ −45.5 (c 0.65, CHCl₃); ¹H NMR (CDCl₃, 300 MHz) δ 1.35 (s, 3H), 1.39 (s, 3H), 3.47 (dd, J = 4.4 Hz, J = 2.6 Hz, 1H), 3.67 (s, 3H), 3.77 (s, 3H), 3.78 (s, 3H), 4.34 (d, J = 4.4 Hz, 1H), 4.47–4.56 (m, 2H), 4.69 (d, J = 12.3 Hz, 1H), 4.71 (d, J = 12.3 Hz, 1H), 6.71 (d, J = 3.2 Hz, 1H), 6.86 (d, J = 8.6 Hz, 2H), 7.31 (d, J = 8.6 Hz, 2H); ¹³C NMR (CDCl₃, 75 MHz) δ 166.6, 159.4, 137.1, 130.2, 129.8, 129.5, 113.9, 111.5, 73.9, 72.9, 72.8, 71.2, 70.6, 61.3, 55.3, 52.2, 27.9, 26.2; IR (neat): 2933, 1720, 1614, 1513, 1440, 1376, 1249, 1052, 825, 511, 412 cm⁻¹; HRMS (ESI) calcd for [M + Na]⁺ (C₂₀H₂₆O₇Na) 401.1576, found 401.1581.

(3aS,6S,7R,7aS)-Methyl 6-methoxy-7-((4-methoxybenzyl)oxy)-2,2-dimethyl-3a,6,7,7a-tetrahydrobenzo[d][1,3]dioxole-5-carboxylate (16)

The procedure used to prepare 15 was followed. Starting with 14 (50 mg, 0.12 mmol) and the second generation Grubbs catalyst (10.4 mg, 0.012 mmol), compound 16 (31.5 mg, 0.088 mmol, 73%) was produced after column chromatography (SiO₂, EtOAc–hexanes, 1 : 2; R_f 0.45) as a light brown oil. [α]_D²⁰ 44.45 (c 0.8, CHCl₃); ¹H NMR (CDCl₃, 300 MHz) δ 1.36 (s, 3H), 1.40 (s, 3H), 3.44 (s, 3H), 3.74 (m, 1H), 3.76 (s, 3H), 3.78 (s, 3H), 4.26 (d, J = 6.2 Hz, 1H), 4.42 (dd, J = 5.8 Hz, J = 3.1 Hz, 1H), 4.59–4.64 (m, 2H), 4.70 (d, J = 12.0 Hz, 1H), 6.70 (d, J = 3.0 Hz, 1H), 6.85 (d, J = 8.7 Hz, 2H), 7.28 (d, J = 8.7 Hz, 2H); ¹³C NMR (CDCl₃, 75 MHz) δ 166.7, 159.3, 135.9, 132.4, 130.1, 129.7, 113.8, 110.3, 75.4, 75.2, 73.9, 72.7, 71.8, 59.8, 55.3, 52.0, 27.1, 25.9; IR (neat): 2985, 2933, 1722, 1612, 1513, 1438, 1375, 1249, 1097, 1033, 858, 821, 516 cm⁻¹; HRMS (ESI) calcd for [M + Na]⁺ (C₂₀H₂₆O₇Na) 401.1576, found 401.1568.

Pericosine B (2b)

Trifluoroacetic acid (1.7 mL) was added to the solution of 15 (20 mg, 0.055 mmol) and methanol (0.66 mL) at 0 °C. The reaction mixture was stirred at rt for 5 h and concentrated. The crude product was further purified by column chromatography (SiO₂, methanol–ethyl acetate, 1 : 4; R_f 0.45) to give 2b (8.9 mg, 0.041 mmol, 74%) as a colourless, viscous oil. [α]_D²⁰ 24.4 (c 0.65, EtOH); ¹H NMR (acetone-d₆/D₂O, 300 MHz) δ 3.56 (s, 3H), 3.76 (s, 3H), 3.83 (dd, J = 2.0 Hz, J = 4.4 Hz, 1H), 3.99 (m, 1H) 4.22 (m, 1H), 6.71 (dd, J = 2.2 Hz, J = 1.3 Hz, 1H); ¹³C NMR (acetone-d₆, 75 MHz) δ 166.6, 141.7, 130.6, 76.8, 72.4, 69.8, 69.1, 61.4, 52.2; IR (neat): 3421, 2940, 1712, 1438, 1259, 1201, 1070 cm⁻¹; HRMS (ESI) calcd for [M + Na]⁺ (C₉H₁₄O₆Na) 241.0688, found 241.0683.

Pericosine C (2c)

The procedure used to prepare 2b was followed. Starting with 16 (20 mg, 0.055 mmol) and trifluoroacetic acid (1.7 mL), compound 2c (9.1 mg, 0.042 mmol, 76%) was produced after column chromatography (SiO₂, methanol–ethyl acetate, 1 : 4; R_f 0.45) as a colourless, viscous oil. [α]_D²⁰ 82.1 (c 0.5, EtOH); ¹H NMR (acetone-d₆/D₂O, 300 MHz) δ 3.45 (s, 3H), 3.72 (s, 3H), 3.88 (m, 1H), 3.93 (dd, J = 4.8 Hz, J = 2.1 Hz, 1H), 4.17 (d, J = 4.8 Hz, 1H), 4.23 (t, J = 3.3 Hz, J = 3.3 Hz, 1H), 6.70 (d, J = 3.8 Hz, 1H); ¹³C NMR (acetone-d₆, 75 MHz) δ 167.8, 140.7, 131.4, 79.0, 73.0, 70.4, 67.4, 59.5, 52.2; IR (neat): 3428, 2921, 1712,1648, 1440, 1272, 1070 cm⁻¹; HRMS (ESI) calcd for [M + Na]⁺ (C₉H₁₄O₆Na) 241.0688, found 241.0686.

(3aS,6R,7R,7aS)-Methyl 6-hydroxy-7-((4-methoxybenzyl)oxy)-2,2-dimethyl-3a,6,7,7a-tetrahydrobenzo[d][1,3]dioxole-5-carboxylate (17)

The procedure used to prepare 15 was followed. Starting with 11a (50 mg, 0.13 mmol) and the second generation Grubbs catalyst (11.0 mg, 0.013 mmol), compound 17 (35.6 mg, 0.098 mmol, 77%) was produced after column chromatography (SiO₂, EtOAc–hexanes, 1 : 2; R_f 0.25) as a light brown oil. [α]_D²⁰ −38.78 (c 0.75, CHCl₃); ¹H NMR (CDCl₃, 300 MHz) δ 1.35 (s, 3H), 1.40 (s, 3H), 3.42 (d, J = 10.2 Hz, 1H), 3.53 (dd, J = 4.3 Hz, J = 2.0 Hz, 1H), 3.78 (s, 3H), 3.80 (s, 3H), 4.53–4.65 (m, 3H), 4.81 (m, 1H), 4.87 (d, J = 11.9 Hz, 1H), 6.73 (dd, J = 3.1 Hz, J = 1.1 Hz, 1H), 6.86 (d, J = 8.6 Hz, 2H), 7.32 (d, J = 8.6 Hz, 2H); ¹³C NMR (CDCl₃, 75 MHz) δ 166.1, 159.5, 135.8, 131.8, 129.8, 129.3, 113.9, 111.5, 75.7, 73.3, 71.8, 69.7, 62.1, 55.3, 52.4, 28.1, 26.4; IR (neat): 3318, 2935, 1722, 1612, 1513, 1438, 1375, 1249, 1106, 1051, 827, 518 cm⁻¹; HRMS (MALDI) calcd for [M + Na]⁺ (C₁₉H₂₄O₇Na) 387.1420, found 387.1431.

(3S,4S,5R,6R)-Methyl 3,4,5,6-tetrahydroxycyclohex-1-enecarboxylate (18)

Trifluoroacetic acid (1.7 mL) was added to the solution of 17 (20 mg, 0.055 mmol) and methanol (0.66 mL) at 0 °C. The reaction mixture was stirred at rt for 5 h and concentrated. The crude product was further purified by column chromatography (SiO₂, methanol–ethyl acetate, 1 : 4; R_f 0.35) to give 18 (7.7 mg, 0.038 mmol, 76%) as a colourless oil. ¹H NMR (D₂O, 300 MHz) δ 3.84 (dd, J = 4.6 Hz, J = 1.8 Hz, 1H), 3.87 (s, 3H), 4.20 (d, J = 3.8 Hz, 1H), 4.49 (m, 1H), 4.62 (m, 1H), 6.92 (t, J = 1.7 Hz, J = 1.7 Hz, 1H); ¹³C NMR (D₂O, 75 MHz) δ 168.0, 141.1, 131.0, 71.5, 67.9, 65.2, 52.7.^9b

Acknowledgements

This research was supported by the National Science Council (NSC 101-2113-M-008-002), Taiwan. We are grateful to Ms Ping-Yu Lin at the Institute of Chemistry, Academia Sinica, and Valuable Instrument Center in National Central University for obtaining mass analysis.

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Footnote

† Electronic supplementary information (ESI) available: Copies of the ¹H NMR and ¹³C NMR spectra for the new compounds. See DOI: 10.1039/c3ra45871g

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