Palladium catalyzed allylic substitution for the

ASIAN JOURNAL OF ORGANIC CHEMISTRY www.asianjoc.org

Accepted Article Title: Palladium catalyzed allylic substitution for the synthesis of pericosines

Authors: Duen-Ren Hou; Cheng-Yu Chung; Venkatachalam Angamuthu; LongShiang Li

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To be cited as: Asian J. Org. Chem. 10.1002/ajoc.201600355 Link to VoR: http://dx.doi.org/10.1002/ajoc.201600355

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10.1002/ajoc.201600355

FULL PAPER Palladium catalyzed allylic substitution for the synthesis of pericosines

Abstract: A sequence of vinylalumination of α-substituted aldehydes, ring-closing metathesis (RCM) and palladium catalyzed allylic substitution was utilized to prepare the biologically active natural products, pericosines, from D-ribose. The anti-adduct of vinylalumination was transformed into pericosine A after RCM, removal of the 4-methoxybenzyl protecting group and chlorination. The di-acetate of the anti-adduct was converted to pericosine C after the palladium catalyzed, SN2′-type, allylic substitution. However, an unexpected dimeric product was generated in utilizing this approach to prepare pericosine E.

Introduction Marine natural products play an important role in the process of drug discovery and development.1 For example, natural products with the structural feature of carbasugars exhibit biological activities including glycosidase inhibition, antitumor, antiviral, antifungal, antibacterial, and antimalarial activities. 2 Therefore, the synthesis of carbasugars has received considerable attention from organic chemists. The pericosines A-E are one type of carbasugars. They are cytotoxic metabolites isolated from the fungus Periconia byssoides OUPS-N133, collected from the sea hare Aplysia kurodai and first reported in 1997 (Figure 1).3 Their biological activities include growth inhibition against the murine P 388 cell lines, human cancer cell lines HBC-5 and SNB-75, inhibition of protein kinase EGFR and human topoisomerase II.3b-c,4

Figure 1. Structure of naturally occurring pericosines.

There has been considerable interest in the synthesis of pericosines and their derivatives.5-8 Many of the reported approaches started with plant-derived natural products or metabolites from microorganisms, such as shikimic acid, quinic acid and 3,5-cyclohexadiene-cis-1,2-diols.6-8 Although shikimic acid and quinic acid possess the appropriate stereocenters for the synthesis, their high cost and limited availability may limit their further development.9 On the other hand, culturing microorganisms and isolating the key metabolites requires synthetic chemists to acquire additional facilities and skills. Inexpensive, readily available starting materials and usual operations to prepare these carbasugars are desired. For example, the use of ring closing metathesis (RCM) to generate the cyclitol skeletons of pericosines has been explored by several groups.10 The required 1,7-dienes for RCM have been prepared by the Nozaki–Hiyama–Kishi (NHK) reaction11,12 or Morita–Baylis–Hillman (MBH) reactions.13 Recently, our group reported the utilization the vinylalumination of an optical active aldehyde to generate the 1,7-dienes and the following RCM to construct the cyclitol skeletons.14a Here, we present our progress with this approach in the preparation of (+)-pericosine A, and the combination of the vinylalumination and palladium catalyzed allylic substitution to prepare (‒)-pericosine C from inexpensive D-ribose. Our attempt to synthesize pericosine E, which led to an unexpected dimeric compound, is also reported.

Results and Discussion

[a]

C.-Y. Chung, V. Angamuthu, L.-S. Li and D.-R. Hou Department of Chemistry National Central University 300 Jhong-Da Rd, Jhong-Li, Taoyuan, Taiwan 32001 E-mail: [email protected]

Retrosynthetic analysis of the pericosines is shown in Scheme 1, which indicates that cyclitol 1 is the key intermediate. Further manipulations to the allylic alcohol, such as SN2, SN2′ or palladium catalyzed substitution reactions, could lead to the target pericosine A, C and E. Cyclitol 1 could be obtained from the RCM reaction of the 1,7-diene 3, derived from the vinylalumination of the aldehyde 5. The required aldehyde 5 could be prepared from a one carbon homologation of D-ribose (6).

Supporting information for this article is given via a link at the end of the document.

This article is protected by copyright. All rights reserved

Accepted Manuscript

Cheng-Yu Chung,[a] Venkatachalam Angamuthu,[a] Long-Shiang Li,[a] and Duen-Ren Hou*[a]


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Scheme 1. Retrosynthetic analysis of pericosine A, C and E.

The conventional condition to remove the PMB protecting group (DDQ in dichloromethane-water) was complicated by the migration of the resulting para-methoxybenzoyl group (compound 8, 50%). This issue was resolved by performing the reaction in a mixed solvent of CH2Cl2-methanol (3:1) to give the desired diol 7. The Mattocks’ procedure was applied to convert the diol 7 to the chloro-acetate 9 via a SN2 reaction pathway.16 Acidic hydrolysis of 9 gave (+)-pericosine A,17 whose spectroscopic data were consistent with the reported values. 5a,6b Thus, the stereochemistry of the vinylalumination was confirmed and in accord with the Felkin-Anh model during the addition of the vinyl group to the carbonyl group. The synthesis of (‒)-pericosine C is shown in Scheme 3. Vicinal diol 7 was converted to the diacetate 11 with a good yield. Here, we attempted to utilize the palladium catalyzed allylic substitution reaction18 to replace the allyl acetate to the methoxy group. The desired compound 12 was produced in 50% yield after optimizing the reaction conditions, such as the catalysts, solvents and reaction time (supporting information). The stereochemistry of 12 was validated after the removal of the acetonide group to provide (-)-pericosine C.

The synthesis of (+)-pericosine A is shown in Scheme 2. Vinylalumination of the α-substituted aldehyde 5, which was derived from D-ribose in six steps,14a-b gave 3 as the major product with a diastereomeric ratio of 4:1. Although several reaction conditions were screened to improve the diastereoselectivity, only a modest ratio was obtained. The compound 3 was subjected to ring closing metathesis using Grubbs second generation catalyst in toluene at reflux to give the cyclitol 1.15 Scheme 3. Synthesis of (‒)-pericosine C.

On the basis of the obtained product 12 and the precedent work on palladium-catalyzed reactions,18 the plausible mechanism for this palladium catalyzed allyllic substitution reaction is illustrated in Scheme 4. The palladium allyl complex A was generated through the SN2 type, oxidative addition of tetrakis(triphenylphosphine)palladium to 11. Under a basic environment, the ligand exchange between methoxide anion and acetate yielded the Pd intermediate B, which underwent the regio-selective, reductive elimination to give C. Further hydrolysis of the remaining acetyl group gave the product 12. Therefore, the overall process is equal to a SN2′ substitution reaction of allylic acetate 11 with the stereochemistry of inversion.

Scheme 2. Synthesis of pericosine A.


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Scheme 4. Plausible mechanism for the formation of 12.

Although pericosine A is optically active in nature, pericosine E is known to be a racemic mixture. This observation and our experience in the synthesis of pericosine C, prompted us to explore the SN2′ type reaction for the synthesis of pericosine E. Several possible processes leading to the dimer-like products were proposed (Scheme 5) and the corresponding building block 14 was prepared (Scheme 6), in addition to 9 and 10.

two cyclitol derivatives. One interesting product 15 was isolated in 38% yield when Pd(PPh3)2Cl2 was the catalyst (Scheme 7). The structure of 15 was established on the basis of NMR spectroscopies. In 13C NMR, compound 15 showed two ester carbons around δ 165 and a new absorption at δ 195.8, which suggested a ketone moiety and that 15 could be a dimer of 14. The DEPT spectra indicated that there are 9 methine carbons and 6 methyl carbons and no methylene carbon within 15. In 1H NMR, the presence of the six methyl absorptions due to the two methyl esters and the two acteonides reconfirmed its dimeric structure. The absorptions at δ 6.68 and 6.98 were attributed to the two olefinic hydrogens. The absorption at δ 2.74 was assigned as the hydroxyl proton after the D 2O test and coupled with a methine hydrogen in the 1H-1H COSY. The five relatively downfielded protons, located in the region of δ 4.404.70, were assigned to the oxygen-attached methine groups. The remaining two protons at δ 3.35 and 3.08, also coupled to each other, should belong to the two methines connecting the two cyclohexene rings. The stereochemistry of 15 was later established with its benzoylated derivative 16, whose 3J1H-1H coupling constants were thoroughly deduced (Figure 2). All the cis-vicinal hydrogens have a 3J1H-1H around 5 Hz. In contrast, the corresponding values for the trans-vicinal hydrogens are less than 2 Hz. More importantly, the stereochemistry of the ring A was confirmed by the observed 3J1H-1H of the C3-H and C4-H, 1.9 Hz, which is very similar to the corresponding value of the reported compound 17.6b The IR, COSY, HMQC, and the analysis of high-resolution mass spectrometry were consistent with the proposed structures of 15 and 16.19 The proposed reaction mechanism for the formation of the dimeric product 15 is shown in Scheme 8. Under the basic condition, the palladium assisted elimination of 14 produced the enol/enolate, which was the nucleophile for the palladium allyl complex to give the inversed, SN2′ type product, same as the reaction shown in Scheme 4. We noticed that no reaction occurred in the absence of the Pd catalyst.

Scheme 5. Synthetic design of pericosine E.

Scheme 6. Preparation of the synthetic block 14.

Scheme 7. Synthesis leading to the dimeric product 15 and its derivative 16.

Unfortunately, these attempts to prepare pericosine E were unsuccessful in spite of numerous trials intended to couple the


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3

Figure 2. J1H-1H conpling constants of 16 and the reported value of 17.

Scheme 8. Proposed mechanism for the formation of 15.

Conclusions In summary, we have developed a new and efficient route for the synthesis of pericosines from the common intermediate 7, which was prepared by vinylalumination of the aldehydes derived from D-ribose. The following ring-closing metathesis, then the chlorination or Pd-catalyzed allyl nucleophilic substitution provided pericosine A and C, respectively. The rational attempt to synthesize pericosine E through the Pd catalyzed allyl nucleophilic substitution was unfruitful, but provided an interesting -unsaturated -ketoester.

Experimental Section General information: All reactions were carried out under a nitrogen atmosphere. TLC spots were examined under UV light or revealed by KMnO4 solution. Dichloromethane was distilled from calcium hydride; tetrahydrofuran and diethyl ether were distilled from sodium/benzophenone. Reagents were purchased from commercial sources and used without further purification. Chemical shifts in NMR were reported in δ units (parts per million) with reference to solvent residual peaks. The multiplicities are abbreviated as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of doublets, td = triplet of doublets. Assignments of 1H and 13C resonances for complex structures were confirmed by extensive 2D experiments (COSY, HMQC, and HMBC). IR spectra were obtained using a FTIR spectrophotometer as a thin film or using KBr pellets and recorded in cm 1 . Optical rotations were measured on a digital polarimeter with sodium light (589.3 nm) at 20 °C. Thin layer chromatography (TLC) was conducted using pre-coated silica gel 60 F254 plates containing a

(3R,4R)-Methyl-4-((4S,5S)-2,2-dimethyl-5-vinyl-1,3-dioxolan-4-yl)-3hydroxy-4-(4-methoxybenzyloxy)-2-methylenebutanoate (3): Methyl propiolate (204 μL, 3.23 mmol) at 0 °C was added to a solution of DIBALH (1.1 M in cyclohexane, 2.67 mL, 2.94 mmol), HMPA (766 μL, 4.41 mmol) in THF (10 mL). After stirred at 0 °C for 1 h, the reaction mixture became yellowish and was then warmed up to room temperature (rt) in 20 min. A solution of 5 (300 mg, 0.98 mmol) in THF (4 mL) was added to the above solution of [α-(methoxycarbonyl)vinyl]diisobutylaluminum (4). 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 (3 × 10 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated. The diastereomeric mixture (4:1) was purified by column chromatography (SiO2, ethyl acetate/hexanes, 1:3; Rf 0.30) to afford 3 (184.0 mg, 0.47 mmol, 49%) as colorless liquid. [α]20D 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. (3aS,6R,7R,7aS)-Methyl-6-hydroxy-7-(4-methoxybenzyloxy)-2,2dimethyl-3a,6,7,7a-tetrahydrobenzo[d][1,3]dioxole-5-carboxylate (1): Grubbs catalyst 2nd generation (11.0 mg, 0.013 mmol) was added to a solution of 3 (50.0 mg, 0.13 mmol) in toluene (12.8 mL) at rt. The reaction mixture was refluxed for 14 h under a nitrogen atmosphere and then concentrated. The crude product was purified by column chromatography (SiO2, ethyl acetate/hexanes, 1:2; Rf 0.25) to give 1 (35.6 mg, 0.098 mmol, 77%) as a viscous liquid. [α]20D 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, 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. (3aS,6R,7R,7aR)-Methyl-6,7-dihydroxy-2,2-dimethyl-3a,6,7,7atetrahydrobenzo[d][1,3]dioxole-5-carboxylate (7): DDQ (192.0 mg, 0.850 mmol) was added to a solution of 1 (123.8 mg, 0.34 mmol) in CH2Cl2/methanol (3:1, 8 mL) and stirred at rt for 23 h. The reaction mixture was quenched and neutralized with sat. NaHCO3(aq), concentrated, diluted with water and extracted with EtOAc (10 mL × 3). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography (SiO2, ethyl acetate; Rf 0.55) to give 7 (51.7 mg, 21.2 mmol, 62%) as a light yellow oil. [α]20D 21.9° (c 0.18, CHCl3); 1H NMR (CDCl3, 300 MHz) δ 1.36 (s, 3H), 1.39 (s, 3H), 3.02 (d, J = 11.1 Hz, 1H), 3.22 (d, J = 7.2 Hz, 1H), 3.80 (s, 3H), 4.56-4.61 (m, 2H), 4.70 (dd, J = 3.0 Hz, J = 4.8 Hz, 1H), 6.80 (dd, J = 0.6 Hz, J = 2.7 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ 26.1, 28.1, 52.4, 65.2, 67.0, 73.0, 111.2, 131.5, 136.6, 144.4, 165.8; HRMS (ESI) calcd for [M+Na]+ (C11H16O6Na) 267.0845, found 267.0842.


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fluorescent indicator; purification by chromatography was conducted using silica gel (230-400 mesh).


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(3aS,6S,7S,7aS)-Methyl-7-acetoxy-6-chloro-2,2-dimethyl-3a,6,7,7atetrahydrobenzo[d][1,3]dioxole-5-carboxylate (9): 1-Chlorocarbonyl-1methyl-ethylacetate (12.3 µL, 0.085 mmol) was added dropwise to a solution of acetonide 7 (12.8 mg, 0.057 mmol) and acetonitrile (2 mL) by a syringe over 15 min at 0 °C under a nitrogen atmosphere. The reaction mixture was stirred for 15 min at 0°C and then at rt for 1 h. The solvent was removed, and the residue was diluted with EtOAc (20 mL). The organic solution was washed with sat. NaHCO3 (10 mL × 2), dried over Na2SO4 and concentrated to give acetate 9 (17.0 mg, 0.056 mmol, 98%) as a yellow liquid. [α]20D +122.5 (c 0.45, CHCl3); 1H NMR (CDCl3, 300 MHz) δ 1.38 (s, 3H), 1.40 (s,3H), 2.06 (s, 3H), 3.81 (s, 3H), 4.71 (dd, J = 3.6 Hz, J = 6.9 Hz, 1H), 4.77 (dd, J = 3.3 Hz, J = 6.9 Hz, 1H), 4.91(d, J = 4.5, 1H), 5.45 (dd, J = 3.6 Hz, J = 4.5 Hz, 1H), 7.06 (d, J = 3.3 Hz, 1H); 13 C NMR (CDCl3, 75 MHz) δ 21.0, 25.1, 26.5, 49.6, 52.5, 68.8, 70.4, 71.1, 110.5, 130.6, 137.5, 164.8, 169.7; HRMS (ESI) calcd for [M+Na]+ (C13H17O6NaCl) 327.0611, found 327.0610. (+)-Pericosine A (10): Acetyl chloride (2.6 μL, 0.033 mmol) was added to a solution of acetate 9 (10.0 mg, 0.033 mmol) in methanol (2 mL) at 0 °C. The reaction mixture was stirred at rt for 12 h and concentrated. The crude product was purified by column chromatography (SiO2, ethyl acetate; Rf 0.30) to afford (+)-percosine A (10) (5.1 mg, 0.022 mmol, 70%) as a colorless liquid. [α]20D +75.5° (c 0.49, EtOH); 1H NMR (acetone-d6/D2O, 300 MHz ) δ 3.77 (s, 3H), 4.05 (t, J = 2.1 Hz, 1H), 4.09 (t, J = 1.8 Hz, J = 2.7 Hz, 1H), 4.35 (d, J = 3.6 Hz, 1H), 4.87 (d, J = 4.5 Hz, 1H), 6.89 (d, J = 3.9 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ 52.4, 57.8, 67.2, 68.6, 75.8, 130.6, 141.9, 166.2; HRMS (ESI) calcd for [M+Na]+ (C8H11O5NaCl) 245.0193, found 245.0192. (3aS,4R,5R,7aS)-6-(Methoxycarbonyl)-2,2-Dimethyl-3a,4,5,7atetrahydrobenzo[d][1,3]dioxole-4,5-diyl diacetate (11): Triethylamine (123 μL, 0.88 mmol) and 4-(dimethylamino)pyridine (DMAP, 0.3 mg) were added to a solution of 7 (10.3 mg, 0.042 mmol) in CH2Cl2 (2 mL) at rt. The reaction mixture was cooled to 0 °C, added with acetic anhydride (41.8 μL), heated to 45 °C, stirred for another 4 h and diluted with EtOAc (20 mL). The organic layer was washed with sat.NaHCO3(aq), dried over Na2SO4, filtered and concentrated to afford 11 (13.2 mg, 0.043 mmol, 96%) as a light yellow liquid. [α]D20 23.5 (c 0.3, CHCl3); 1H NMR (CDCl3, 300 MHz ) δ 1.38 (s, 3H), 1.43 (s, 3H), 2.05 (s, 3H), 2.10 (s, 3H), 3.75 (s, 3H), 4.46 (m, 1H), 4.78 (dd, J = 3.3 Hz, J = 5.7 Hz, 1H), 5.16 (dd, J = 2.7 Hz, J = 4.5 Hz, 1H), 6.04 (d, J = 4.5 Hz, 1H), 6.97 (d, J = 3.3 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ 20.8, 20.9, 52.4, 62.0, 67.4, 72.7, 72.8, 112.0, 127.4, 139.7, 164.8, 170.1, 170.4; HRMS (ESI) calcd for [M+Na]+ (C15H20O8Na) 351.1056, found 351.1049.

(3aS,4R,7R,7aR)-Methyl-7-hydroxy-4-methoxy-2,2-dimethyl3a,4,7,7a-tetrahydrobenzo[d][1,3]dioxole-5-carboxylate (12): Pd(PPh3)4 (2.2 mg, 0.002 mmol) and anhydrous K2CO3 (5.2 mg, 0.038 mmol) were added to a solution of 11 (10.3 mg, 0.038 mmol) and methanol (2mL) at rt under a nitrogen atmosphere. The reaction mixture was stirred at rt for 16 h and then concentrated. The crude product was purified by column chromatography (SiO2, ethyl acetate/hexanes, 2:1; Rf 0.58) to afford 12 (4.1 mg, 0.016 mmol, 50%) as a light yellow liquid. [α]D20 33.6 (c 0.25, CHCl3); 1H NMR (CDCl3, 300 MHz) δ 1.26 (s, 3H), 1.32 (s, 3H), 2.69 (d, J = 10.8 Hz, 1H), 3.26 (s, 3H), 3.78 (s, 3H), 4.44– 4.51 (m, 2H), 4.57–4.66 (m, 2H), 7.11 (d, J = 1.2 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ 24.4, 26.0, 25.1, 57.0, 66.8, 71.9, 75.2, 75.6, 109.2, 130.0, 148.1, 165.9; HRMS (FAB) calcd for [M+H]+ (C12H19O6) 259.1182, found 259.1177. (‒)-Pericosine C (13): Acetyl chloride (2.6 μL, 0.033 mmol) was added to a solution of acetonide 12 (8.6 mg, 0.033 mmol) and methanol (2 mL) at 0 °C. The reaction mixture was stirred at rt for 12 h and concentrated. The crude product was purified by column chromatography (SiO2, ethyl acetate; Rf 0.30) to afford (‒)-percosine C (4.3 mg, 0.02 mmol, 60%) as a light yellow liquid. [α]D20 ‒55.3 (c 0.1, EtOH); 1H NMR (acetone-d6, 300 MHz) δ 3.47 (s, 3H), 3.75 (s, 3H), 3.88–3.99 (m, 4H), 4.18-4.27 (m, 2H), 4.40 (dd, J = 3.0 Hz, J = 5.7 Hz, 1H), 6.75 (d, J = 3.9 Hz, 1H); 13C NMR (acetone-d6, 75 MHz) δ 52.0, 59.5, 67.5, 70.2, 73.4, 79.2, 131.6, 140.6, 167.6; HRMS (ESI) calcd for [M+Na]+ (C9H14O6Na) 241.0688, found 241.0691. (3aS,6R,7R,7aS)-Methyl-6-acetoxy-7-((4-methoxybenzyl)oxy)-2,2dimethyl-3a,6,7,7a-tetrahydrobenzo[d][1,3]dioxole-5-carboxylate (2): Triethylamine (390 μL, 2.77 mmol) and DMAP (0.9 mg, 7 μmol) were added to a solution of 1 (50.5 mg, 0.14 mmol) and CH2Cl2 (10 mL) at rt. The reaction mixture was cooled to 0 °C, added with acetic anhydride (42 μL), heated to 45 °C, stirred for another 16 h, quenched with water (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with sat. NaHCO3(aq), dried over Na2SO4, filtered and concentrated to afford 2 (51.1 mg, 0.13 mmol, 90%) as a yellow liquid. [α]20D ‒19.2 (c 0.10, CHCl3); 1H NMR (CDCl3, 300 MHz) δ 1.36 (s, 3H), 1.40 (s, 3H), 2.08 (s, 3H), 3.51 (dd, J = 2.7 Hz, J = 4.8 Hz, 1H), 3.76 (s, 3H), 3.77 (s, 3H), 4.37 (m, 1H), 4.56–4.62 (m, 2H), 4.77 (d, J = 9.6 Hz, 1H), 6.20 (d, J = 4.2 Hz, 1H), 6.84 (m, 2H), 6.90 (d, J = 2.7 Hz, 1H), 7.30 (d, J = 8.7 Hz, 2H); 13C NMR (CDCl3, 75 MHz) δ 21.0, 26.3, 27.7, 52.3, 55.2, 60.9, 71.1, 71.3, 72.8, 73.8, 111.6, 113.9, 127.6, 129.9, 139.9, 159.4, 165.4, 170.4; HRMS (ESI) calcd for [M+Na]+ (C21H26O8Na) 429.1525, found 429.1518. (3aS,6R,7R,7aR)-Methyl-6-acetoxy-7-hydroxy-2,2-dimethyl3a,6,7,7a-tetrahydrobenzo[d][1,3]dioxole-5-carboxylate (14): DDQ (13.3 mg, 0.056 mmol) was added to a solution of 2 (15.2 mg, 0.037 mmol) in CH2Cl2/H2O (18:1, 2 mL). The reaction mixture was stirred at rt for 16 h, quenched with sat. NaHCO3(aq) (2 mL), concentrated and extracted with EtOAc (5 mL × 3). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography (SiO2, ethyl acetate/hexanes, 1:2; Rf 0.3) to afford 14 (7.5 mg, 0.026 mmol, 70%) as a light yellow liquid. [α]D20 ‒51.4 (c 0.11, CHCl3); 1H NMR (CDCl3, 300 MHz) δ 1.36 (s, 3H), 1.40 (s, 3H), 2.07 (s, 3H), 2.91 (d, J = 5.7 Hz, 1H), 3.75 (s, 3H), 3.99 (td, J = 3.0 Hz, J = 4.5 Hz, 1H), 4.50 (m, 1H), 4.72 (ddd, J = 0.9 Hz, J = 3.6 Hz, J = 6.0 Hz, 1H), 5.97 (d, J = 4.5 Hz, 1H), 6.95 (t, J = 3.3 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ 21.0, 26.1, 27.5, 52.3, 65.1, 67.7, 72.3, 73.8, 111.4, 127.8, 139.4, 165.2, 172.0; HRMS (ESI) calcd for [M+Na]+ (C13H18O7Na) 309.0950, found 309.0957. (3aS,6R,7R,7aS)-Methyl-6-hydroxy-7-(((3aS,7aS)-5(methoxycarbonyl)-2,2-dimethyl-7-oxo-3a,4,7,7a-


Accepted Manuscript

(3aS,6R,7R,7aR)-Methyl-7-hydroxy-6-((4-methoxybenzyl)oxy)-2,2dimethyl-3a,6,7,7a-tetrahydrobenzo[d][1,3]dioxole-5-carboxylate (8): DDQ (33.6 mg, 0.15 mmol) was added to a solution of 1 (21.6 mg, 0.06 mmol) and CH2Cl2/water (4:1, 1.8 mL). The reaction mixture was stirred at rt for 4 h, quenched and neutralized with sat. NaHCO3(aq), concentrated and extracted with EtOAc (5 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography (SiO2, ethyl acetate/hexanes, 1:4; Rf 0.55) to afford 8 (11.2 mg, 50%) and 7 (3.7 mg, 26%). 1H NMR (CDCl3, 300 MHz) δ 1.42 (s, 3H), 1.54 (s, 3H), 2.64 (d, J = 9.3 Hz, 1H), 2.91 (d, J = 6.3 Hz, 1H), 3.73 (s, 3H), 3.85 (s, 3H), 4.10–4.13 (m, 1H), 4.59 (dd, J = 5.8 Hz, J = 2.8 Hz, 1H), 4.80 (dd, J = 5.2 Hz, J = 3.4 Hz, 1H), 6.27 (d, J = 4.7 Hz, 1H), 6.90 (d, J = 8.9 Hz, 2H), 7.04 (d, J = 3.2 Hz, 1H), 8.0 (d, J = 8.9 Hz, 2H); 13C NMR (CDCl3, 75 MHz) δ 26.2, 28.0, 52.3, 55.4, 65.0, 67.8, 72.6, 74.1, 111.4, 113.6, 122.0, 128.0, 132.0, 139.7, 163.6, 165.3, 164.0; HRMS (ESI) calcd for [M+Na]+ (C19H22O8Na) 401.1212, found 401.1213.


10.1002/ajoc.201600355

tetrahydrobenzo[d][1,3]dioxol-4-yl)oxy)-2,2-dimethyl-3a,6,7,7atetrahydrobenzo[d][1,3]dioxole-5-carboxylate (15): Bis(triphenylphosphine)palladium(II)dichloride (2.7 mg, 3.8 μmol) and K2CO3 (21 mg) was added to a solution of 14 (21.7 mg, 0.076 mmol) and CH2Cl2 (3.0 mL) at rt under a nitrogen atmosphere. The reaction mixture was stirred for 16 h at rt, quenched with water (2 mL) and extracted with CH2Cl2 (4 mL × 3). The combined organic layers were dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (SiO2, ethyl acetate/hexanes, 1:2; Rf 0.45) to afford 15 (6.6 mg, 0.014 mmol, 38%) as a viscous liquid. [α]D20 ‒33.5° (c 0.2, CHCl3); IR (neat) 3493, 2988, 2925, 1722, 1693, 1437, 1375, 1247 cm -1; 1 H NMR (CDCl3, 300 MHz) δ 1.25 (s, 3H), 1.27 (s, 3H), 1.35 (s, 3H), 1.40 (s, 3H), 2.74 (d, J = 10.2 Hz, OH), 3.09 (d, J = 9.5 Hz, 1H), 3.34 (dd, J = 9.5 Hz, J = 1.8 Hz, 1H), 3.63 (s, 3H), 3.76 (s, 3H), 4.44–4.52 (m, 2H), 4.68–4.76 (m, 3H), 6.69 (s, 1H), 6.99 (d, J = 1.2 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ 24.3, 25.8, 26.0, 27.3, 36.5, 40.3, 52.2, 53.0, 66.3, 74.1, 75.7, 75.8, 76.5, 109.1, 110.4, 127.9, 132.0, 144.7, 146.3, 165.6, 166.6, 195.8; HRMS (ESI) calcd for [M+Na]+ (C22H28O10Na ) 475.1580, found 475.1574.

(3aS,3′aS,4R,4'S,7R,7aS,7'aS)-Dimethyl-7-(benzoyloxy)-2,2,2',2'tetramethyl-7'-oxo-3a,3'a,4,4',7,7a,7',7'a-octahydro-[4,4'bibenzo[d][1,3]dioxole]-5,5'-dicarboxylate (16): Triethylamine (60 μL, 0.43 mmol) and DMAP (0.13 mg) were added to a stirred solution of 15 (9.7 mg, 0.021 mmol) in CH2Cl2 (2.0 mL) at 0°C under a nitrogen atmosphere. The reaction mixture was stirred for 5 min, added with benzoyl anhydride (48.5 mg, 0.21 mmol), stirred at rt for 12 h and refluxed for another 12 h. The solution was cooled to rt, quenched with water (2 mL) and extracted with CH2Cl2 (4 mL × 3). The combined organic layers were dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (SiO2, ethyl acetate/hexanes, 1:2; Rf 0.5) to afford 16 (6.6 mg, 0.014 mmol, 38%) as a colorless viscous liquid. [α]D20 ‒88.0 (c 0.3, CHCl3); 1H NMR (CDCl3, 300 MHz), δ 1.27 (s, 3H), 1.28 (s, 3H), 1.32 (s, 3H), 1.41 (s, 3H), 3.15 (d, J = 9.2 Hz, 1H), 3.50 (dd, J = 1.9 Hz, J = 9.2 Hz, 1H), 3.65 (s, 3H), 3.82 (s, 3H), 4.56 (d, J = 4.9 Hz, 1H), 4.72 (d, J = 6.5 Hz, 1H), 4.80 (dd, J = 4.9 Hz, J = 1.9 Hz, 1H), 5.00 (ddd, J = 6.5 Hz, J = 4.9 Hz, J = 1.5 Hz, 1H), 5.77 (dd, J = 2.2 Hz, J = 4.9 Hz, 1H), 6.74 (s, 1H) , 7.08 (d, J = 2.2 Hz, 1H) , 7.45 (m, 2H) , 7.57 (m, 1H) , 8.09 (m, 2H); 13C NMR ( CDCl3, 75 MHz) δ 24.6, 25.8, 26.1, 27.3, 36.8, 41.1, 52.4, 53.3, 69.4, 74.1, 74.6, 76.4, 77.2, 109.6, 110.5, 128.4, 129.0, 129.4, 130.0, 130.1, 132.1, 133.4, 133.6, 141.7, 144.7, 165.5, 165.7, 166.5, 196.0; HRMS (ESI) calcd for [M+Na]+ (C22H28O10Na) 579.1842, found 579.1844

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Acknowledgements Financial support from the Ministry of Science and Technology (NSC 101-2113-M-008-002), Taiwan, is gratefully acknowledged. We thank the Institute of Chemistry, Academia Sinica and the Valuable Instrument Center at National Central University, Taiwan, for mass analysis. Keywords: carbasugar • cyclitol • allylic substitution • palladium • vinylalumination

References

[11] [12]

a) R. E. Moore, T. H. Corbett, G. M. L. Patterson, F. A. Valeriote, Current Pharmaceutical Design 1996, 2, 317-330; b) D. J. Newman, G. M. Cragg, J. Nat. Prod. 2007, 70, 461-477. a) T. Suami, Pure Appl. Chem. 1987, 59, 1509-1520; b) A. Berecibar, C. Grandjean, A. Siriwardena, Chem. Rev. 1999, 99, 779-844; c) O. Arjona, A. M. Gómez, J. C. López, J. Plumet, Chem. Rev. 2007, 107, 1919-2036. a) A. Numata, M. Iritani, T. Yamada, K. Minoura, E. Matsumura, T. Yamori, T. Tsuruo, Tetrahedron Lett. 1997, 38, 8215–8218; b) T. Yamada, M. Iritani, H. Ohishi, K. Tanaka, M. Doi, K. Minoura, A. Numata, Org. Biomol. Chem. 2007, 5, 3979–3986; c) J. Duchek, D. R. Adams, T. Hudlicky, Chem. Rev., 2011, 111, 4223-4258. a) Y. Usami, H. Ichikawa, M. Arimoto, Int. J. Mol. Sci. 2008, 9, 401– 421; b) Y. Usami, K. Suzuki, K. Mizuki, H. Ichikawa, M. Arimoto, Org. Biomol. Chem., 2009, 7, 315–318. L. Sánchez-Abella, S. Fernández, N. Armesto, M. Ferrero, V. Gotor, J. Org. Chem. 2006, 71, 5396-5399. Reported syntheses using quinic acid or shikimic acid as the starting material: a) Y. Usami, K. Suzuki, K. Mizuki, H. Ichikawa, M. Arimoto, Org. Biomol. Chem., 2009, 7, 315-318; b) Y. Usami, I. Takaoka, H. Ichikawa, Y. Horibe, S. Tomiyama, M. Ohtsuka, Y. Imanishi, M. Arimoto, J. Org. Chem., 2007, 72, 6127-6134; c) Y. Usami, K. Mizuki, J. Nat. Prod., 2011, 74, 877-881; d) Y. Usami, M. Ohsugi, K. Mizuki, H. Ichikawa, M. Arimoto, Org. Lett., 2009, 11, 2699-2701; e) Y. Usami, Y. Horibe, I. Takaoka, H. Ichikawa, M. Arimoto, Synlett., 2006, 1598-1600; f) Y. Usami, Y. Ueda, Chem. Lett., 2005, 34, 1062-1063; g) Y. Usami, Y. Ueda, Synthesis, 2007, 3219-3225; h) Y. Usami, K. Mizuki, H. Ichikawa, M. Arimoto, Tetrahedron: Asymmetry, 2008, 19, 1461-1464. Using 3,5-cyclohexadiene-cis-1,2-diols: a) T. J. Donohoe, K. Blades, M. Helliwell, M. J. Waring, Tetrahedron Lett., 1998, 39, 8755-8758; b) D. R. Boyd, N. D. Sharma, C. A. Acaru, J. F. Malone, C. R. O’Dowd, C. C. R. Allen, P. J. Stevenson, Org. Lett., 2010, 12, 2206-2209. Syntheses of related cyclitol/carbasugar natural products: a) M. J. Palframan, G. Kociok-Kohn, S. E. Lewis, Chem.–Eur. J. 2012, 18, 4766-4774; b) M. J. Palframan, G. Kociok-Köhn, S. E. Lewis, Org. Lett., 2011, 13, 3150-3153; c) S. Pilgrim, G. Kociok-Köhn, M. D. Lloyd, S. E. Lewis, Chem. Commun., 2011, 47, 4799-4801; d) M. Ali Khan, J. P. Lowe, A. L. Johnson, A. J. W. Stewart, S. E. Lewis, Chem. Commun., 2011, 47, 215-217; e) D. R. Adams, C. Aichinger, J. Collins, U. Rinner, T. Hudlický, Synlett, 2011, 725-729. a) S. Roche, P. Harrington, H. Iding, M. Karpf, B. Wirz, U. Zutter, U. Chimia 2004, 58, 621-629; b) Y. Yeung, S. Hong, E. J. Corey, J. Am. Chem. Soc. 2006, 128, 6310-6311; c) T. K. M. Shing, H. M.; Cheng, W. F. Wong, C. S. K. Kwong, J. Li, C. B. S. Lau, P. S.; Leung, C. H. K. Cheng, Org. Lett. 2008, 10, 3145-3148. a) D. C. Babu, C. B. Rao, K. Venkatesham, J. J. P. Selvam, Y. Venkateswarlu, Carbohydr. Res. 2014, 388, 130-137; b) C. Ramstadius, O. Hekmat, L. Eriksson , H. Stalbrand, I. Cumpstey, Tetrahedron: Asymmetry, 2009, 20, 795-807; c) G. Kumaraswamy, K. Sadaiah, D. S. Ramakrishna, N. P. B. Sridhar, J. Bharatam, Chem. Commun., 2008, 5324-5326; d) V.R. Doddi, Y. D. Vankar, Tetrahedron, 2008, 64, 91179122; e) G. Luchetti, K. Ding, M. Alarcao, A. Kornienko, Synthesis, 2008, 19, 3142-3147; f) Y.-K. Chang, B.-Y. Lee, D. J. Kim, G. S. Lee, H. B. Jeon, K. S. Kim, J. Org. Chem. 2005, 70, 3299-3302; g) G. F. Busscher, F.P. J. T. Rutjes, F.L. van Delft, Chem. Rev., 2005, 105, 775-791; h) O. N. Nadein, A. Kornienko, Org. Lett., 2004, 6, 831-834; i) S. H. L. Verhelst, T. Wennekes, G. A. V. Marel, H. S. Overkleeft, C. A. A. van Boeckel, J. H. van Boom, Tetrahedron, 2004, 60, 2813-2822; j) M. Jørgensen, E. H. Iversen, A. L. Paulsen, R. Madsen, J. Org. Chem. 2001, 66, 4630-4634; k) A. Kornienko, M. Alarcao, Tetrahedron: Asymmetry 1999, 10, 827-829. S. Tripathi, A. C. Shaikh, C. Chen, Org. Biomol. Chem. 2011, 9, 73067308. C. MuniRaju, J. P. Rao, B. V. Rao, Tetrahedron: Asymmetry 2012, 23, 86-93.


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[14]

[15] [16] [17]

Y. S. Reddy, P. Kadigachalam, R. K. Basak, A. P. J. Pal, Y. D. Vankar, Tetrahedron Lett.,2012, 53, 132-136. a) L.-S. Li, D.-R. Hou, RSC Advances 2014, 4, 91-97; b) H. R. Moon, W. J. Choi, H. O. Kim, L. S. Jeong, Tetrahedron: Asymmetry, 2002, 13, 1189-1193. S. D. M. Scholl, C. W. Lee, R. H. Grubbs, Org. Lett. 1999, 1, 953-956. A. R. Mattocks, J. Chem. Soc. 1964, 1918–1930. S. Y. Yeom, Y. J. Kim, B. M. Kim, Synlett. 2005, 10, 1527–1530.

[18]

[19]

a) S. A. Godleski in Comprehensive Organic Synthesis, Vol. 4 (Eds.: B. M. Trost, I. Fleming), Pergamon, Oxford, 1991, pp. 585-661; b) J. Tsuji in Palladium Reagent and Catalysts, Wiley; Chichester, 1995, pp. 376377. For 2D NMR data, see supporting information.

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FULL PAPER Natural product synthesis Cheng-Yu Chung, Venkatachalam Angamuthu, Long-Shiang Li and DuenRen Hou** Page No. – Page No. Text for Table of Contents

Palladium catalyzed allylic substitution for the synthesis of pericosines


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