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Synthesis 2016; 48(06): 917-923
DOI: 10.1055/s-0035-1561319
paper
© Georg Thieme Verlag Stuttgart · New York

Synthesis of the C1–C13 Fragment of Mandelalide A

Sudhakar Athe
CSIR-Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad 500007, India   Email: subhash@iict.res.in
,
Subhash Ghosh*
CSIR-Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad 500007, India   Email: subhash@iict.res.in
› Author Affiliations
Further Information

Publication History

Received: 06 November 2015

Accepted after revision: 15 December 2015

Publication Date:
11 January 2016 (online)

 
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Abstract

This communication describes the synthesis of the fully functionalized C1 to C13 segment (southern part) of highly potent cytotoxic marine natural product mandelalide A. Pd-catalyzed oxa-­Michael cyclization followed by stereoselective reduction of the C7-ketone were carried out to construct the tetrahydropyran unit with required stereochemistry. The α,β-unsaturated ester moiety was constructed via cross-metathesis and the vinyl iodide was installed through modified Takai olefination.


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Key words

mandelalide - oxa-Michael cyclization - modified Takai olefination - cross-metathesis

Marine organisms are a prolific source of pharmacologically active compounds for drug development. However, very few drugs have been developed based on marine natural products, mainly because of their limited availability from the natural source.[1] Therefore, making these biologically potent compounds in sufficient quantity via their total synthesis is an active area of research.[2] Mandelalide A (2)[3] (Figure [1]) is an example of marine natural product whose systematic biological studies could not be carried out because of its scarcity (0.8 mg was obtained from the natural source), although preliminary biological study revealed that it had impressive cytotoxic activity against human NCI-H460 lung cancer and mouse Neuro-2A neuroblastoma cell lines (IC50, 12 and 44 nM, respectively).[3] McPhail et al. isolated this cytotoxic glycosylated macrolide from a rare South African ascidian of the Lissoclinum genus and the structure was proposed to be 1 on the basis of extensive NMR study. However, synthesis of the proposed structure by Fürstner et al.[4] and Ye et al.[5] revealed that the structural assignment done by McPhail et al. was incorrect. Subsequently Ye et al. proposed the structure of natural mandelalide A to be 2 by comparing its structure with another natural product madeirolide A[6] and confirmed the same via its total synthesis.[5] Very recently Fürstner et al. reconfirmed the stereochemical revision and also reassessed the biological activity of mandelalide A.[7]

Zoom Image
Figure 1 Structure of mandelalide A (proposed and natural)

Recently we disclosed an approach, where an intermolecular Masamune–Roush reaction, followed by intramolecular Heck cyclization were used to construct the fully functionalized aglycone of the proposed structure of mandelalide A.[8a] We also planned to develop another strategy by which mandelalide A could be synthesized from compounds 3 and 4 via esterification followed by intramolecular Sonogashira reaction[9] and cis-selective alkyne reduction. Herein, we report the progress of the strategy by describing the synthesis of the entire southern part (C1–C13 fragment 4) of mandelalide A.

Retrosynthetically we envisaged that compound 4 could be synthesized from the alcohol 6 via glycosylation with the known sugar derivative 5 [4] (Scheme [1]). Compound 6 could be obtained from compound 7 by means of PMB deprotection, oxidation of the resulting primary alcohol followed by Takai olefination.[10] Further, we visualized that a cross metathesis reaction[11] between (6R)-8 and tert-butyl acrylate followed by stereoselective reduction of the C7 ketone would install the α,β-unsaturated ester functionality and the stereocenter at C7 position in the molecule. The highly substituted tetrahydropyran unit with proper stereochemistry at C5 and C9 positions (mandelalide numbering) might be obtained via Pd-catalyzed intramolecular oxa-­Michael reaction of 9, a methodology developed by ­Gouverneur et al.[12] Finally the α,β-unsaturated enone compound 9 could be obtained from 10 and 11 by means of ketophosphonate coupling.[13]

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Scheme 1 Retrosynthetic analysis

The synthesis of 4 commenced from the known compound 12,[14] which on reaction with the anion of dimethyl methylphosphonate followed by oxidation of the resulting alcohol gave the β-ketophosphonate 10 (Scheme [2]). Coupling of β-ketophosphonate 10 with the known aldehyde 11 [15] in the presence of DIPEA and LiCl furnished enone 13 [13] (82%). TBS deprotection of 13 gave compound 9, which underwent Pd-catalyzed oxa-Michael addition in presence of [Pd(MeCN)4](BF4)2 [12] to give the chromatographically separable tetrahydropyran compound (6R)-8 (52%) and (6S)-8 (13%). The required major isomer (6R)-8 was subjected to cross metathesis with tert-butyl acrylate under different conditions[11] (Table [1]) to provide compound 14 in good yield. The best result was obtained when the cross-meta­thesis reaction was performed with Grubbs second-generation catalyst in the presence of CuI[11f] to give compound 14 in 84% yield. Stereoselective reduction of the ketone 14 with NaBH4 gave alcohol 15 (de >95%), which on TBS protection followed by DDQ-mediated PMB deprotection[16] furnished primary alcohol 16. Oxidation of the primary alcohol with DMP gave an aldehyde which on modified Takai olefination[10] afforded vinyl iodide 17. TBS deprotection of 17 gave alcohol 6, which on glycosidation[4] with the known sugar 5 completed the synthesis of the entire southern part (C1 to C13 segment) of mandelalide A (Scheme [2]).

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Scheme 2 Reagents and conditions: (a) i. n-BuLi, MePO(OMe)2, THF, –78 °C to r.t., 1 h, ii. DMP, CH2Cl2, 81% (over two steps); (b) LiCl, DIPEA, MeCN, r.t., 30 min then 11, 12 h, 82%; (c) HF·Py, MeCN, 0 °C to r.t., 12 h, 90%; (d) [Pd(MeCN)4](BF4)2, CH2Cl2, r.t., 30 min, (6R)-8 (53%) and (6S)-8 (13%); (e) tert-butyl acrylate, Grubbs II, CuI, Et2O, r.t., 2 h, 84%; (f) NaBH4, MeOH, –10 °C, 15 min, 91%; (g) TBSOTf, 2,6-lutidine, CH2Cl2, 30 min, 96%; (h) DDQ, pH 7 buffer, CH2Cl2, 10 min, 88%; (i) i. DMP, NaHCO3, CH2Cl2, 0 °C to r.t.,1 h, ii. CHI3, CrCl3, Zn dust, NaI, r.t., 30 min, 91% (over two steps); (j) HF·Py, MeCN, 0 °C to r.t., 12 h, 94%; (k) 5, TESOTf, 4 Å MS, CH2Cl2, 0 °C to –50 °C, 30 min, 86%.

Table 1 Screened Conditions for Cross Metathesis

Entry

Catalyst (10 mol%)

Conditions

Yield (%)

1

Grubbs II[11d]

CH2Cl2, 40 °C, 4 h

58

2

Grubbs II

toluene, 100 °C, 4 h

61

3

Hoveyda–Grubbs II[11e]

CH2Cl2, 40 °C, 4 h

65

4

Hoveyda–Grubbs II

toluene, 100 °C, 4 h

68

5

Grubbs II

Et2O, CuI, 40 °C, 2 h

84

In conclusion, the synthesis of the entire C1 to C13 segment 4 (southern part) of the highly potent cytotoxic marine natural product mandelalide A has been achieved in 13 longest linear sequence with an overall yield of 14.7% from the known compound 12. In the developed strategy, Pd- catalyzed oxa-Michael reaction was used to construct the highly substituted tetrahydropyran ring. The α,β-unsaturated ester moiety was installed by means of cross metathesis and the vinyl iodide moiety was constructed through modified Takai olefination. Total synthesis of mandelalide A (2) is in progress, and will be reported in due course.

All the air- and moisture-sensitive reactions were carried out under an inert atmosphere (N2 or argon). Oven-dried glass apparatus were used to perform all the reactions. Freshly distilled anhydrous solvents were used for air and moisture sensitive reactions. Commercially available reagents were used as such. Purification of compounds was carried out via column chromatography by using silica gel (60–120 or 100–200 mesh) packed in glass columns. 1H NMR spectra were recorded in CDCl3 solvent on 300 MHz, 400 MHz, 500 MHz, or 700 MHz spectrometer and 13C NMR spectra were recorded in CDCl3 solvent on 75 MHz, 100 MHz, or 125 MHz spectrometer, respectively, using TMS as an internal standard. Chemical shifts are measured as ppm values relative to internal CHCl3 δ = 7.26 or TMS δ = 0.0 for 1H NMR and ­CHCl3 δ = 77 for 13C NMR. Standard abbreviations were used to denote the signal multiplicities. Optical rotation values were recorded on Horiba sepa 300 polarimeter using a 2 mL cell with a 10 mm path length. FTIR spectra were recorded on Alpha (Bruker) IR spectrophotometer. High-resolution mass spectra (HRMS) [ESI+] were obtained using either a TOF or a double focusing spectrometer.


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Dimethyl (S)-4-(tert-Butyldimethylsilyloxy)-2-oxohept-6-enylphosphonate (10)

To a solution of dimethyl methylphosphonate (2.8 mL, 26.3 mmol) in anhydrous THF (7 mL) was added n-BuLi (1.6 M solution in hexane 13.6 mL, 21.7 mmol) slowly at –78 °C and stirred at the same temperature for 1 h. A solution of compound 12 (2 g, 8.7 mmol) in THF (24 mL) was added to the above reaction mixture over a period of 10 min and the resulting mixture was stirred for 1 h at the same temperature, quenched with sat. aq NH4Cl (10 mL) at 0 °C, and extracted with EtOAc (2 × 75 mL). The combined organic extracts were washed with H2O (2 × 20 mL) and brine (40 mL), dried (Na2SO4), and concentrated in vacuum. The crude alcohol (2.7 g, 7.6 mmol) was dissolved in anhydrous CH2Cl2 (20 mL) and treated with NaHCO3 (966 mg, 10.6 mmol) and Dess–Martin periodinane (4.8 g, 11.5 mmol) at 0 °C. The reaction mixture was stirred for 1 h at r.t. under a N2 atmosphere and then quenched with aq Na2S2O3 (20 mL) and NaHCO3 (20 mL). The biphasic mixture was stirred for 15 min and extracted with EtOAc (2 × 70 mL). The combined organic layers were washed with H2O (2 × 20 mL) and brine (40 mL), dried (Na2SO4), and concentrated under vacuum. Purification of the residue by column chromatography (SiO2, 30% EtOAc in hexane) provided pure compound 10 as a colorless oil (2.5 g, 81% over two steps); Rf = 0.5 (SiO2, 50% EtOAc in hexane); [α]D 26 +39.73 (c 3.05, CHCl3).

IR (neat): 3448, 2955, 2929, 2856, 1714, 1251, 1027, 832, 775 cm–1.

1H NMR (500 MHz, CDCl3): δ = 5.77 (m, 1 H), 5.01–5.09 (m, 2 H), 4.21 (tt, J = 6.6, 5.2 Hz, 1 H), 3.78 (d, J = 2.13 Hz, 3 H), 3.76 (d, J = 1.9 Hz, 3 H), 3.10 (dABq, J = 22.5, 13.8 Hz, 2 H), 2.76 (dd, J = 16.1, 7.0 Hz, 1 H), 2.68 (dd, J = 16.0, 5.0 Hz, 1 H), 2.29–2.18 (m, 2 H), 0.85 (s, 9 H), 0.06 (s, 3 H), 0.02 (s, 3 H).

13C NMR (75 MHz, CDCl3): δ = 200.7 (d, J = 10 Hz), 133.9, 117.8, 68.2, 52.9 (d, J = 5 Hz), 52.8 (d, J = 5 Hz), 50.5, 42.5 (d, J = 127 Hz), 41.8, 25.7, 17.8, –4.6, –4.9.

MS (ESI): m/z = 373 [M + Na]+.

HRMS: m/z calcd for C15H31O5PSiNa [M + Na]+: 373.1570; found: 373.1581.


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(4S,10R,E)-4-(tert-Butyldimethylsilyloxy)-11-(4-methoxybenzyl­oxy)-10-methylundeca-1,7-dien-6-one (13)

To a solution of compound 10 (2 g, 5.7 mmol) in anhydrous MeCN (17 mL) were added sequentially LiCl (240 mg, 5.7 mmol) and DIPEA (0.78 mL, 4.56 mmol) at r.t. and the reaction mixture was stirred for 30 min. A solution of aldehyde 11 (1.26 g, 5.7 mmol) in MeCN (15 mL) was transferred to the above reaction mixture and the resulting mixture was stirred at the same temperature for 12 h. MeCN was evaporated on a rotary evaporator and the residue was dissolved in EtOAc (60 mL) and washed with sat. aq NH4Cl (20 mL), H2O (20 mL) and brine (20 mL), dried (Na2SO4), and concentrated under vacuum. Purification of the crude mixture by column chromatography (SiO2, 3% EtOAc in hexane) gave the pure compound 13 (2.09 g, 82%) as a colorless liquid; Rf = 0.5 (SiO2, 5% EtOAc in hexane); [α]D 25 +30.36 (c 2.45, CHCl3).

IR (neat): 2954, 2855, 1667, 1512, 1247, 1083, 915, 776 cm–1.

1H NMR (500 MHz, CDCl3): δ = 7.25 (d, J = 8.5 Hz, 2 H), 6.90 (d, J = 8.5 Hz, 2 H), 6.78 (dt, J = 15.8, 7.3 Hz, 1 H), 6.10 (d, J = 15.8 Hz, 1 H), 5.81 (m, 1 H), 5.08 (dd, J = 10.2, 1.8 Hz, 1 H), 5.07 (dd, J = 15.7, 1.8 Hz, 1 H), 4.42 (s, 2 H), 4.28 (m, 1 H), 3.80 (s, 3 H), 3.31–3.24 (m, 2 H), 2.72 (dd, J = 15.2, 7.3 Hz, 1 H), 2.54 (dd, J = 15.2, 5.1 Hz, 1 H), 2.40 (m, 1 H), 2.30–2.20 (m, 1 H), 2.06 (m, 1 H), 1.95 (m, 1 H), 0.93 (d, J = 6.7 Hz, 3 H), 0.85 (s, 9 H), 0.06 (s, 3 H), 0.01 (s, 3 H).

13C NMR (125 MHz, CDCl3): δ = 199.2, 159.1, 146.2, 134.4, 132.6, 130.5, 129.1, 117.5, 113.7, 74.6, 72.7, 68.9, 55.2, 46.8, 42.3, 36.7, 33.2, 25.8, 18.0, 16.8, –4.6, –4.8.

MS (ESI): m/z = 469 [M + Na]+.

HRMS: m/z calcd for C26H42O4SiNa [M + Na]+: 469.2744; found: 469.2759.


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(4S,10R,E)-4-Hydroxy-11-(4-methoxybenzyloxy)-10-methyl­undeca-1,7-dien-6-one (9)

To a solution of compound 13 (500 mg, 1.1 mmol) in anhydrous MeCN (5 mL) was added HF·Py complex (0.034 mL) at 0 °C and the mixture was stirred for 12 h at r.t. The reaction mixture was quenched with aq NaHCO3 (2 mL) and extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with H2O (5 mL) and brine (5 mL), dried (Na2SO4), and concentrated under vacuum. Purification of the crude product by column chromatography (SiO2, 12% EtOAc in hexane) afforded the pure compound 9 (335 mg, 90%) as a colorless oil; Rf = 0.5 (SiO2, 25% EtOAc in PE); [α]D 28 +23 (c 1.6, CHCl3).

IR (neat): 3423, 2931, 2872, 1659, 1512, 1245, 1081, 820 cm–1.

1H NMR (500 MHz, CDCl3): δ = 7.25 (d, J = 8.6 Hz, 2 H), 6.90 (d, J = 8.6 Hz, 2 H), 6.83 (dt, J = 15.7, 7.6 Hz, 1 H), 6.08 (dt, J = 15.7, 1.37 Hz, 1 H), 5.83 (m, 1 H), 5.10–5.09 (m, 2 H), 4.42 (s, 2 H), 4.13 (m, 1 H), 3.81 (s, 3 H), 3.31 (dd, J = 9.1, 5.5 Hz, 1 H), 3.24 (dd, J = 9.1, 6.8 Hz, 1 H), 3.21(br s, 1 H), 2.72 (dd, J = 17.4, 3.0 Hz, 1 H), 2.61 (dd, J = 17.4, 8.8 Hz, 1 H), 2.40 (m, 1 H), 2.32–2.21 (m, 2 H), 2.09 (m, 1 H), 1.96 (m, 1 H), 0.93 (d, J = 6.8 Hz, 3 H).

13C NMR (75 MHz, CDCl3): δ = 200.6, 159.2, 147.4, 134.3, 131.7, 130.3, 129.1, 117.8, 113.7, 74.6, 72.7, 67.2, 55.2, 45.2, 40.9, 36.9, 33.2, 16.8.

MS (ESI): m/z = 332 [M + Na]+.

HRMS: m/z calcd for C20H28O4Na [M + Na]+: 355.1879; found: 355.1892.


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(2S,6R)-2-Allyl-6-[(R)-3-(4-methoxybenzyloxy)-2-methylpropyl]dihydro-2H-pyran-4(3H)-one [(6R)-8]

A solution of compound 9 (332 mg, 1 mmol) in anhydrous CH2Cl2 (5 mL) was treated with [Pd(MeCN)4](BF4)2 (44.4 mg, 10 mol%) at r.t. under an argon atmosphere and stirred for 30 min. The reaction mixture was then diluted with Et2O (15 mL) and filtered through a short pad of silica gel. The solvent was evaporated under reduced pressure and the resulting crude product was purified by column chromatography (SiO2, 4% EtOAc in hexane) to afford compounds (6R)-8 (172 mg, 52%) and (6S)-8 (43 mg, 13%) as colorless liquids.


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(6R)-8

Rf = 0.6 (SiO2, 25% EtOAc in hexane); [α]D 28 +1.68 (c 2.25, CHCl3).

IR (neat): 2956, 1714, 1611, 1511, 1300, 1032, 818 cm–1.

1H NMR (500 MHz, CDCl3): δ = 7.25 (d, J = 8.1 Hz, 2 H), 6.88 (d, J = 8.6 Hz, 2 H), 5.83 (m, 1 H), 5.13–5.06 (m, 2 H), 4.46–4.40 (m, 2 H), 3.80 (s, 3 H), 3.69–3.55 (m, 2 H), 3.33 (dd, J = 6.1, 9.1 Hz, 1 H), 3.25 (dd, J = 6.4, 9.0 Hz, 1 H), 2.43–2.20 (m, 7 H), 2.0 (m, 1 H), 1.80 (m, 1 H), 0.94 (d, J = 6.8 Hz, 3 H).

13C NMR (125 MHz, CDCl3): δ = 207.6, 159.1, 133.6, 130.6, 129.1, 117.6, 113.7, 76.4, 75.5, 74.8, 72.6, 55.2, 48.3, 47.3, 40.5, 40.4, 30.0, 16.9.

MS (ESI): m/z = 355 [M + Na]+.

HRMS: m/z calcd for C20H28O4 [M + Na]+: 355.1893; found: 355.1893.


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(6S)-8a

Rf = 0.5 (SiO2, 25% EtOAc in hexane); [α]D 30 –13.4 (c 0.35, CHCl3).

IR (neat): 2921, 1717, 1611, 1512, 1246, 1087, 1036, 820 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.24 (d, J = 8.6 Hz, 2 H), 6.87 (d, J = 8.6 Hz, 2 H), 5.76 (m, 1 H), 5.12–5.05 (m, 2 H), 4.41 (ABq, J = 11.7 Hz, 2 H), 4.18–4.10 (m, 2 H), 3.80 (s, 3 H), 3.29 (d, J = 5.7 Hz, 2 H), 2.52 (dt, J = 4.9, 1.3 Hz, 1 H), 2.48 (dt, J = 4.9, 1.6 Hz, 1 H), 2.38–2.17 (m, 4 H), 1.89 (m, 1 H), 1.55–1.47 (m, 2 H), 0.97 (d, J = 6.8 Hz, 3 H).

13C NMR (100 MHz, CDCl3): δ = 207.6, 159.3, 133.6, 130.7, 129.0, 117.9, 113.6, 74.4, 72.6, 71.8, 70.4, 55.2, 47.2, 46.2, 38.7, 38.4, 30.0, 18.0.

MS (ESI): m/z = 355 [M + Na]+.

HRMS: m/z calcd for C20H28O4Na [M + Na]+: 355.1893; found: 355.1893.


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tert-Butyl (E)-4-{(2S,6R)-6-[(R)-3-(4-Methoxybenzyloxy)-2-methylpropyl]-4-oxotetrahydro-2H-pyran-2-yl}but-2-enoate (14)

To a stirred solution of enone (6R)-8 (160 mg, 0.48 mmol) and tert-butyl acrylate (0.21 mL, 1.44 mmol) in anhydrous Et2O (3 mL) were added sequentially Grubbs second generation catalyst (4 mg, 1 mol%) and CuI (1.4 mg, 1.5 mol%) under an argon atmosphere. The reaction mixture was heated at 40 °C for 2 h and then allowed to attain r.t. The solvent was evaporated under vacuum and the residue was purified by column chromatography (SiO2, 6% EtOAc in hexane) to furnish the pure compound 14 (174 mg, 84%) as a colorless oil; Rf = 0.3 (SiO2, 10% EtOAc in hexane); [α]D 26 +2.20 (c 1.0, CHCl3).

IR (neat): 2924, 1713, 1512, 1247, 1156, 979, 819 cm–1.

1H NMR (300 MHz, CDCl3): δ = 7.25 (d, J = 7.5 Hz, 2 H), 6.88 (d J = 8.5 Hz, 2 H), 6.86 (dt, J = 15.6, 6.9 Hz, 1 H), 5.81 (d, J = 15.6 Hz, 1 H), 4.42 (s, 2 H), 3.80 (s, 3 H), 3.72–3.60 (m, 2 H), 3.33–3.23 (m, 2 H), 2.54–2.17 (m, 7 H), 2.06 (m, 1 H), 1.80 (m, 1 H), 1.47 (s, 9 H), 0.93 (d, J = 6.8 Hz, 3 H).

13C NMR (75 MHz, CDCl3): δ = 206.9, 165.5, 159.1, 142.2, 130.7, 129.2, 125.8, 113.7, 80.3, 75.4, 75.3, 74.8, 72.5, 55.2, 48.2, 47.3, 40.3, 38.5, 28.1, 16.8.

MS (ESI): m/z = 455 [M + Na]+.

HRMS: m/z calcd for C25H36O6Na [M + Na]+: 455.2410; found: 455.2412.


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tert-Butyl (E)-4-{(2S,4R,6R)-4-Hydroxy-6-[(R)-3-(4-methoxybenzyloxy)-2-methylpropyl]tetrahydro-2H-pyran-2-yl}but-2-enoate (15)

To a solution of ketone 14 (150 mg, 0.34 mmol) in MeOH (2 mL) at –10 °C was added NaBH4 (26.2 mg, 0.69 mmol) and the reaction mixture was stirred at the same temperature for 20 min. The reaction was quenched with sat. aq NH4Cl (2 mL) and MeOH was evaporated in vacuum and the residue was extracted with EtOAc (2 × 10 mL). The combined organic phases were washed with H2O (5 mL) and brine (5 mL), dried (Na2SO4), and evaporated under reduced pressure. The resulting crude product was purified by column chromatography (SiO2, 30% EtOAc in hexane) providing the pure compound 15 (137 mg, 91%) as a colorless oil; Rf = 0.5 (SiO2, 50% EtOAc in hexane); [α]D 28 –2.59 (c 0.5, CHCl3).

IR (neat): 3437, 2924, 1709,1512, 1300, 1156, 1035, 819 cm–1.

1H NMR (300 MHz, CDCl3): δ = 7.25 (d, J = 8.6 Hz, 2 H), 6.86 (d, J = 8.6 Hz, 2 H), 6.85 (dt, J = 15.7, 6.9 Hz, 1 H), 5.78 (d, J = 15.7 Hz, 1 H), 4.41 (s, 2 H), 3.80 (s, 3 H), 3.74 (m, 1 H), 3.40–3.20 (m, 4 H), 2.47–2.24 (m, 2 H), 2.08–1.86 (m, 3 H), 1.77 (br s, 1 H), 1.65 (m,1 H), 1.46 (s, 9 H), 1.25–1.08 (m, 3 H), 0.92 (d, J = 6.6 Hz, 3 H).

13C NMR (75 MHz, CDCl3): δ = 165.8, 159.0, 143.6, 130.8, 129.1, 125.0, 113.7, 80.1, 75.6, 74.1, 73.3, 72.5, 68.1, 55.2, 41.6, 40.8, 40.0, 38.4, 29.8, 28.1, 17.0.

MS (ESI): m/z = 457 [M + Na]+.

HRMS: m/z calcd for C25H38O6Na [M + Na]+: 457.2560; found: 457.2562.


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tert-Butyl (E)-4-{(2S,4R,6R)-4-(tert-Butyldimethylsilyloxy)-6-[(R)-3-(4-methoxybenzyloxy)-2-methylpropyl]tetrahydro-2H-pyran-2-yl}but-2-enoate (7)

To a solution of 15 (130 mg, 0.3 mmol) in CH2Cl2 (2 mL) was added 2,6-lutidine (0.1 mL, 0.9 mmol) at 0 °C. After stirring for 5 min at the same temperature, TBSOTf (76.5 μL, 0.33 mmol) was added. After stirring for 30 min, the reaction mixture was quenched with sat. aq ­NaHCO3 (2 mL) and extracted with EtOAc (2 × 4 mL). The combined organic extracts were washed with aq CuSO4 (2 × 2 mL), H2O (2 mL) and brine (2 mL), and dried (Na2SO4). Evaporation of the solvent under reduced pressure gave the crude product, which on purification by column chromatography (SiO2, 5% EtOAc in hexane) afforded the pure compound 7 (157 mg, 96%) as a colorless oil; Rf = 0.5 (SiO2, 10% EtOAc in hexane); [α]D 24 –2.06 (c 1.45, CHCl3).

IR (neat): 2929, 2854, 1713, 1612, 1512, 1247, 1155, 1071, 835, 775 cm–1.

1H NMR (300 MHz, CDCl3): δ = 7.25 (d, J = 8.6 Hz, 2 H), 6.87 (d, J = 8.6 Hz, 2 H), 6.86 (dt, J = 15.7, 7.1 Hz, 1 H), 5.78 (d, J = 15.7 Hz, 1 H), 4.42 (s, 2 H), 3.80 (s, 3 H), 3.73 (m, 1 H), 3.39–3.29 (m, 3 H), 3.22 (m, 1 H), 2.44–2.23 (m, 2 H), 2.03 (m, 1 H), 1.81–1.59 (m, 3 H), 1.47 (s, 9 H), 1.26–1.14 (m, 3 H), 0.93 (d, J = 6.6 Hz, 3 H), 0.87 (s, 9 H), 0.05 (s, 6 H).

13C NMR (75 MHz, CDCl3): δ = 165.8, 159.0, 144.0, 130.9, 129.0, 124.8, 113.6, 80.0, 75.8, 74.2, 73.3, 72.4, 68.7, 55.2, 42.1, 41.4, 40.0, 38.6, 29.8, 28.1, 25.8, 18.0, 17.0, –4.5.

MS (ESI): m/z = 571 [M + Na]+.

HRMS: m/z calcd for C31H52O6SiNa [M + Na]+: 571.3434; found: 571.3433.


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tert-Butyl (E)-4-{(2S,4R,6R)-4-(tert-Butyldimethylsilyloxy)-6-[(R)-3-hydroxy-2-methylpropyl]tetrahydro-2H-pyran-2-yl}but-2-enoate (16)

To a stirred solution of 7 (120 mg, 0.21 mmol) in CH2Cl2–phosphate buffer (pH 7) (20:1, 5 mL) was added DDQ (71 mg, 0.31 mmol) at 0 °C. The reaction mixture was stirred at the same temperature for 30 min, then quenched with sat. aq NaHCO3 (5 mL), and extracted with EtOAc (2 × 15 mL). The combined organic layers were washed with H2O (5 mL) and brine (5 mL), and dried (Na2SO4). Evaporation of the organic extract under reduced pressure and purification of the crude mixture by column chromatography (SiO2, 15% EtOAc in hexane) afforded the pure compound 16 (82 mg, 88%) as a colorless oil; Rf = 0.5 (SiO2, 25% EtOAc in hexane); [α]D 28 +7.5 (c 1.05, CHCl3).

IR (neat): 3435, 2927, 2855, 1714, 1253, 1155, 1071, 775, 669 cm–1.

1H NMR (500 MHz, CDCl3): δ = 6.82 (dt, J = 15.7, 7.12 Hz, 1 H), 5.79 (d, J = 15.7 Hz, 1 H), 3.75 (m, 1 H), 3.50 (dd, J = 4.8, 10.9 Hz, 1 H), 3.44–3.35 (m, 3 H), 2.44–2.30 (m, 2 H), 1.85–1.74 (m, 3 H), 1.57 (m, 1 H), 1.47 (s, 9 H), 1.35–1.19 (m, 3 H), 0.91 (d, J = 6.8 Hz, 3 H), 0.87 (s, 9 H), 0.05 (s, 6 H).

13C NMR (125 MHz, CDCl3): δ = 165.7, 143.1, 125.4, 80.1, 75.0, 74.4, 68.5, 68.3, 42.3, 40.9, 40.8, 38.3, 34.3, 28.1, 25.8, 18.0, 17.9, –4.5.

MS (ESI): m/z = 429 [M + H]+.

HRMS: m/z calcd for C23H45O5Si [M + H]+: 429.3036; found: 429.3035.


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tert-Butyl (E)-4-{(2S,4R,6R)-4-(tert-Butyldimethylsilyloxy)-6-[(R,E)-4-iodo-2-methylbut-3-enyl]tetrahydro-2H-pyran-2-yl}but-2-enoate (17)

To a solution of 16 (60 mg, 0.14 mmol) in CH2Cl2 (3 mL) at 0 °C were added NaHCO3 (17.6 mg, 0.21 mmol) and Dess–Martin periodinane (89 mg, 0.21 mmol) under a N2 atmosphere. After stirring for 1 h at r.t., sat. aq NaHCO3 (1 mL) and sat. aq Na2S2O3 (1 mL) were added and the resulting biphasic mixture was stirred for 30 min. The mixture was then extracted with EtOAc (2 × 5mL) and the combined organic extracts were washed with H2O (5 mL) and brine (5 mL), and dried (Na2SO4). Evaporation of the solvent under reduced pressure gave the crude aldehyde, which was used directly for the next reaction without further purification. CrCl3 (132.7 mg, 0.84 mmol), Zn dust (27.4 mg, 0.42 mmol), and dehydrated NaI (105 mg, 0.7 mmol) were taken in a round-bottomed flask and the mixture was heated at 100 °C under vacuum for 2–3 min without stirring and then for 10 min with stirring. Anhydrous THF (4 mL) was added to the above mixture under an argon atmosphere and the resulting green colored solution was treated with a mixture of the above obtained aldehyde and CHI3 (83 mg, 0.21 mmol) in anhydrous THF (2 mL) and stirred at r.t. for 30 min. The mixture was filtered through Celite and the filtrate was evaporated under reduced pressure. The crude product thus obtained was purified by column chromatography (SiO2, 3% EtOAc in PE) to give the pure compound 17 (70 mg, 91%) as a colorless liquid; Rf = 0.5 (SiO2, 5% EtOAc in hexane); [α]D 25 –20.3 (c 1.2, CHCl3).

IR (neat): 2928, 2855, 1713, 1369, 1253, 1156, 1071, 775, 671, 819 cm–1.

1H NMR (400 MHz, CDCl3): δ = 6.84 (dt, J = 15.2, 7.6 Hz, 1 H), 6.44 (dd, J = 14.4, 8.4 Hz, 1 H), 5.96 (d, J = 14.4 Hz, 1 H), 5.78 (d, J = 15.2 Hz, 1 H), 3.73 (m, 1 H), 3.37–3.23 (m, 2 H), 2.45–2.36 (m, 2 H), 2.31 (m, 1 H), 1.80–1.72 (m, 2 H), 1.63 (m, 1 H), 1.47 (s, 9 H), 1.32–1.12 (m, 3 H), 0.99 (d, J = 6.7 Hz, 3 H), 0.87 (s, 9 H), 0.05 (s, 6 H).

13C NMR (100 MHz, CDCl3): δ = 165.8, 151.9, 143.7, 124.9, 80.1, 74.18, 73.24, 72.9, 68.6, 41.8, 41.6, 41.2, 38.5, 36.9, 28.1, 25.8, 18.9, 18.1, –4.5, –4.6.

MS (ESI): m/z = 568 [M + NH4]+.

HRMS: m/z calcd for C24H47INO4Si [M + NH4]+: 568.2319; found: 568.2318.


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tert-Butyl (E)-4-{(2S,4R,6R)-4-Hydroxy-6-[(R,E)-4-iodo-2-methylbut-3-enyl]tetrahydro-2H-pyran-2-yl}but-2-enoate (6)

TBS deprotection of 17 (30 mg, 0.05 mmol) was carried out with HF·Py (15.6 μL) according to the procedure mentioned above to give the pure compound 6 (22.5 mg, 94%) as a colorless oil; Rf = 0.5 (SiO2, 30% EtOAc in hexane); [α]D 26 –31 (c 0.7, CHCl3).

IR (neat): 3411, 2926, 1710, 1369, 1156, 984, 854, 819 cm–1.

1H NMR (500 MHz, CDCl3): δ = 6.83 (dd, J = 15.5, 7.3 Hz, 1 H), 6.44 (dd, J = 14.3, 8.1 Hz, 1 H), 5.98 (d, J = 14.3 Hz, 1 H), 5.79 (d, J = 15.7 Hz, 1 H), 3.78 (m, 1 H), 3.40–3.28 (m, 2 H), 2.46–2.39 (m, 2 H), 2.31 (m, 1 H), 1.96–1.88 (m, 2 H), 1.66 (m, 1 H), 1.47 (s, 9 H), 1.33 (m, 1 H), 1.19–1.09 (m, 2 H), 1.0 (d, J = 6.7 Hz, 3 H).

13C NMR (125 MHz, CDCl3): δ = 165.7, 151.8, 143.4, 125.2, 80.1, 74.1, 73.4, 73.0, 68.0, 41.9, 41.0, 40.7, 38.4, 37.0, 28.15, 19.0.

MS (ESI): m/z = 459 [M + Na]+.

HRMS: m/z calcd for C18H29IO4Na [M + Na]+: 459.1002; found: 459.1009.


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(2S,3S,4R,5R,6R)-6-{(2S,4R,6R)-2-[(E)-4-tert-Butoxy-4-oxobuten­yl]-6-[(R,E)-4-iodo-2-methylbut-3-enyl]tetrahydro-2H-pyran-4-yloxy}-5-methoxy-2-methyltetrahydro-2H-pyran-3,4-diyl Diacetate (4)

To a suspension of flame dried 4 Å MS (100 mg) in CH2Cl2 (3 mL) was added compound 6 (10 mg, 0.023 mmol) in CH2Cl2 (1 mL). Rahmnosyl donor 5 (14 mg, 0.034 mmol) was added as a solid to the above mixture at 0 °C and stirred at r.t. for 45 min and then cooled to –50 °C. A solution of TESOTf (1.6 μL, 6.9 μmol) in CH2Cl2 (2 mL) was added to the reaction mixture in a dropwise manner and stirred at the same temperature for 30 min. The mixture was quenched with Et3N (25 μL) and filtered through a short pad of Celite, and the filtrate was evaporated under reduced pressure. The crude compound was purified by column chromatography (SiO2, 18% EtOAc in hexane) to furnish compound 4 (13.4 mg, 86%) as a colorless oil; Rf = 0.5 (SiO2, 30% EtOAc in hexane); [α]D 31 –54.0 (c 0.45, CHCl3).

IR (neat): 2924, 1746, 1712, 1454, 1369, 1242, 1157, 1113, 1042, 848, 819 cm–1.

1H NMR (500 MHz, CDCl3): δ = 6.82 (dt, J = 15.4, 7.3 Hz, 1 H), 6.46 (dd, J = 14.3, 8.0 Hz, 1 H), 5.99 (dd, J = 14.3, 0.9 Hz, 1 H), 5.80 (dt, J = 15.5, 1.3 Hz, 1 H), 5.20 (dd, J = 10.1, 3.2 Hz, 1 H), 5.10 (dd, J = 9.7, 9.9 Hz, 1 H), 4.97 (d, J = 1.52 Hz, 1 H), 3.83 (m, 1 H), 3.75 (m, 1 H), 3.56 (dd, 3.2, 1.9 Hz, 1 H), 3.48 (s, 3 H), 3.38–3.29 (m, 2 H), 2.47–2.39 (m, 2 H), 2.32 (m, 1 H), 2.07 (s, 3 H), 2.03 (s, 3 H), 1.97 (m, 1 H), 1.89 (m, 1 H), 1.66 (m, 1 H), 1.48 (s, 9 H), 1.35–1.23 (m, 3 H), 1.20 (d, J = 6.2 Hz, 3 H), 1.00 (d, J = 6.71 Hz, 3 H).

13C NMR (125 MHz, CDCl3): δ = 170.3, 169.8, 165.7, 151.8, 143.2, 125.29, 95.5, 80.2, 78.8, 74.0, 73.4, 73.2, 73.1, 71.6, 71.5, 66.7, 59.6, 41.9, 39.0, 38.5, 37.0, 36.9, 28.1, 20.9, 20.8, 18.9, 17.4.

MS (ESI): m/z = 698 [M + NH4]+.

HRMS: m/z calcd for C29H49INO10 [M + NH4]+: 698.2395; found: 698.2413.


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Acknowledgment

S. Athe is thankful to the CSIR, New Delhi for research fellowships. S.G. thanks the CSIR for funding the project through the 12th five-year plan ORIGIN and CSIR Young Scientist Research Grant.

Supporting Information

    Supporting information for this article is available online at http://dx.doi.org.accesdistant.sorbonne-universite.fr/10.1055/s-0035-1561319.
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Zoom Image
Figure 1 Structure of mandelalide A (proposed and natural)
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Scheme 1 Retrosynthetic analysis
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Scheme 2 Reagents and conditions: (a) i. n-BuLi, MePO(OMe)2, THF, –78 °C to r.t., 1 h, ii. DMP, CH2Cl2, 81% (over two steps); (b) LiCl, DIPEA, MeCN, r.t., 30 min then 11, 12 h, 82%; (c) HF·Py, MeCN, 0 °C to r.t., 12 h, 90%; (d) [Pd(MeCN)4](BF4)2, CH2Cl2, r.t., 30 min, (6R)-8 (53%) and (6S)-8 (13%); (e) tert-butyl acrylate, Grubbs II, CuI, Et2O, r.t., 2 h, 84%; (f) NaBH4, MeOH, –10 °C, 15 min, 91%; (g) TBSOTf, 2,6-lutidine, CH2Cl2, 30 min, 96%; (h) DDQ, pH 7 buffer, CH2Cl2, 10 min, 88%; (i) i. DMP, NaHCO3, CH2Cl2, 0 °C to r.t.,1 h, ii. CHI3, CrCl3, Zn dust, NaI, r.t., 30 min, 91% (over two steps); (j) HF·Py, MeCN, 0 °C to r.t., 12 h, 94%; (k) 5, TESOTf, 4 Å MS, CH2Cl2, 0 °C to –50 °C, 30 min, 86%.