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Journal of the Brazilian Chemical Society

Print version ISSN 0103-5053On-line version ISSN 1678-4790

J. Braz. Chem. Soc. vol.30 no.8 São Paulo Aug. 2019  Epub Aug 12, 2019

http://dx.doi.org/10.21577/0103-5053.20190126 

Communication

Synthesis of the C(7)-C(20) Fragment of Spirotoamides A, B and C

Allan F. C. Rossinia 

Luiz C. Dias*  a 
http://orcid.org/0000-0003-0628-9928

aInstituto de Química, Universidade Estadual de Campinas, Rua Monteiro Lobato, 270, 13083-970 Campinas-SP, Brazil


ABSTRACT

This work describes the preparation of the C(7)-C(20) fragment of spirotoamides A to C in a very elegant fashion, achievement very high levels of stereocontrol. The synthesis has been accomplished by a sequence involving 14 steps (0.36% overall yield, average of 81% for each step) in high diastereo and enantioselectivity, employing, as determining steps, asymmetric Mukaiyama and boron-mediated 1,5-anti promoted aldol reactions between α-methyl-β-hydroxyketones and aldehydes.

Keywords: total synthesis; natural products; aldol reactions; Mukaiyama reaction; spirotoamides

Introduction

Recently, four new polyketides containing 6,6-spiroketal cores with two anomeric effects, and terminal amide were isolated. Spirotoamides A and B in 2012 by Nogawa et al.1 and the spirotoamides C and D in 2017 by Yang et al.2 All compounds were isolated from a fraction of the microbial metabolite of Streptomyces griseochromogenes JC82-1223,3 presenting 9 or 10 stereogenic centers, in which the fragment containing the spiroketal contains 7 of them.

Having only the structural knowledge from their isolation, the high structural complexity of such compounds inspired us to prepare the C(7)-C(20) fragment, similar to spirotoamides A to C, which contains the same stereogenic centers of spiroketal (Figure 1).

Figure 1 Structure of spirotoamides A, B and C and fragment C7-C20. 

Results and Discussion

Our disconnection strategy is summarized in Scheme 1. Intermediate 4 (C(7)-C(20) fragment) can be obtained by a Mukaiyama aldol reaction (key step) between the aldehyde 5 and the enolsilane 6. The enolsilane 6 (C(7)-C(16) fragment), in turn, can be obtained by a boron-mediated aldol reaction between α-methyl-β-hydroxyketone 9 (C(12)-C(16) fragment) and the aldehyde 10 (C(7)-C(11) fragment). Both the aldehyde 5 and the methylketone 9 can be prepared by the boron-mediated aldol reaction in good levels of 1,4-anti induction between a-hydroxyethylketone 8 and acetaldehyde (7) (Scheme 1).

Scheme 1 Retrosynthetic analysis. 

Our approach to the C(7)-C(20) fragment of spirotoamides A, B and C began with the asymmetric alkylation of the Evans auxiliary411 with 3-iodo-2-methylprop-1-ene (13), leading to the formation of the alkylation product 12 in 82% yield and diastereoselectivity (ds) of > 95:05. Reduction of 12 in the presence of LiAlH4 led to the formation of alcohol 14 in 95% isolated yield.4 Alcohol 14 was subjected to oxidation following Swern reaction conditions,5 resulting in the aldehyde 10 (C(7)-C(11) fragment) in quantitative yield (Scheme 2).

Scheme 2 Synthesis of aldehyde 10

In the meantime, ethyl ketone 8 was reacted with acetaldehyde (7) in an asymmetric 1,4-anti induced aldol reaction leading to the formation of the aldol adduct 15 in 81% yield and ds > 95:05, according to literature procedure.6 Subsequently, the alcohol 15 was subjected to reaction with p-methoxybenzyl (PMB) trichloroacetimidate, resulting in the PMB ether 16 in 84% yield.6 Ketone 16 was then treated with LiBH4 followed by oxidative cleavage reaction, leading to formation of the aldehyde 17 in 98% yield for two steps,7 thereafter the aldehyde 17 was reacted with MeLi,8 leading to a mixture of diastereoisomers which were transformed into methylketone 9 through Swern oxidation (Scheme 3).5

Scheme 3 Synthesis of α-methyl-β-hydroxyketone 9

In an analogous manner, aldehyde 5 can be prepared by subjecting aldol adduct 15 to protection reaction in presence of tert-butyldimethylsilyl trifluoromethanesulfonate (TBSOTf),6 followed by reduction with LiBH4 and oxidative cleavage (Scheme 4).7

Scheme 4 Synthesis of α-methyl-β-hydroxyaldehyde 5

Aldehyde 10, previously prepared (Scheme 2), was employed in the aldol reaction with the boron enolate formed from methylketone 9, leading to the formation of the aldol adduct 19 in good yield and ds > 95:05 (Scheme 5).9

Scheme 5 Preparation of aldol adduct 19

In the next step, alcohol 19 was diastereoselectively reduced under Evans-Saksena reaction conditions, using Me4NHB(OAc)3 as a complexing agent and camphorsulfonic acid (CSA) in acetic acid, resulting in diol 20 in high yield and excellent diastereoselectivity in favor of the 1,3-anti isomer.10 Subsequently, diol 20 was subjected to the protection reaction with 2,2-dimethoxypropane (DMP) catalyzed by CSA for 12 h,10 resulting in acetonide 21 in 91% yield. The acetonide 21 made it possible to determine the relative stereochemistry of C(11) and C(13) by 13C nuclear magnetic resonance (NMR) analysis according to Rychnovsky’s method.11 The observed 13C NMR chemical shifts at δ 24.5, 24.4 and 100.1 ppm are characteristic of a trans acetonide (Scheme 6).

Scheme 6 Synthesis of acetonide 21 and indirect determination of the stereochemistry of diol 20

For the determination of C(14) and C(15) absolute configurations, PMB ether 20 was subjected to cyclization reaction in the presence of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and molecular sieves,10 leading to the formation of the p-methoxyphenyl (PMP) acetal 22 in 79% yield. 1H NMR analysis showed coupling between hydrogens Hb-Hd (10.2 Hz) and Hc-Hd (9.8 Hz), characteristic of hydrogens in a trans relationship and selective nuclear Overhauser effect (NOE) experiment showed increments of 5.61% between Ha and Hb and of 4.90% between Ha and Hc, possibly for hydrogen atoms in 1,3-diaxial positions (Scheme 7).

Scheme 7 Determination of the stereochemistry of the aldol adduct 19

Subsequently, the PMP acetal 22 was subjected to cyclization under acidic conditions, leading to the formation of the hydrofuran 23 in 79% yield.12 Compound 23 was analyzed by nuclear Overhauser effect spectroscopy (NOESY; from this experiment, two chemical shifts were selected, 1.21 and 1.31 ppm), allowing to visualize increments of 0.48% between Ha and Mea, 0.64% between Hb and Mea, 1.27% between Hc and Mea and 0.72% between Hd and Meb, according to Felkin relationship between C(10) and C(11) (Scheme 8).

Scheme 8 Determination of the relative stereochemistry of hydrofuran 23

Reaction of diol 20 with chloromethyl methyl ether (MOMCl) and N,N-diisopropylethylamine (DIPEA) in dichloromethane resulted in the formation of intermediate 24,13 which in the presence of DDQ was transformed into alcohol 25,10 which after oxidation under Dess-Martin conditions afforded methylketone 26 in 97% yield.14 Methylketone 26 was converted to the enolsilane 6 in the presence of lithium diisopropylamide (LDA) and trimethylsilyl chloride (TMSCl) in 91% isolated yield (Scheme 9).15

Scheme 9 Synthesis of the enolsilane 6

With the requisite C(7)-C(16) and C(17)-C(20) fragments in hand, their coupling (key step) was undertaken using Mukaiyama conditions,16 with selective 1,3-anti induction, leading to the product of interest (4) in 89% yield and diastereoselectivity > 95:05 (Scheme 10).

Scheme 10 Mukaiyama aldol reaction (key step) for the preparation of the C(7)-C(19) fragment. 

1H NMR analysis following the ABX method17 gave us indications that the relative stereochemistry between C18 methyl and C17 hydroxyl is 1,3-anti. It can be seen that adduct 4 has coupling constants for Ha of 8.0 Hz (expected 7.8-10.0 Hz) and Hb of 4.6 Hz (expected 1.1-5.4 Hz). The experimental values are consistent with a Felkin compound, therefore confirms the 1,3-anti induction (Scheme 10).

Conclusions

In conclusion, we have described an efficient asymmetric synthesis of the C(7)-C(20) fragment of spirotoamides A, B and C. This approach required 14 steps for the longest linear sequence (0.36% overall yield, average of 81% for each step). The determinant steps of this work involved the boron-mediated 1,5-anti aldol reaction between α-methyl-β-hydroxyketone 9 and aldehyde 10 and the induction promoted by the Mukaiyama aldol reaction between α-methyl-β-hydroxyaldehyde 5 and enolsilane 6. As a result, the C(7)-C(20) fragment can be obtained in highly diastereoselective form and all the stereocenters could be determined during the synthesis or by derivatization. Extension of this work toward completion on the synthesis of spirotoamides A, B, and C is underway and results will be described in due course.

Experimental

All reactions were carried out under an atmosphere of argon with dry solvents under anhydrous conditions unless otherwise stated. Tetrahydrofuran (THF) and diethyl ether (Et2O) were distilled from sodium/benzophenone prior to use. Triethylamine (Et3N), 2,6-lutidine, N,N-dimethylethylamine (DMEA), DIPEA, dichloromethane (CH2Cl2), and acetonitrile (MeCN) were distilled from calcium hydride prior to use. Acetic acid (AcOH) was fractionally distilled from acetic anhydride and chromium (VI) oxide prior to use. CSA was recrystallized from ethyl acetate. All other reagents were used without further purification, unless otherwise stated. The purification of reaction products was performed by flash column chromatography using silica gel (230-400 mesh). Organic solutions were concentrated under reduced pressure on a Büchi rotary evaporator R-215, B-491. Reactions were monitored by thin layer chromatography carried out on silica-gel 60 and GF (5-40 µm thickness) plates with fluorescent indicator, and visualization was accomplished using UV light, phosphomolybdic acid (PMA), KMnO4 or vanillin followed by heating. Optical rotations were measured on a PerkinElmer 341 polarimeter with a sodium lamp using a 1.0 cm cell and are reported as follows: [α]DT(ºC) (c (g per 100 mL), solvent). Melting points were measured with a Buchi M-565 equipment and are uncorrected. 1H and proton-decoupled 13C NMR spectrum were acquired on a Bruker DPX250 (250 MHz for 1H NMR and 62.5 MHz for 13C NMR), Bruker Avance 400 (400 MHz for 1H NMR and 100 MHz for 13C NMR), Bruker Avance 500 (500 MHz for 1H and 125 MHz for 13C NMR), or Bruker Avance 600 (600 MHz for 1H and 150 MHz for 13C NMR). Chemical shifts (δ) are reported in ppm using residual undeuterated solvent as an internal standard (CHCl3 at 7.26 ppm and TMS at 0.00 ppm for 1H NMR spectrum and CDCl3 at 77.0 ppm for 13C NMR spectrum). Multiplicity data are reported as follows: s = singlet, br s = broad singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublets, ddd = doublet of doublet of doublets, dt = doublet of triplets, dq = doublet of quartets, ddt = doublet of doublets of triplets, td = triplet of doublets, tt = triplet of triplets, tq = triplet of quartets, qdd = quartet of doublets of doublets, and m = multiplet. The multiplicity is followed by the coupling constant(s) in Hz and integration. Infrared spectrum (IR) was recorded on PerkinElmer Spectrum Two spectrometer. Wavelengths of maximum absorbance (max) are quoted in wavenumbers (cm-1). High-resolution mass spectrometry (HRMS) were measured using electrospray ionization (ESI) (Thermo Scientific LTQ, FT Ultra).

Synthesis, characterization and spectra data of aldehyde 10 (C(7)-C(11) fragment)

(R)-4-Benzyl-3-((S)-2,4-dimethylpent-4-enoyl)oxazolidin-2-one (12)

To a 250 mL flask containing n-BuLi (47.7 mmol, 19.0 mL, 2.5 M in hexane) in THF (50 mL) at –78 ºC was added diisopropylamine (DIPA) (47.7 mmol, 4.82 g, 6.7 mL). The reaction mixture was stirred for 1 h at -78 ºC. Subsequently, a solution containing the oxazolidinone 11 (44.6 mmol, 10.40 g in 20 mL of THF) was added via cannula and the mixture was stirred at -78 ºC for a further 30 min. Thereafter, the alkyl iodide 13 (90 mmol, 17.00 g, 10.4 mL) was added dropwise. The reaction was stirred at -78 ºC for 1 h and at -40 ºC for 2 h. The reaction was warmed to 0 ºC, then the mixture was washed with saturated aqueous ammonium chloride solution (50 mL), which was extracted with dichloromethane (CH2Cl2) (4 × 50 mL). The organic phase was dried with MgSO4. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography using silica gel as the stationary phase and hexane/ethyl acetate (17:3) as the eluent to afford the corresponding alkylation product 12 (yellow oil) in 10.40 g, 82% yield (36.6 mmol). Rf: 0.30, UV/PMA (Hex:EtOAc, 17:3); [α]D20 –54.2 (c 1.0, CH2Cl2); IR (attenuated total reflectance (ATR)) ν / cm-1 3074, 3030, 2975, 2936, 1775, 1697, 1455, 1385, 1207, 1195, 701; 1H NMR (500 MHz, CDCl3) δ 7.35-7.31 (m, 2H), 7.29-7.25 (m, 1H), 7.22-7.20 (m, 2H), 4.81 (br s, 1H), 4.76 (br s, 1H), 4.69 (ddt, J 7.4, 6.6, 3.2 Hz, 1H), 4.19 (dd, J 8.9, 7.8 Hz, 1H), 4.15 (dd, J 9.1, 3.1 Hz, 1H), 4.03 (apparent sextet, J 7.1 Hz, 1H), 3.27 (dd, J 13.4, 3.2 Hz, 1H), 2.71 (dd, J 13.4, 9.7 Hz, 1H), 2.57 (dd, J 13.8, 7.0 Hz, 1H), 2.09 (dd, J 13.8, 7.5 Hz, 1H), 1.78 (s, 3H), 1.16 (d, J 6.8 Hz, 3H); 13C NMR (150 MHz, CDCl3) d 176.9, 153.1, 142.9, 135.3, 129.4, 128.9, 127.3, 112.5, 65.9, 55.3, 41.8, 37.9, 35.5, 22.2, 16.6.

(S)-2,4-Dimethylpent-4-en-1-ol (14)

To a flask containing compound 12 (1 equiv., 28.0 mmol, 8.00 g), it was added methanol (1.1 equiv., 32 mmol, 1.3 mL) in Et2O (mL). The mixture was cooled to 0 ºC, LiBH4 (1 equiv., 28.0 mmol, 16.0 mL, 2 M in tetrahydrofuran) was added and the mixture stirred at 0 ºC for 45 min. The reaction was then warmed to room temperature and was stirred for 90 min, then the reaction was quenched in the presence of NaOH (4.50 g in 50 mL of water) and extracted with ethyl ether (Et2O) (3 × 80 mL). The organic phase was dried with MgSO4. After filtration the solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography using silica gel as the stationary phase and pentane/ethyl ether (2:1) as eluent, resulting in alcohol 14 (colorless oil) in 3.46 g, 95% yield (26.6 mmol). Rf: 0.34, PMA (Hex:Et2O, 2:1); [α]D20 –5.7 (c 2.0, CH2Cl2); IR (ATR) ν / cm-1 3338, 3075, 2956, 2918, 2873, 1651; 1H NMR (500 MHz, CDCl3) δ 4.76 (br s, 1H), 4.71 (br s, 1H), 3.50 (dd, J 10.6, 5.5 Hz, 1H), 3.43 (dd, J 10.6, 5.6 Hz, 2H), 2.18-2.10 (m, 1H), 1.97 (s, 1H), 1.90-1.80 (m, 1H), 1.72 (s, 3H), 0.90 (d, J 6.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) d 144.4, 111.6, 68.2, 42.2, 33.5, 22.1, 16.5.

(S)-2,4-Dimethylpent-4-enal (10)

To a flask of 15 mL containing oxalyl chloride (3 equiv., 3 mmol, 0.5908 g, 0.40 mL) in dichloromethane (5 mL) was added dimethyl sulfoxide (DMSO; 5.5 equiv., 5.5 mmol, 0.4297 g, 0.39 mL). The mixture was stirred at -78 ºC for 30 min. Then the alcohol 14 (1 equiv., 1 mmol, 0.1142 g) was added and the mixture stirred at -78 ºC for a further 30 min. The mixture was warmed to 0 ºC followed by addition of triethylamine (12 equiv., 12 mmol, 1.1673 g, 1.6 mL) while stirring at 0 ºC for 90 min. The reaction was washed with saturated aqueous ammonium chloride solution (NH4Cl) (20 mL), which was extracted with ethyl ether (Et2O) (3 × 30 mL). The organic phase was dried with MgSO4. After filtration, the solvent was evaporated under reduced pressure, giving aldehyde 10 (yellowish oil) in 0.1122 g, in quantitative yield (1 mmol). Rf: 0.50, PMA (Hex:EtOAc, 9:1); [α]D20 +3.7 (c 2.0, CH2Cl2); IR (ATR) ν / cm-1 3074, 2955, 2920, 2871, 2855, 1724, 1650, 1457; 1H NMR (500 MHz, CDCl3) δ 9.64 (d, J 1.9 Hz, 1H), 4.82 (br s, 1H), 4.73 (br s, 1H), 2.58-2.51 (m, 1H), 2.17 (d, J 16.3 Hz, 1H), 2.03 (dd, J 14.3, 8.0 Hz, 1H), 1.73 (s, 3H), 1.08 (d, J 7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 204.8, 142.2, 112.8, 44.2, 38.8, 22.2, 13.4.

Synthesis, characterization and spectra data of ketone 9 (C(12)-C(16) fragment)

(2S,4R,5R)-5-Hydroxy-4-methyl-3-oxohexan-2-yl benzoate (15)

To a 100 mL flask containing dicyclohexylborane chloride ((c-C6H11)2BCl) (1.5 equiv., 7.2 mmol, 1.5270 g, 1.60 mL) in 20 mL of diethyl ether at -78 ºC dimethylethylamine (Me2NEt) (11.8 equiv., 8.6 mmol, 0.2632 g, 0.38 mL) and ethylketone 8 (4.8 mmol, 1.00 g in 20 mL of Et2O, via cannula) were added dropwise. The mixture was warmed to 0 ºC and was stirred for 2 h. The reaction mixture was then cooled to -78 ºC, followed by a dropwise addition of the acetaldehyde (5 equiv., 24.0 mmol, 1.0570 g, 1.3 mL in 20 mL of Et2O, via cannula). After 1 h at -78 ºC the mixture was warmed to -20 ºC (freezer) and stirred for 14 h. The temperature was raised to 0 ºC, followed by the slow addition of MeOH (20 mL), phosphate buffer pH 7 (20 mL) and H2O2 30% solution (20 mL). The reaction was stirred at 0 ºC for 1 h, then the mixture was extracted with dichloromethane (CH2Cl2) (3 × 50 mL). The organic phase was dried with MgSO4. After filtration the solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography using silica gel as the stationary phase and dichloromethane/ethyl ether (4:1) as the eluent to give the aldol adduct 15 (off-white solid) in 0.9720 g, 81% yield (3.9 mmol) and ds > 95:05. Rf: 0.49, PMA (CH2Cl2:Et2O, 4:1); [α]D20 +38.1 (c 1.4, CHCl3); mp 85.2-86.7 ºC; IR (ATR) ν / cm-1 3348, 2976, 2935, 2880, 1732, 1719, 1602, 1585, 1485, 1451, 1264, 1111, 1006, 706; 1H NMR (500 MHz, CDCl3) δ 8.08 (dd, J 8.4, 1.3 Hz, 2H), 7.59 (t, J 7.4, 1.3 Hz, 1H), 7.46 (t, J 7.7 Hz, 2H), 5.44 (q, J 7.1 Hz, 1H), 3.98 (pentet, J 6.4 Hz, 1H), 2.81 (pentet, J 7.2 Hz, 1H), 2.51 (br s, 1H), 1.57 (d, J 7.1 Hz, 3H), 1.25 (d, J 7.2 Hz, 3H), 1.23 (d, J 6.4 Hz, 3H); 13C NMR (125 MHz, CDCl3) d 211.7, 165.8, 133.3, 129.7, 129.4, 128.4, 74.5, 69.4, 49.9, 20.8, 15.8, 14.4.

(2S,4R,5R)-5-((4-Methoxybenzyl)oxy)-4-methyl-3-oxohexan-2-yl benzoate (16)

To a mixture with p-methoxybenzyl alcohol (1.5 equiv., 36.0 mmol, 4.9740 g, 4.4 mL) in diethyl ether (19 mL) at room temperature under an inert atmosphere, it was added sodium hydride in mineral oil (0.15 equiv., 3.6 mmol, 0.1440 g of NaH). The suspension was stirred for 1 h. The mixture was cooled to 0 ºC followed by addition of trichloroacetonitrile (1.5 equiv., 36.0 mmol, 5.1980 g, 3.6 mL) over 15 min. The mixture was maintained at 0 ºC for 5 min and at room temperature for a further 1 h. The reaction was washed with saturated NaHCO3 (20 mL). The organic phase was dried with MgSO4. After filtration, the solvent was evaporated under reduced pressure. To the residue, it was added the alcohol 15 (1 equiv., 24.0 mmol, 6.00 g), CSA (0.2 equiv., 4.8 mmol, 1.12 g) and CH2Cl2 (40 mL). The reaction mixture was stirred at room temperature for 18 h. Subsequently, the reaction was washed with saturated aqueous NaHCO3 solution (200 mL), which was extracted with Et2O (4 × 100 mL). The organic phase was dried with MgSO4. The product was purified by flash column chromatography on hexane/ethyl acetate (9:1) as eluent, providing a colorless oil (16) in 7.4683 g, 84% yield (20.2 mmol). Rf: 0.12, PMA (Hex:EtOAc, 9:1); [α]D20 –26.6 (c 2.0, CHCl3); IR (ATR) ν / cm-1 3064, 3034, 2975, 2937, 2909, 2879, 2837, 1716, 1613, 1513, 1451, 1246, 1114, 1028, 823, 712; 1H NMR (500 MHz, CDCl3) δ 8.08 (d, J 7.2 Hz, 2H), 7.57 (t, J 7.4 Hz, 1H), 7.44 (t, J 7.7 Hz, 2H), 7.16 (d, J 8.6 Hz, 2H), 6.83 (d, J 8.6 Hz, 2H), 5.37 (q, J 7.0 Hz, 1H), 4.42 (d, J 10.8 Hz, 1H), 4.27 (d, J 10.8 Hz, 1H), 3.78 (s, 3H), 2.94 (dq, J 14.2, 7.1 Hz, 1H), 1.47 (d, J 7.0 Hz, 3H), 1.18 (d, J 6.2 Hz, 3H), 1.14 (d, J 7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 209.9, 165.8, 159.0, 133.1, 130.5, 129.8, 129.3, 128.3, 113.6, 76.8, 75.1, 71.1, 55.2, 49.0, 16.7, 15.2, 13.6.

(2R,3R)-3-((4-Methoxybenzyl)oxy)-2-methylbutanal (17)

To a 500 mL flask containing the benzoate ester 16 (1 equiv., 20.0 mmol, 5.3670 g) in THF (20 mL) at -78 ºC and argon atmosphere, lithium borohydride (LiBH4) (10 equiv., 200.0 mmol, 100.0 mL, 2 M in THF) was added. The mixture was stirred at -78 ºC for 10 min, then warmed to room temperature and stirred for a further 12 h. The reaction was cooled to 0 ºC, then 100 mL of water was added and the mixture was washed with saturated aqueous ammonium chloride solution (NH4Cl) (100 mL), then extracted with Et2O (4 × 100 mL). The organic phase was dried with MgSO4. After filtration, the solvent was evaporated under pressure. To the mixture of diols, methanol (200 mL), water (100 mL) and sodium periodate (NaIO4) (5 equiv., 100.0 mmol, 21.4877 g) were added. The reaction mixture was stirred for 1 h at room temperature. Subsequently, distilled water (100 mL) was added to the reaction, which was extracted with Et2O (3 × 100 mL). The organic phase was dried with MgSO4. After filtration the solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography using silica gel as the stationary phase and hexane/EtOAc (4:1) as eluent to afford a colorless oil (17) in 4.3567 g, 98% yield (19.6 mmol). Rf: 0.32, PMA (Hex:EtOAc, 4:1); [α]D20 –46.7 (c 2.0, CHCl3); IR (ATR) ν / cm-1 2974, 2936, 2876, 2831, 2718, 1722, 1612, 1513, 1245, 1033, 819; 1H NMR (400 MHz, CDCl3) d 9.70 (d, J 2.4 Hz, 1H), 7.23 (d, J 8.6 Hz, 2H), 6.87 (d, J 8.7 Hz, 2H), 4.54 (d, J 11.3 Hz, 1H), 4.37 (d, J 11.3 Hz, 1H), 3.79 (s, 3H), 3.78-3.74 (m, 1H), 2.53 (apparent pentet, J 7.1 and 2.4 Hz, 1H), 1.23 (d, J 6.3 Hz, 3H), 1.06 (d, J 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 204.5, 159.1, 130.2, 129.2, 113.7, 74.8, 70.3, 55.2, 51.7, 16.8, 10.0.

(3R,4R)-4-((4-Methoxybenzyl)oxy)-3-methylpentan-2-one (9)

To a 250 mL flask containing the aldehyde 17 (1 equiv., 20.0 mmol, 4.4456 g) in Et2O (80 mL) at -78 ºC and argon atmosphere was added methyllithium (MeLi) (3 equiv., 45.0 mmol, 28.1 mL, 1.6 M in THF) dropwise. The mixture was stirred at -78 ºC for 30 min, subsequently warmed to -30 ºC and stirred for an additional 1 h. Then, buffer solution pH 7 (120 mL) was added. The mixture was extracted with Et2O (4 × 80 mL), washed with saturated sodium chloride (NaCl) solution (100 mL). The organic phase was dried with MgSO4. After filtration, the solvent was evaporated under reduced pressure, and the mixture of alcohols was used in the next step without purification. To a 250 mL flask containing oxalyl chloride (1.5 equiv., 30.0 mmol, 3.8079 g, 2.4 mL) in dichloromethane (120 mL, 0.25 M) at -78 ºC, it was added DMSO (3.0 equiv., 60.0 mmol, 4.6878 g, 4.3 mL). The mixture was stirred at -78 ºC for 30 min. Thereafter, the pre-prepared mixture of the alcohols was added and stirred at -78 ºC for 30 min. The mixture was warmed to 0 ºC followed by addition of triethylamine (Et3N) (5 equiv., 100.0 mmol, 10,1190 g, 14.0 mL), and stirred at 0 ºC for 90 min. The reaction was washed with saturated aqueous NH4Cl solution (100 mL) and extracted with Et2O (3 × 100 mL). The organic phase was washed with water (100 mL), saturated aqueous NaCl solution (100 mL), and dried over MgSO4. After filtration, the solvent was evaporated under reduced pressure, affording a yellowish oil (9) in 4.4899 g, 95% yield over two steps (19.0 mmol), and was used in the next step without purification. Rf: 0.32, PMA (Hex:EtOAc, 4:1); [α]D20 –37.9 (c 2.4, CHCl3); IR (ATR) ν / cm-1 2973, 2936, 2911, 2878, 2837, 1711, 1613, 1513, 1456, 1377, 1355, 1245, 1033, 821; 1H NMR (400 MHz, CDCl3) δ 7.20 (d, J 8.7 Hz, 2H), 6.86 (d, J 8.7 Hz, 2H), 4.48 (d, J 11.0 Hz, 1H), 4.32 (d, J 11.0 Hz, 1H), 3.79 (s, 3H), 3.71 (dq, J 8.2, 6.1 Hz, 1H), 2.73 (pentet, J 7.2, 1H), 2.15 (s, 3H), 1.17 (d, J 6.2 Hz, 3H), 1.02 (d, J 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 212.1, 159.0, 130.4, 129.2, 113.7, 76.7, 70.6, 55.2, 52.6, 30.0, 16.6, 12.6.

Synthesis, characterization and spectra data of aldehyde 5 (C(17)-C(19) fragment)

(2S,4R,5R)-5-((tert-Butyldimethylsilyl)oxy)-4-methyl-3-oxohexan-2-yl benzoate (18)

To a flask, it was added the alcohol 15 (1 equiv., 5.0 mmol, 1.2515 g) in dichloromethane (50 mL). The reaction mixture was cooled to -78 ºC, 2,6-lutidine (2.0 equiv., 10.0 mmol, 1.15 mL) and TBSOTf (1.5 equiv., 7.5 mmol, 1.70 mL) were added. The reaction was stirred for 1 h at -78 ºC. Then, the reaction was washed with saturated aqueous solution of NaHCO3 (100 mL) and extracted with Et2O (3 × 100 mL). The organic phase was dried with MgSO4. The product was purified by flash column chromatography on hexane/dichloromethane (1:1) as eluent to provide aldol 18 (colorless oil) adduct in 1.80 g, 99% yield (4.9 mmol). Rf: 0.41, PMA (Hex:CH2Cl2, 1:1); [α]D20 –15.5 (c 1.0, CHCl3); IR (ATR) ν / cm-1 3065, 2956, 2930, 2886, 2858, 1721, 1603, 1586, 1472, 1452, 1380, 1266, 1116, 711; 1H NMR (250 MHz, CDCl3) δ 8.08 (dt, J 7.0, 1.5 Hz, 2H), 7.57 (tt, J 7.3, 2.0 Hz, 1H), 7.45 (tt, J 6.4, 1.5 Hz, 2H), 5.41 (q, J 7.0 Hz, 1H), 4.06 (dq, J 8.4, 6.1 Hz, 1H), 2.85 (dq, J 14.1, 7.1 Hz, 1H), 1.52 (d, J 7.0 Hz, 3H), 1.15 (d, J 6.1 Hz, 3H), 1.09 (d, J 7.1 Hz, 3H), 0.84 (s, 9H), 0.04 (s, 3H), –0.03 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 209.4, 165.7, 133.2, 129.8, 129.7, 128.4, 75.1, 70.1, 50.5, 25.8, 21.1, 17.9, 15.2, 13.8, –4.7, –4.9; HRMS (ESI) m/z, calcd. for [M + Na]+: 387.19621, found: 387.19548.

(2R,3R)-3-((tert-Butyldimethylsilyl)oxy)-2-methylbutanal (5)

The aldehyde 5 was prepared under the same conditions as showed for the preparation of compound 17, resulting in a colorless oil in 0.5302 g, 98% yield. Rf: 0.40, PMA (Hex:EtOAc, 9:1); [α]D20 –48.1 (c 1.0, benzene); IR (ATR) ν / cm-1 2957, 2931, 2886, 2858, 2711, 1727, 1473, 1463, 1253, 1115, 1005; 1H NMR (400 MHz, CDCl3) δ 9.74 (d, J 2.6 Hz, 1H), 4.02 (pentet, J 6.2 Hz, 1H), 2.36 (qdd, J 7.0, 5.8, 2.6 Hz, 1H), 1.21 (d, J 6.3 Hz, 3H), 1.06 (d, J 7.0 Hz, 3H), 0.86 (s, 9H), 0.06 (s, 3H), 0.05 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 205.2, 69.8, 53.6, 26.0, 21.7, 17.9, 10.6, 8.9, –4.2, –5.0.

Synthesis and characterization, spectra data and stereochemistry determination of diol 20

(2R,3R,6S,7S)-6-Hydroxy-2-((4-methoxybenzyl)oxy)-3,7,9-trimethyldec-9-en-4-one (19)

To a flask containing methyl ketone 9 (1.0 equiv., 8.5 mmol, 2.0086 g) in Et2O (170 mL, 0.05 M) at -30 ºC, it was added slowly (c-hex)2BCl (2.0 equiv., 17.0 mmol, 3.6066 g, 3.7 mL) and Et3N (2.1 equiv., 17.8 mmol, 1.7996 g, 2.5 mL), resulting in a white solution. After the addition of Et3N, the mixture was cooled to -78 ºC. Subsequently, the aldehyde 17 (3.0 equiv., 25.5 mmol, 2.8603 g) was added dropwise. The reaction mixture was stirred at -78 ºC. After 1 h, methanol (MeOH) (170 mL) was added to the reaction, which was warmed to room temperature. The solvent was evaporated under vacuum and the residue was purified by flash column chromatography using silica gel as the stationary phase and hexane/ethyl acetate (4:1) as eluent to provide aldol 19 (colorless oil) adduct in 2.4881 g, 84% yield (7.1 mmol) and ds > 95:05. Rf: 0.23, PMA (Hex:EtOAc, 4:1); [α]D20 –32.1 (c 1.0, CHCl3); IR (ATR) ν / cm-1 3485, 3073, 2967, 2931, 2879, 1708, 1614, 1514, 1378, 1249, 1104, 1036, 824; 1H NMR (500 MHz, CDCl3) δ 7.17 (d, J 8.6 Hz, 2H, ArH), 6.85 (d, J 8.6 Hz, 2H, ArH), 4.76 (s, 1H, H-7), 4.68 (s, 1H, H-7), 4.48 (d, J 10.8 Hz, 1H), 4.25 (d, J 10.8 Hz, 1H), 3.95 (ddd, J 9.5, 3.6, 2.7 Hz, 1H, H-11), 3.79 (s, 3H, OCH3), 3.68 (dq, J 8.7, 6.1 Hz, 1H, H-15), 2.98 (br s, 1H, OH), 2.72 (dq, J 8.7, 7.0 Hz, 1H, H-14), 2.64 (dd, J 17.6, 2.4 Hz, 1H, H-12), 2.55 (dd, J 17.6, 9.6 Hz, 1H, H-12), 2.15 (dd, J 13.4, 5.3 Hz, 1H, H-9), 1.80 (dd, J 13.5, 9.3 Hz, 1H, H-9), 1.68 (s, 1H, H-22), 1.66-1.60 (m, 1H, H-10), 1.20 (d, J 6.1 Hz, 3H, H-16), 1.01 (d, J 7.0 Hz, 3H, H-23), 0.80 (d, J 6.8 Hz, 3H, H-24); 13C NMR (125 MHz, CDCl3) δ 215.9, 159.2, 144.1, 130.2, 129.4, 113.7, 111.9, 77.6, 70.8, 70.0, 55.2, 52.2, 47.8, 41.4, 35.4, 22.1, 16.9, 13.8, 13.0; HRMS (ESI) m/z, calcd. for [M + Na]+: 371.21983, found: 371.21912.

(2R,3S,4S,6S,7S)-2-((4-Methoxybenzyl)oxy)-3,7,9-trimethyldec-9-ene-4,6-diol (20)

To a flask containing tetramethylammonium triacetoxyborohydride (4.0 equiv., 28.0 mmol, 7.3563 g) in acetonitrile (MeCN) (21.0 mL), it was added glacial acetic acid (AcOH) (21.0 mL). The mixture was stirred for 30 min. Then, the reaction was cooled to -40 ºC, followed by the addition of a solution of the alcohol 19 (1.0 equiv., 7.0 mmol, 2.4394 g) in AcOH (21.0 mL), dropwise via the cannula and a mixture of CSA (0.5 equiv., 3.5 mmol, 0.8131 g), anhydrous MeCN (21.0 mL) and glacial AcOH (21.0 mL). The reaction mixture was stirred at -20 ºC for 48 h. Subsequently, the mixture was transferred to an Erlenmeyer flask under stirring with saturated aqueous solution of NaHCO3 (250 mL). After the total gas evolution, a saturated solution of Rochelle’s salt (KNaC4H4O6) (250 mL) and CH2Cl2 (250 mL) was added. The resulting mixture was stirred at room temperature for 3 h. Thereafter, the mixture was extracted with CH2Cl2 (4 × 100 mL). The organic phase was dried with MgSO4. After filtration the solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography using stationary phase silica gel and hexane/ethyl acetate (3:2) as eluent to provide diol 20 (yellow oil) at 2.2817 g, 93% yield (6.5 mmol) and ds > 95:05. Rf: 0.31, UV/PMA (Hex:EtOAc, 3:2); [α]D20 –8.1 (c 1.0, CHCl3); IR (ATR) ν / cm-1 3403, 3073, 2967, 2934, 2912, 2838, 1613, 1514, 1455, 1376, 1248, 1036, 888, 821; 1H NMR (600 MHz, CDCl3) δ 7.25 (d, J 8.6 Hz, 2H), 6.87 (d, J 8.6 Hz, 2H), 4.75 (s, 1H), 4.69 (s, 1H), 4.59 (d, J 11.1 Hz, 1H), 4.52 (s, 1H), 4.36 (d, J 11.1 Hz, 1H), 3.88-3.81 (m, 2H), 3.79 (s, 3H), 3.55 (dq, J 8.0, 6.1 Hz, 1H), 3.16 (br s, 1H), 2.20 (dd, J 13.5, 4.9 Hz, 1H), 1.82 (dt, J 15.2, 9.1 Hz, 2H), 1.75-1.70 (m, 2H), 1.69 (s, 3H), 1.53 (ddd, J 14.5, 6.8, 1.9 Hz, 1H), 1.26 (d, J 6.1 Hz, 3H), 0.86 (d, J 6.8 Hz, 3H), 0.79 (d, J 6.9 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 159.3, 144.5, 129.9, 129.5, 113.9, 111.6, 80.3, 73.9, 71.3, 70.3, 55.2, 43.4, 41.5, 36.5, 22.1, 17.3, 13.9, 13.0; HRMS (ESI) m/z, calcd. for [M + Na]+: 373.23548, found: 373.23481.

(4S,6S)-4-((2R,3R)-3-((4-Methoxybenzyl)oxy)butan-2-yl)-2,2-dimethyl-6-((S)-4-methylpent-4-en-2-yl)-1,3-dioxane (21)

To a 250 mL flask containing the diol 20 (1 equiv., 2.0 mmol, 0.7010 g) in 2,2-dimethoxypropane (70 mL), CSA (0.1 equiv., 0.2 mmol, 0.0465 g) was added. The reaction mixture was stirred for 12 h at room temperature. Subsequently, the reaction was diluted with Et2O (50 mL), followed by saturated aqueous solution of NaHCO3 (50 mL) and extraction with Et2O (3 × 50 mL). The organic phase was dried over MgSO4. After filtration the solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography using silica gel as the stationary phase and hexane/EtOAc (9:1) as eluent to provide acetonide 21 (colorless oil) in 0.7108 g, 91% yield (1.8 mmol). Rf: 0.43, UV/PMA (Hex:EtOAc, 9:1); [α]D20 –40.7 (c 1.0, CHCl3); IR (ATR) ν / cm-1 3074, 2982, 2968, 2836, 1613, 1513, 1457, 1376, 1240, 1224, 1108, 1038, 886, 820; 1H NMR (500 MHz, CDCl3) δ 7.26 (d, J 8.5 Hz, 2H), 6.86 (d, J 8.6 Hz, 2H), 4.76 (s, 1H), 4.68 (s, 1H), 4.45 (d, J 11.3 Hz, 1H), 4.40 (d, J 11.3 Hz, 1H), 3.63 (td, J 9.1, 6.1 Hz, 1H), 3.53 (dt, J 9.8, 6.1 Hz, 1H), 3.79 (s, 3H), 3.75 (dq, J 6.2, 5.1 Hz, 1H), 2.15 (dd, J 13.6, 4.8 Hz, 1H), 2.03-1.95 (m, 1H), 1.74 (dd, J 13.2, 9.8 Hz, 1H), 1.70-1.52 (m, 6H), 1.30 (s, 3H), 1.29 (s, 3H), 1.08 (d, J 6.3 Hz, 3H), 0.86 (d, J 6.5 Hz, 3H), 0.84 (d, J 6.9 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 158.9, 144.0, 131.4, 129.1, 113.7, 111.8, 100.1, 74.4, 69.9, 69.8, 68.0, 55.2, 41.8, 40.9, 35.4, 34.6, 24.5, 24.4, 22.1, 14.7, 14.3, 8.9; HRMS (ESI) m/z, calcd. for [M + Na]+: 413.26592, found: 413.26678.

(2S,3S)-1-((2R,4S,5R,6R)-2-(4-Methoxyphenyl)-5,6-dimethyl-1,3-dioxan-4-yl)-3,5-dimethylhex-5-en-2-ol (22)

To a flask containing diol 20 (1 equiv., 57.1 µmol, 20 mg) in CH2Cl2 (2 mL, 0.03 M) under argon atmosphere was added activated 4 Å molecular sieves (36 mg). After 15 min, the mixture was cooled to -10 ºC followed by addition of DDQ (1.25 equiv., 32.0 µmol, 32 mg). The mixture was stirred for 5 min at -10 ºC and 2 h at 0 ºC. Then the reaction was purified by flash column chromatography using silica gel as the stationary phase and hexane/EtOAc (9:1) as the eluent, affording acetal 22 (yellowish oil) in 15.7 mg, 79% yield (45.1 µmol). Rf: 0.12, PMA (Hex:EtOAc, 9:1); [α]D20 –4.9 (c 0.5, CHCl3); IR (ATR) ν / cm-1 3497, 3073, 2968, 2933, 2892, 2840, 1615, 1518, 1455, 1401, 1250, 1075, 1035, 826; 1H NMR (500 MHz, CDCl3) δ 7.40 (d, J 8.7 Hz, 2H), 6.87 (d, J 8.7 Hz, 2H), 5.51 (s, 1H), 4.77 (s, 1H), 4.70 (s, 1H), 3.91 (ddd, J 9.9, 3.8, 1.7 Hz, 1H), 3.79 (s, 3H), 3.75 (ddd, J 10.2, 7.7, 2.8 Hz, 1H), 3.58 (dq, J 9.8, 6.1 Hz, 1H), 2.40 (br s, 1H), 2.20 (dd, J 13.5, 5.0 Hz, 1H), 1.92-1.84 (m, 2H), 1.77-1.62 (m, 5H), 1.62-1.53 (m, 1H), 1.33 (d, J 6.1 Hz, 3H), 0.87 (d, J 6.8 Hz, 3H), 0.85 (d, J 6.7 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 159.8, 144.4, 131.2, 113.6, 111.7, 100.5, 80.0, 78.5, 70.6, 55.3, 41.7, 39.7, 36.4, 36.2, 22.1, 19.4, 13.7, 12.3; HRMS (ESI) m/z, calcd. for [M + Na]+: 371.21918, found: 371.21983.

(2R,4R,5R,6S)-2-(4-Methoxyphenyl)-4,5-dimethyl-6-(((2S,3S)-3,5,5-trimethyltetrahydrofuran-2-yl)methyl)-1,3-dioxane (23)

To a solution containing the acetal 24 (1 equiv., 9.4 µmol, 3.3 mg) in MeCN (1 mL, 0.01 M), it was added HCl(aq) (37%) (0.5 equiv., 4.7 µmol, 0.4 µL). The reaction mixture was stirred for 24 h. Subsequently, the reaction was washed with saturated aqueous solution NaHCO3 (10 mL) and extracted with Et2O (3 × 15 mL). The organic phase was dried with MgSO4. After filtration the solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography using silica gel as the stationary phase and hexane/EtOAc (9:1) as the eluent to give the hydrofuran 23 in 2.6 mg, 79% yield (7.4 µmol). Rf: 0.16, PMA (Hex:EtOAc, 9:1); [α]D20 –54.7 (c 0.35, CHCl3); IR (ATR) ν / cm-1 2967, 2931, 2889, 2838, 1615, 1518, 1457, 1379, 1248, 1036, 826; 1H NMR (600 MHz, CDCl3) δ 7.44-7.41 (m, 2H, ArH), 6.89-6.85 (m, 2H, ArH), 5.56 (s, 1H, OC(H)O), 4.27 (ddd, J 9.8, 6.6, 2.9 Hz, 1H, H-11), 3.79 (s, 3H, OCH3), 3.68 (td, J 10.1, 1.4 Hz, 1H, H-13), 3.57 (dq, J 9.7, 6.1 Hz, 1H, H-15), 2.43 (apparent septet, J 7.2 Hz, 1H, H-10), 1.92 (dd, J 12.3, 7.4 Hz, 1H, H-9), 1.75 (ddd, J 13.9, 10.2, 1.5 Hz, 1H, H-12), 1.50-1.44 (m, 2H, H-9 and H-12), 1.39 (tq, J 9.8, 6.7 Hz, 1H, H-14), 1.31 (d, J 6.1 Hz, 3H, H-16), 1.31 (s, 3H, H-7), 1.21 (s, 3H, H-22), 0.95 (d, J 7.0 Hz, 3H, H-23), 0.85 (d, J 6.6 Hz, 3H, H-24); 13C NMR (150 MHz, CDCl3) δ 159.6, 131.8, 127.3, 113.4, 99.9, 79.3, 78.9, 78.4, 76.8, 55.3, 46.6, 41.2, 36.5, 34.5, 30.8, 29.2, 19.5, 14.8, 12.5; HRMS (ESI) m/z, calcd. for [M + Na]+: 371.21909, found: 371.21983.

Synthesis and characterization, spectra data of enolsilane 6 (C(7)-C(16) fragment)

(2R,3R,4S,6S,7S)-4,6-Bis(methoxymethoxy)-3,7,9-trimethyl­dec-9-en-2-ol (25)

To a flask containing the diol 21 (1 equiv., 2.0 mmol, 0.702 g) in CH2Cl2 (20 mL, 0.1 M) at 0 ºC, it was added DIPEA (9 equiv., 36.0 mmol, 4.6520 g, 6.2 mL) and MOMCl (6 equiv., 24.0 mmol, 2.8980 g, 2.73 mL). The reaction mixture was stirred for 12 h at room temperature. Subsequently, saturated aqueous solution of NH4Cl (10 mL) was added, followed by extraction with CH2Cl2 (3 × 10 mL). The organic phase was dried with MgSO4. After filtration, the solvent was evaporated under reduced pressure. To a mixture of PMB ether 24, it was added a mixture of CH2Cl2:phosphate buffer pH 7 (9:1) (35 mL, 0.5 M) at 0 ºC, followed by the addition of DDQ (1.5 equiv., 3.0 mmol, 0.7175 g). The reaction was stirred at 0 ºC for 90 min, then the reaction was quenched with a saturated aqueous solution of NaHCO3 (100 mL). The reaction mixture was filtered through Celite and washed with CH2Cl2 (6 × 70 mL). The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography using silica gel as the stationary phase and hexane/ethyl acetate (7:3) as eluent to provide the alcohol 25 (colorless oil) in 0.5031 g, 79% yield for two steps (1.6 mmol). Rf: 0.16, vanillin (Hex/EtOAc, 7:3); [α]D20 –37.1 (c 1.0, CHCl3); IR (ATR) ν / cm-1 3437, 3074, 2996, 2934, 2889, 1649, 1455, 1377, 1147, 1093, 1039, 918; 1H NMR (500 MHz, CDCl3) δ 4.78-4.63 (m, 6H), 4.01 (ddd, J 8.5, 4.0, 1.4 Hz, 1H), 3.68 (dt, J 7.4, 2.4 Hz, 1H), 3.57 (dq, J 8.5, 6.2 Hz, 1H), 3.42 (s, 3H), 3.39 (s, 3H), 2.27 (dd, J 13.5, 3.7 Hz, 1H), 2.03-1.93 (m, 1H), 1.79-1.68 (m, 6H), 1.58 (ddd, J 14.7, 9.5, 1.3 Hz, 1H), 1.48 (ddd, J 15.0, 8.8, 1.8 Hz, 1H), 1.22 (d, J 6.2 Hz, 3H), 0.85 (d, J 6.9 Hz, 3H), 0.84 (d, J 6.9 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 144.3, 111.6, 96.9, 96.1, 80.7, 76.9, 69.8, 55.9, 55.7, 44.5, 39.8, 34.6, 32.1, 22.2, 21.4, 14.9, 10.8; HRMS (ESI) m/z, calcd. for [M + Na]+: 341.22985, found: 341.22976.

(3S,4S,6S,7S)-4,6-Bis(methoxymethoxy)-3,7,9-trimethyldec-9-en-2-one (26)

To a solution containing the alcohol 25 (1 equiv., 0.9 mmol, 0.3180 g) in CH2Cl2 (3 mL), it was added NaHCO3 (2.4 equiv., 0.21 mmol, 0.1764 g) and DMP (1.2 equiv., 1.08 mmol, 0.4578 g). The reaction mixture was stirred at room temperature for 90 min. The reaction was washed with saturated aqueous solution of NaHCO3 (30 mL) and Na2SO3 (30 mL) and stirred at room temperature for 10 min. This mixture was extracted with dichloromethane (4 × 30 mL). The organic layer was washed with saturated aqueous solution of NaCl (20 mL) and dried with MgSO4. After filtration the solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography using silica gel as the stationary phase and hexane/EtOAc (4:1) as eluent to afford methyl ketone 26 (colorless oil) in 0.2761 g, 97% yield (0.9 mmol). Rf: 0.17, PMA (Hex:EtOAc, 4:1); [α]D20 –5.1 (c 1.0, CHCl3); IR (ATR) ν / cm-1 3074, 2962, 2934, 2890, 2824, 1712, 1455, 1366, 1148, 1092, 917; 1H NMR (500 MHz, CDCl3) d 4.75 (s, 1H), 4.72-4.67 (m, 5H), 4.07 (ddd, J 9.4, 5.5, 1.5 Hz, 1H), 3.65 (dt, J 7.6, 2.4 Hz, 1H), 3.41 (s, 3H), 3.38 (s, 3H), 2.98-2.91 (apparent pentet, J 6.5 Hz, 1H), 2.27-2.18 (m, 1H), 2.20 (s, 3H), 2.00-1.92 (m, 1H), 1.76-1.68 (m, 1H), 1.69 (s, 3H), 1.50 (ddd, J 14.6, 9.7, 1.8 Hz, 1H), 1.36 (ddd, J 14.7, 9.8, 1.6 Hz, 1H), 1.08 (d, J 7.0 Hz, 3H), 0.82 (d, J 6.9 Hz, 3H); 13C NMR (125 MHz, CDCl3) d 210.2, 144.3, 111.6, 97.1, 97.0, 79.5, 76.7, 55.9, 55.8, 51.7, 39.7, 34.7, 33.2, 29.6, 22.2, 14.9, 10.5; HRMS (ESI) m/z, calcd. for [M + Na]+: 339.21420, found: 339.21421.

(5S,6S,8S)-6-(Methoxymethoxy)-2,2,5-trimethyl-4-methylene-8-((S)-4-methylpent-4-en-2-yl)-3,9,11-trioxa-2-siladodecane (6)

To a solution containing LDA (2.0 equiv., 0.6 mmol, 1.2 mL of a 0.5 M solution in THF) in THF (5 mL) at -78 ºC, it was added TMSCl (6.0 equiv., 1.8 mmol, 0.2151 g, 0.25 mL) and sequentially the ketone 26 (1 equiv., 0.3 mmol, 0.9481 g) in THF (2 mL) via cannula. The mixture was stirred at -78 ºC for 30 min. After this time, the reaction was warmed to room temperature and it was added hexane (30 mL) to the reaction. The organic layer was washed with saturated aqueous solution of NaHCO3 (30 mL) and dried with MgSO4. After filtration, the solvent was evaporated under reduced pressure, resulting in enolsilane 6 (colorless oil) in 0.1061 g, 91% yield (0.55 mmol). Rf: 0.57, PMA (Hex:EtOAc, 4:1); [α]D20 –2.5 (c 1.0, CHCl3); IR (ATR) ν / cm-1 3074, 2989, 2958, 2822, 1651, 1619, 1456, 1376, 1252, 1149, 1096, 912, 841; 1H NMR (250 MHz, CDCl3) δ 4.77-4.65 (m, 6H), 4.12-4.06 (m, 2H), 3.90 (ddd, J 9.8, 4.8, 1.9 Hz, 1H), 3.64 (dt, J 7.0, 3.0 Hz, 1H), 3.39 (s, 6H), 2.50 (dq, J 6.9, 5.0 Hz, 1H), 2.27 (dd, J 13.2, 3.4 Hz, 1H), 1.97 (ddd, J 13.8, 6.9, 3.7 Hz, 1H), 1.74 (dd, J 13.3, 10.5 Hz, 1H), 1.69 (s, 3H), 1.57-1.49 (m, 1H), 1.47-1.34 (m, 1H), 1.00 (d, J 7.0 Hz, 3H), 0.82 (d, J 6.8 Hz, 3H), 0.21 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 160.5, 144.6, 111.5, 96.9, 89.9, 79.6, 77.4, 55.8, 55.7, 43.9, 39.9, 34.8, 32.1, 22.2, 14.9, 11.8, 5.4; HRMS (ESI) m/z, calcd. for [M+Na]+: 411.25372, found: 411.25373.

Key step and characterization, spectra data of adduct 4 (C(7)-C(20) fragment)

(5S,7S,8S,12S,13R)-11-Hydroxy-7-(methoxymethoxy)-8,12,13,15,15,16,16-heptamethyl-5-((S)-4-methylpent-4-en-2-yl)-2,4,14-trioxa-15-silaheptadecan-9-one (4)

To a flask containing the enolsilane 6 (1 equiv., 0.85 mmol, 0.3303 g), and the aldehyde 5 (1.25 equiv., 1.1 mmol, 0.2400 g) in CH2Cl2 (10 mL) at -78 ºC, it was added BF3.Et2O (1.25 equiv., 1.1 mmol, 1.1 mL). The reaction mixture was stirred at -78 ºC for 90 min. The reaction was washed with saturated aqueous solution of NaHCO3 (30 mL), extracted with dichloromethane (3 × 30 mL) and dried with MgSO4. After filtration the solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography using silica gel as the stationary phase and hexane/EtOAc (4:1) as eluent, resulting in aldol adduct 4 (colorless oil) in 0.4031 g, 89% yield (0.76 mmol) and ds > 95:05. Rf: 0.30, PMA (Hex:EtOAc, 4:1); [α]D20 –7.1 (c 1.0, CHCl3); IR (ATR) ν / cm-1 3503, 3074, 2957, 2931, 2888, 2857, 1709, 1649, 1462, 1377, 1254, 1148, 1094, 1036, 918, 836, 775; 1H NMR (500 MHz, CDCl3) δ 4.70 (s, 1H), 4.66-4.58 (m, 5H), 4.58-4.53 (m, 1H), 4.01 (dd, J 7.8, 6.4 Hz, 1H), 3.86 (dq, J 6.2, 4.0 Hz, 1H), 3.60 (d, J 10.1 Hz, 1H), 3.45 (s, 1H), 3.35 (s, 3H), 3.32 (s, 3H), 2.93 (apparent pentet, J 6.7 Hz, 1H), 2.73 (dd, J 16.8, 8.0 Hz, 1H), 2.41 (dd, J 16.8, 4.6 Hz, 1H), 2.19 (dd, J 13.5, 3.4 Hz, 1H), 1.95-1.88 (m, 1H), 1.69-1.62 (m, 1H), 1.64 (s, 3H), 1.44 (ddd, J 14.4, 9.5, 1.3 Hz, 1H), 1.41-1.35 (m, 1H), 1.31 (ddd, J 14.3, 9.9, 0.9 Hz, 1H), 1.23 (d, J 6.3 Hz, 3H), 1.02 (d, J 6.9 Hz, 3H), 0.92 (d, J 7.1 Hz, 3H), 0.84 (s, 9H), 0.76 (d, J 6.9 Hz, 3H), 0.04 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 211.7, 144.1, 111.5, 96.9, 79.4, 76.6, 73.4, 66.2, 55.7, 55.7, 51.4, 47.7, 42.7, 39.5, 34.5, 33.1, 25.7, 22.1, 21.8, 17.8, 14.8, 11.0, 10.4, –4.4, –5.2; HRMS (ESI) m/z, calcd. for [M + Na]+: 555.36875, found: 555.36878.

Supplementary Information

Supplementary information (characterization data and copies of 1H and 13C NMR spectra) is available free of charge at http://jbcs.sbq.org.br as a PDF file.

Acknowledgments

We are grateful to FAPESP (2015/50655-9) for financial support. A. F. C. R. thanks CNPq (160646/2014-6) for fellowships.

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Received: April 3, 2019; Accepted: June 6, 2019

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