A rapid convergent strategy to access unsaturated analoguesof peloruside A has been demonstrated. This is depicted asan original C11–C12 aldol connection between a C12–C20ketone fragment and a C2–C11 pyran fragment bearing an
Introduction
Some of the most effective anticancer medications usedover recent decades have been drugs targeting tubulin.[1] Pa-clitaxel (Taxol®), which is a member of the taxane family,can be considered as one of the most successful drugs inthe battle against cancer. However, difficulties in its formu-lation owing to its high hydrophobicity and the emergenceof drug resistance have triggered an interest in the searchfor new microtubule stabilizing agents, acting in the samemanner as paclitaxel.[2] In 2000, peloruside A 1 (Figure 1),a marine sponge macrolide, was isolated by Northcote andco-workers and characterized as a polyoxygenated 16-mem-bered macrocycle containing a pyran ring.[3] Peloruside Awas found to arrest cells in the G2/M phase of the cell cycleand to induce cytotoxicity at the nanomolar range in aseries of human cancer cells.[4] Like paclitaxel, peloruside Abinds to microtubules and induces apoptosis throughmicrotubule stabilization.[5] In the last decade, some com-putational[6] and biological[7] studies have been publishedproposing a localization of the binding site for peloruside Aon the α- or β-tubuline of the microtubules. Althoughhypotheses were argued, the common conclusion was that
[a] Université de Nantes, CNRS, UMR 6230, Chimie etInterdisciplinarité: Synthèse, Analyse, Modélisation(CEISAM), UFR Sciences et Techniques,2, rue de la Houssinière, BP 92208, 44322 Nantes Cedex 3,FranceE-mail: [email protected]
symbiose.php[b] Université de Rennes, Institut des Sciences Chimiques
de Rennes UMR CNRS 6226, Campus de Beaulieu, Bât 10A,avenue du Géneral Leclerc, 35042 Rennes, France
[c] Université du Maine, IMMM UMR CNRS 6283,Avenue O. Messiaen, 72085 Le Mans, FranceSupporting information for this article is available on theWWW under http://dx.doi.org/10.1002/ejoc.201201728.
aldehyde function, with high yield and a good level of dia-stereoselectivity. The desired unsaturated macrocycle wasobtained by a late-stage ring closing metathesis reaction.
peloruside A seemed to bind to a site distinct from thetaxoid one. In fact, synergistic phenomena have been ob-served with drug combinations relative to single-drug ad-ministration in a tubulin assembly model,[8] and recentbinding studies carried out with labeled [3H]-peloruside Aconfirmed that paclitaxel was unable to displace [3H]-pelo-ruside A from its binding site.[6b]
Figure 1. Structure of peloruside A 1 and natural or synthetic ana-logues 2–5.
To date six total syntheses of peloruside A[9] 1 and oneof peloruside B[10] 2 have been detailed in the literature. Thefirst, published by De Brabander confirmed the absoluteconfiguration of the natural (+)-peloruside A with the syn-thesis of the (–)-enantiomer.[9a] Few analogues have beenpublished since 2003.[11,12] Among them, conformationally
J. Lebreton, M. Mathé-Allainmat et al.FULL PAPERconstrained analogues such as natural peloruside C 3[12a] orsynthetic compound 4 obtained by replacement of the C11and C13 stereogenic centers with a set of olefinic Z and Eisomers[12b] [compounds (E)-4 and (Z)-4, Figure 1] havebeen recently characterized. At the same time, a stereoselec-tive synthesis of monocyclic peloruside A analogue 5 hasallowed the importance of the pyranose ring in the bicycliccore structure of the macrocycle to be outlined (Figure 1,IC50 = 16.4 μm on A549 cells).[13]
In an effort to open the route to a flexible approachtowards the synthesis of new unsaturated analogues of pelo-ruside and to identify simple macrolides as anti-canceragents, we proposed a convergent strategy involving a late-stage macrocyclization step through ring-closing olefin me-tathesis (RCM) and an original aldolization step to createthe C11–C12 bond starting from preformed pyran carb-aldehyde 7 as depicted in Scheme 1. A similar aldol couplingwas implicit in recent work published by Teesdale-Spittleand co-workers[14] who prepared a C1–C11 dihydropyranfragment with a carbaldehyde function at the C11 position.Aldolization with a methyl ketone to construct a dihydro-
Scheme 1. Retrosynthetic analysis for a simplified unsaturated ana-logue of peloruside.
pyran constrained analogue of peloruside A was suggestedbut not carried out.
Most of the total syntheses of peloruside A or analoguespublished so far install the tetrahydropyran moiety after themacrolactonization or macrocyclization step. In those syn-theses, a C11–C12 bond formation by using an aldol reac-tion was proposed by the groups of Evans[9d] and Hoye[9f]
starting from C11 α,α-gem-dimethyl aldehyde acceptor in-troduced on a C1–C11 open chain and a methyl ketone do-nor similar to our methyl ketone C12–C20 7 (Scheme 1).The pyran ring of the targeted macrocycle was formed dur-ing the last deprotection step under acidic conditions withacceptable yield (66 or 49% yield, respectively). Our retro-synthetic analysis of unsaturated macrolide analogue of pe-loruside is more flexible and led to two fragments beingtargeted: (1) the 2,6-disubstituted tetrahydropyran C2–C11fragment bearing an aldehyde functional group and an eth-ylenic moiety for both the C11–C12 and the C1–C2 connec-tions; (2) the C12–C20 fragment bearing a terminal methylketone and a protected C15 hydroxy group for future func-tionalization to give the corresponding acrylate (Scheme 1).
Results and Discussion
The ethylenic enantiopure compound C12-C20 6 was ob-tained by classical Wittig reaction between racemic phos-phonium salt 13 and enantiomerically pure protected α-hy-droxy aldehyde 11, followed by a Tsuji–Wacker oxidationreaction[15] (Scheme 3). To access unsaturated aldehyde 11,we applied the strategy proposed by Whei-Shan Zhou andco-workers[16a] but starting from protected d-glyceraldehyde9 (Scheme 2, a). Following a literature procedure, stereose-lective allylation of aldehyde 9 with diallylzinc at room tem-perature gave a mixture of the expected homoallylicalcohols[16b] (dr 78:22) and both diastereomers were benzyl-ated with 4-methoxybenzyl chloride (PMBCl) and sepa-rated on silica gel to give pure protected homoallylicalcohol (+)-10 in 73 % yield. Oxidative cleavage of this acet-onide with periodic acid afforded aldehyde (–)-11 in 87%yield. To access expected ethylenic ketone 6 (Scheme 3) orits (2R,5R) isomer we proposed to prepare phosphonium
Towards the Synthesis of Restricted Analogues of Peloruside A
Scheme 3. Reagents and conditions: (i) KHMDS, THF, –78 °C to room temp., 63%; (ii) TBAF, THF, 48 h, diastereomer separation 17(45%) and 18 (47%); (iii) TBDPSCl, imidazole, DMF, 48 h, 91%; (iv) O2/PdCl2/CuCl, DMF/H2O, 5 d; (v) NaClO2, NaH2PO4, tBuOH/H2O, 16 h, 82% (two steps).
salt 13 in racemic form (Scheme 2, b).[17] Starting fromcommercial diethyl 2-ethylmalonate, racemic monosilylateddiol 12 was prepared by hydride reduction and subsequentsilylation, followed by phosphonium formation in a classi-cal two-step manner with N-iodosuccinimide (NIS) and tri-phenylphosphane. Compound (�)-13 was thus rapidly ob-tained in 31 % overall yield.
A Wittig reaction was then performed between racemicphosphonium salt (�)-13 and pure aldehyde (–)-11 to giveZ-disubstituted olefins 15/16 (yield 63%) by using oneequivalent of potassium bis(trimethylsilyl)amide (KHMDS)at low temperature (Scheme 3). This yield could not be opti-mized by either addition of hexamethylphosphoramide(HMPA) or by using sodium hexamethyldisilazane. Bothdiastereomers could not be separated at this stage but wereobtained in 45 and 47% yields for (2R,5S)-17 and (2S,5S)-isomer 18, respectively, after alcohol desilylation. A Tsuji–Wacker oxidation reaction[15] of diene 15, obtained after sil-ylation of pure alcohol 17,[17] afforded ketone 6 with 8% ofthe terminal aldehyde coproduct which was oxidised to thecorresponding acid under Pinnick conditions[18] for easypurification. The optically pure methyl ketone 6 was thusobtained in 33 % overall yield starting from racemic phos-phonium salt (�)-13. To access the methyl ketone with thetrisubstituted double bond (e.g. with a methyl group in theC16 position versus the peloruside A structure) we envis-aged, as suggested by Zhou and Liu,[16] a simple Wittig re-action between phosphonium 13 and a methyl ketone ob-tained by methylation (AlMe3) followed by Swern oxidationof aldehyde (–)-11. Under conditions described by Still[19]
[tetrahydrofuran (THF)/HMPA (9:1, v/v); KHMDS] we didnot obtain the expected trisubstituted olefin.
Disubstituted enantiopure pyran C2–C11 7 was the re-sult of a ten-step sequence starting from commercially avail-able 5-hexen-1-ol (Scheme 4). Racemic epoxide (�)-19 wassubjected to (R,R)-Jacobsen’s chiral (salen)CoII catalyst forhydrolytic kinetic resolution[20a] to give known (–)-(R)-ep-
oxide 19 in 45% yield.[20b] Copper-mediated ring openingof (–)-19 with vinyl magnesium bromide, followed by depro-tection of the primary alcohol, gave optically pure diol (+)-20. A clean and efficient oxidation–cyclization reaction pro-cedure of 1,5-diol 20, by using 4-acetamido-2,2,6,6-tet-ramethylpiperidine 1-oxyl (Ac-TEMPO)[21] as the catalyst,gave lactone 21 in quantitative yield. The latter was engagedin reaction with the lithium enolate derived from methylisobutyrate[22] and the corresponding lactol was reducedwith triethylsilane in the presence of BF3·Et2O to give tetra-
J. Lebreton, M. Mathé-Allainmat et al.FULL PAPERhydropyran cis-22 in 86% yield (two steps) with no tracesof the trans isomer. Reduction of cis-22 followed by Swernoxidation gave gem-dimethyl pyran carbaldehyde 7 with thecorrect C5 and C9 configurations relative to peloruside A.
The aldol reaction has frequently been used in strategiespublished in the literature to prepare peloruside fragmentsto control hydroxylated stereocenters. The boron-mediatedaldol reaction was proved to proceed with 1,5-anti induc-tion with a wide range of methyl ketone donors with a β-OPMB alkoxy substituent.[23] In the total synthesis of pelo-ruside A published by Hoye et al. a late-stage Patersonboron aldol coupling reaction was planned between an α,α-gem-dimethyl (C1–C11) linear aldehyde acceptor and amethylketone similar to our C12–C20 fragment 6 bearing aβ(C15)-OPMB substituent. The hydroxy ketone was ob-tained with essentially complete 1,5-anti stereocontrol.[9f]
In our convergent strategy, the first C11–C12 connectionhas to be made starting from enantiopure β-alkoxy ketone6 and pyran aldehyde 7 (Scheme 5). The dicyclohexylboronenolate of ketone 6 was formed and added to aldehyde 7(2 equiv., –78 °C)[23b] to give hydroxy ketone 23 in 83 %yield (Scheme 5). An acceptable 1,5-anti,syn diastereoselec-tivity (dr 7:3) was obtained, which was not as good asHoye’s group.[9f] Ketone 23 was reduced in a controlledmanner with Me4NBH(OAc)3
[24a] to give pure 1,3-anti diol24 in 65 % yield. Some model experiments to access amonoprotected 1,3-anti diol with a samarium-catalyzed in-tramolecular Tischenko[24b] reduction starting from similarhindered β-hydroxy ketone and benzaldehyde failed. Toavoid protection–deprotection steps of the C11 hydroxygroup, we envisaged the protection of diol 24 as its aceton-
ide and selective O-methylation of the C13 hydroxy groupat a late stage. The preparation of acetonide 25 allowed usto confirm unambiguously the 1,3-anti stereochemical rela-tionship in diol 24 by 13C NMR analysis (resonances forthe isopropylidene methyl groups at δ = 25.4 and 24.8 ppm).Acrylate 26 was obtained in 81% yield (two steps) aftertreating 25 with pH-7 buffer 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) to cleave the C15 PMB ether. Triene26 underwent RCM cyclization with Grubbs’ II catalyst(Scheme 5). The geometry for resulting E-olefin 27 was eas-ily assigned by 1H NMR analysis (H2 proton δ = 5.86 ppm;JH2-H3 = 15.9 Hz), and compound 27 was formed as a singleisomer. Furthermore 1H NMR NOESY experiments weredone on conformationally restricted intermediate 27. Inapolar solvent, NOE cross-peaks were clearly observed be-tween H9–H11 and H13–H16 (see Supporting Infor-mation), which supports a (S,S) absolute configuration ofthe C11 and C13 carbon centers in 24 and allowed us toconclude the major 1,5-anti stereoisomer formation in thealdol reaction step. The acetonide TBDPS-ether protectivegroups were sequentially removed by acid hydrolysis andtetra-n-butylammonium fluoride (TBAF) treatment to ac-cess pure triol 8, an unsaturated simplified analogue of pe-loruside (Scheme 5).
Compounds 28 and 8 were tested for their in vitro inhibi-tion of cell proliferation on a panel of five human tumorcell lines (Huh7, CaCo2, HCT116, PC3 and NCI) in ad-dition to normal diploid skin fibroblasts as the control. Al-though no activity (IC50 � 25 μm) was observed with pro-tected compound 28, some effect was observed with triol 8on colon carcinoma (CaCo2: IC50 = 12 μm; HCT116: IC50
Towards the Synthesis of Restricted Analogues of Peloruside A
= 15 μm) and prostate carcinoma (PC3: IC50 = 15 μm),which is encouraging for such a constrained compoundlacking five stereocenters relative to natural peloruside A.
Conclusions
We have validated a convergent strategy to construct pe-loruside analogues starting with a pyran carbaldehyde frag-ment. We first focussed our work on the synthesis of theenantiopure C12–C20 fragment and proposed a rapid andefficient diastereomeric approach to scale-up the prepara-tion of ketone 6 and its (2R,5R)-diastereomer. Both cou-pling reactions between C12–C20 ketone fragment 6 andC2–C11 pyran fragment 7 have been successfully achieved.Aldol coupling of ketone 6 with hindered pyran aldehyde7 gave very good yields under Paterson conditions and ametathesis macrocyclisation reaction afforded exclusivelythe E-stereoisomer. A new unsaturated simplified analogueof peloruside A 8, was then prepared in eight steps and itscytotoxicity on selected tumor cell lines was found to bearound 10 μm. This convergent strategy opens the way tothe synthesis of a series of analogues, involving more com-plex tri- or tetra substituted α,α-gem-dimethyl pyran frag-ments.
Experimental SectionGeneral Remarks: Water-sensitive reactions were performed underan argon atmosphere in flame-dried glassware. All solvents usedwere reagent grade. Et2O and THF were freshly distilled from so-dium/benzophenone under argon. Toluene was freshly distilledfrom sodium under argon. CH2Cl2, CH3CN, methanol, triethanol-amine (TEA), diisopropylamine and diisopropylethylamine werefreshly distilled from calcium hydride under argon. TLC was per-formed on silica-covered aluminum sheets (Kieselgel 60F254,MERCK). Flash column chromatography was performed on silicagel 60 ACC 40–63 μm (SDS-Carlo Erba). NMR spectra were re-corded with a Bruker AC300 (300 MHz for 1H) or a Bruker 400(400 MHz for 1H) at room temperature, and samples dissolved inan appropriate deuterated solvent. Tetramethylsilane was used areference for 1H NMR spectra, deuterated solvent signal for 13CNMR spectra (C(IV) stands for quaternary C atom), and 85% aq.phosphoric acid for 31P NMR spectra. HPLC analyses were per-formed with a Hewlett–Packard 1100. IR analyses were recordedwith a Bruker Vector 22 spectrometer and performed neat withKBr pellets. Melting points were determined with a RCH (C. Rei-chert) microscope equipped with a Koffler heating system. Specificoptical rotation values were measured at room temperature in a100 mm cell with a Perkin–Elmer 341 Polarimeter under sodiumradiation (λ = 589 nm). Low-resolution mass spectra were per-formed with a Thermo-Finnigan DSQII quadripolar spectrometerin chemical ionization mode (CI) at 70 eV with NH3 gas. High-Resolution Mass Spectrometry (HRMS) analyses were performedat the “Centre Commun de Spectrométrie de Masse” in Lyon(France), with a Micro-TOFOII Thermofischer Scientific for elec-tro-spray ionization (ESI) measurements. Some products were alsoanalyzed with a MALDI-TOF-TOF technique with a Bruker Auto-flex III Smartbeam in the laboratory.
(R)-4-[(S)-1-(4-Methoxybenzyloxy)but-3-enyl]-2,2-dimethyl-1,3-di-oxolane [(+)-10]: From adaptation of the literature procedure, NaH
in oil (60 wt.-%, 0.85 g, 22.30 mmol, 1.2 equiv.) was added at 0 °Cto a dimethylformamide (DMF) solution (50 mL) of a dia-stereomer mixture (dr 78:22) of the corresponding homoallylicalcohols (3.20 g, 18.58 mmol, 1 equiv.) obtained by classical allyl-ation of protected d-glyceraldehyde 9.[16b] The reaction mixture wasstirred at 0 °C for 1 h. PMBCl (3.50 g, 22.35 mmol, 1.2 equiv.) wasadded at the same temperature to the reaction mixture, which wasthen warmed to room temperature and left stirring for 13 h beforebeing quenched by saturated aqueous NH4Cl (40 mL). The aque-ous phase was extracted with Et2O (5 � 25 mL). The combinedorganic layers were washed with water and brine, dried with anhy-drous MgSO4, filtered and concentrated under reduced pressure.This residue was subjected to column chromatography on silica gel(PE/Et2O, 95:5) to give compound (+)-10 (12.9 g, 73%) as a color-less oil. [α]D20 = +28.0 (c = 0.81, CHCl3). 1H NMR (300 MHz,CDCl3): δ = 7.25 (d, J = 8.4 Hz, 2 H, Har), 6.87 (d, J = 8.7 Hz, 2H, Har), 5.89 (ddt, J = 7.2, J = 10.2, J = 17.1 Hz, 1 H, CHCH2),5.18–5.05 (m, 2 H, CHCH2), 4.55 and 4.25 (AB system, J =10.8 Hz, 2 H, CH2), 4.12–3.99 (m, 2 H, CH2O and OCH), 3.86(dd, J = 6.0, J = 7.8 Hz, 1 H, CH2O), 3.80 (s, 3 H, OCH3), 3.54(pq, J = 6.0 Hz, 1 H, OCH), 2.48–2.27 (m, 2 H, CH2), 1.42 (s, 3H, CH3), 1.35 (s, 3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3): δ= 159.4 (C(IV)ar), 134.4 (CH), 130.7 (C(IV)ar), 129.5 (Car), 117.6(CH2), 113.9 (Car), 109.2 (C(IV)), 78.7 (CH), 77.4 (CH), 72.3 (CH2),66.6 (CH2), 55.4 (OCH3), 35.8 (CH2), 26.8 (CH3), 25.5 (CH3) ppm.MS (CI): m/z = 310 [M + NH4]+. HRMS: calcd. for C17H23O4 [M –H]+ 291.1596; found 291.1599.
(S)-2-(4-Methoxybenzyloxy)pent-4-enal [(–)-11]: H5IO6 (2.58 g,11.30 mmol, 1.1 equiv.) was added to a solution of compound (+)-10 (3.01 g, 10.29 mmol, 1 equiv.) in anhydrous ethyl acetate(125 mL). The reaction mixture was stirred at room temperaturefor 13 h. Excess reagent was quenched with the addition of solidsodium thiosulfate (3.7 g) and solid potassium carbonate (3.2 g).The reaction mixture became light brown, and was stirred at roomtemperature for 1 h. Filtration through Celite, washing withCH2Cl2 and concentration under reduced pressure gave a brownoily residue that was subjected to column chromatography on silicagel (PE/Et2O, 9:1 to 7:3) to furnish aldehyde (–)-11 (1.93 g, 87%)as a beige oil (lit. reported enantiomer[25]). [α]D20 = –30.6 (c = 1.2,CHCl3). 1H NMR (300 MHz, CDCl3): δ = 9.62 (d, J = 2.1 Hz, 1H, HC=O), 7.27 (d, J = 9.0 Hz, 2 H, Har), 6.89 (d, J = 8.7 Hz, 2H, Har), 5.80 (ddt, J = 6.9, J = 10.2, J = 17.1 Hz, 1 H, CHCH2),5.18–5.07 (m, 2 H, CHCH2), 4.57 and 4.27 (AB system, J =11.4 Hz, 2 H, CH2), 3.83–3.77 (m, 1 H, OCH), 3.81 (s, 3 H, OCH3),2.50–2.43 (m, 2 H, CH2) ppm. 13C NMR (75 MHz, CDCl3): δ =203.3 (CO), 159.7 (C(IV)ar), 132.6 (CH), 129.8, 129.4 (C(IV)), 118.5(CHCH2), 114.0 (Car), 82.6 (OCH), 72.3 (CH2), 55.4 (OCH3), 34.8(CH2) ppm. MS (CI): m/z = 238 [M + NH4]+.
(�)-2-[(tert-Butyldiphenylsilyloxy)methyl]butan-1-ol [(�)-12]: Li-AlH4 (7.51 g, 198 mmol, 2.5 equiv.) was added at room temperatureunder argon to a solution of diethyl ethylmalonate (15.0 g,79.7 mmol, 1 equiv.) in anhydrous Et2O (300 mL). The reactionmixture was heated to reflux for 14 h and then diluted with Et2O(100 mL), quenched with water (20 mL), followed by an aqueoussolution of NaOH 10% (20 mL). Finally water (20 mL) was addedto the mixture was filtered through Celite. The filtrate was concen-trated under reduced pressure. The resulting diol was obtainedwithout further purification in 95% yield as a colorless oil (lit. re-ported compound[26]). 1H NMR (300 MHz, CDCl3): δ = 3.62–3.84(m, 4 H, CH2OH), 2.27 (s, 2 H, OH), 1.68 (m, 1 H, CH), 1.32(quint, J = 7.6 Hz, 2 H, CH2CH3), 1.24 (t, J = 7.6 Hz, 3 H,CH2CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 66.37 (CH2),43.82 (CH), 20.76 (CH2), 11.84 (CH3) ppm.
J. Lebreton, M. Mathé-Allainmat et al.FULL PAPERnBuLi (2.5 m, 14 mL, 35 mmol, 0.92 equiv.) was added at –25 °Cunder argon to a solution of diol (4.01 g, 38.4 mmol, 1 equiv.) inanhydrous THF (110 mL) and the reaction mixture was stirred atthis temperature for 1 h. tert-Butyldiphenylsilyl chloride(TBDPSCl; 10.55 g, 38.4 mmol, 1 equiv.) in THF (40 mL) wasadded at –30 °C and the colorless solution was stirred for 2 h beforebeing quenched by a saturated aqueous solution of NH4Cl. Theaqueous phase was extracted with CH2Cl2 (3� 50 mL), and thecombined organic layers were dried with anhydrous MgSO4, fil-tered and concentrated under reduced pressure. The resulting crudemixture was then subjected to column chromatography on silicagel (PE/Et2O, 9:1 to 1:1) to give compound (�)-12 (8.60 g, 66%)as a colorless oil (lit. reported compound[27]). 1H NMR (300 MHz,CDCl3): δ = 7.71–7.66 (m, 4 H, Har), 7.47–7.37 (m, 6 H, Har), 3.83–3.61 (m, 4 H, CH2OH and CH2O), 1.75–1.62 (m, 1 H, CH), 1.37–1.18 (m, 2 H, CH2CH3), 1.06 (s, 9 H, tBu), 0.85 (t, J = 7.5 Hz, 3H, CH2CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 135.8 (Car),133.3 (C(IV)ar), 130.0 (Car), 127.9 (Car), 67.3 (CH2O), 66.0(CH2OH), 44.1 (CH), 27.0 (tBu), 20.7 (CH2), 19.3 (C(IV) tBu), 11.8(CH3) ppm. MS (CI): m/z = 343 [M + H]+. HRMS: calcd. forC21H31O2Si [M + H]+ 343.2093; found 343.2099.
(R)-4-Benzyl-3-[(S)-2-(benzyloxymethyl)butanoyl]oxazolidin-2-one(14): To a solution of (R)-4-benzyl-3-butyryloxazolidin-2-one[28]
(10.0 g, 40.4 mmol, 1 equiv.) in anhydrous CH2Cl2 (16 mL), a com-mercial TiCl4 solution (1.0 m in CH2Cl2, 44.4 mL, 44.4 mmol,1.1 equiv.) was added dropwise at 0 °C under argon. A yellowishsolid appeared in the reaction mixture, which was stirred for30 min. Freshly distilled TEA (6.8 mL, 48.5 mmol, 1.2 equiv.) wasthen added dropwise at 0 °C: the solid disappeared and a dark redsolution appeared. After 1 h stirring at the same temperature,freshly-distilled benzyl chloromethyl ether (BOMCl; 14 mL,101 mmol, 2.5 equiv.) was added to the reaction mixture which wasstirred for 5 h at 0 °C and warmed to room temperature. The mix-ture was diluted with CH2Cl2, washed with saturated aqueousNH4Cl (4�), saturated aqueous NaHCO3 (3�) and brine, thendried with anhydrous MgSO4, filtered and concentrated under re-duced pressure. The resulting brown oil was subjected to columnchromatography on silica gel (PE/EA, 95:5 to 60:40) to give a whit-ish solid, which was recrystallized from isopropyl ether. Desiredcompound 14 was obtained (9.01 g, 61%) as a single diastereomeras white crystals, m.p. 70–71 °C (in DIPO). [α]D20 = –39.0 [c = 0.96,CHCl3; lit. enantiomer:[28] [α]D22 = +40.9 (c = 0.94, CHCl3)]. 1HNMR (300 MHz, CDCl3): δ = 7.33–7.18 (m, 10 H, Har), 4.77–4.69(m, 1 H, CHCH2Ph), 4.55 (s, 2 H, CH2Ph), 4.21–4.10 (m, 3 H,CHCO and CH2), 3.81 (pt, J = 9.0 Hz, 1 H, CH2OBn), 3.66 (dd,J = 9.3, J = 5.1 Hz, 1 H, CH2OBn), 3.23 (dd, J = 13.5, J = 3.3 Hz,1 H, CHCH2Ph), 2.70 (dd, J = 13.5, J = 9.3 Hz, 1 H, CHCH2Ph),1 . 83–1 .52 (m, 2 H, CH 2 CH 3 ) , 0 .94 ( t , J = 7.5 Hz , 3 H,CH2CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 175.2 (CO), 153.4(CO), 138.4 (C(IV)ar), 135.5 (C(IV)ar), 129.6 (Car), 129.0 (Car), 128.5(Car), 127.8 (Car), 127.4 (Car), 73.3 (OCH2Ph), 71.2 (CH2OBn),66.0 (CH2), 55.4 (CHBn), 45.0 (CHCO), 37.9 (CH2Ph), 22.3(CH2CH3), 11.7 (CH3) ppm.
(R)-2-[(tert-Butyldiphenylsilyloxy)methyl]butan-1-ol [(+)-12]: Amixture of compound 14[29a] (12.3 g, 33.3 mmol, 1 equiv.) and 10%Pd/C (350 mg, 0.33 mmol, 0.01 equiv.) in EtOH/CH2Cl2 (4:1,100 mL) was stirred for 20 h at room temperature under H2 (5 atm).Filtration through Celite followed by evaporation of the filtrategave the corresponding pure alcohol (9.3 g) as a colorless oil inquantitative yield. [α]D20 = –62.3 [c = 0.82, CHCl3; lit. enantio-mer:[29b] [α]D25 = +71.6 (c = 0.83, CHCl3)]. 1H NMR (300 MHz,CDCl3): δ = 7.37–7.22 (m, 5 H, Har), 4.75–4.67 (m, 1 H, CHBn),4.25–4.16 (m, 2 H, CH2), 3.92–3.84 (m, 3 H, CHCO and CH2),
4-(Dimethylamino)pyridine (DMAP; 397 mg, 3.25 mmol,0.1 equiv.), TEA (9.05 mL, 64.9 mmol, 2 equiv.) and TBDPSCl(10.1 mL, 38.9 mmol, 1.2 equiv.) were successively added at 0 °C toa solution of the previous crude alcohol (9.0 g, 32.4 mmol, 1 equiv.)in anhydrous CH2Cl2 (48 mL). This solution was stirred at roomtemperature for 48 h. After dilution with CH2Cl2, the organicphase was washed with water and brine, then dried with anhydrousMgSO4, filtered and concentrated under reduced pressure. The re-sulting residue was subjected to column chromatography on silicagel (PE/Et2O, 9:1 to 1:1) to give compound (R)-4-benzyl-3-{(S)-2-[(tert-butyldiphenylsilyloxy)methyl]butanoyl}oxazolidin-2-one(16.9 g) in quantitative yield as a colorless oil. [α]D20 = –2.1 (c =0.34, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 7.73–7.66 (m, 4H, Har), 7.44–7.18 (m, 11 H, Har), 4.77–4.69 (m, 1 H, CHBn), 4.20–4.09 (m, 3 H, CHCO and CH2), 4.02 (dd, J = 9.9, J = 8.1 Hz, 1H , C H 2 OT B D P S ) , 3 . 8 3 ( dd , J = 9 . 6 , J = 4 . 8 H z , 1 H ,CH2OTBDPS), 3.38 (dd, J = 13.5, J = 3.3 Hz, 1 H, CHCH2Ph),2.59 (dd, J = 13.5, J = 10.2 Hz, 1 H, CHCH2Ph), 1.78–1.64 (m, 1H, CH2CH3), 1.60–1.46 (m, 1 H, CH2CH3), 1.04 (s, 9 H, tBu), 0.86(t, J = 7.5 Hz, 3 H, CH2CH3) ppm. 13C NMR (75 MHz, CDCl3):δ = 175.2 (CO), 153.4 (CO), 135.8 (Car), 134.9 (Car), 133.6 (Car),133.5 (Car), 129.8, (Car) 129.5 (Car), 129.1 (Car), 127.8 (Car), 127.4(Car), 66.1 (CH2), 65.0 (CH2), 55.6 (CHBn), 47.2 (CHCO), 38.3(CH2Ph), 27.0 (tBu), 21.9 (CH2CH3), 19.4 (C(IV) tBu), 11.6(CH3) ppm. MS (CI): m/z = 516 [M + H]+; 533 [M + NH4]+.HRMS: calcd. for C31H38NO4Si [M + H]+ 516.2570; found516.2573.
To a solution of (R)-4-benzyl-3-{(S)-2-[(tert-butyldiphenylsilyloxy)-methyl]butanoyl}oxazolidin-2-one (16.8 g, 32.5 mmol, 1 equiv.) indry Et2O (260 mL) and dry THF (260 mL), water (711 μL,39.1 mmol, 1.2 equiv.) and a commercial LiBH4 solution (2.0 m inTHF, 21.2 mL, 42.3 mmol, 1.3 equiv.) were added dropwise. Theopaque mixture was stirred at room temperature for 5 h. The reac-tion was quenched with saturated aqueous NH4Cl solution, andthe resulting aqueous phase was extracted with Et2O (2 �). Thecombined organic fractions were then washed with brine, driedwith anhydrous MgSO4, filtered and concentrated under reducedpressure. The obtained residue was subjected to columnchromatography on silica gel (PE/Et2O, 9:1 to 7:3) to give alcohol(+)-12 (8.96 g, 80%) as a beige oil. [α]D20 = +7.9 (c = 0.45, CHCl3).
(�)-{2-[(tert-Butyldiphenylsilyloxy)methyl]butyl}triphenyl-phosphonium Iodide [(�)-13]: Triphenylphosphane (1.38 g,5.25 mmol, 1.5 equiv.), then NIS (1.17 g, 5.23 mol, 1.5 equiv.) werecautiously added at 0 °C under argon to a solution of alcohol (�)-12 (1.2 g, 3.5 mmol, 1 equiv.) in anhydrous CH2Cl2 (20 mL). Thereaction mixture was stirred at room temperature for 13 h. Afterdilution with CH2Cl2 (20 mL), the organic layer was washed with10% aqueous Na2S2O3 (20 mL) and brine, then dried with anhy-drous MgSO4, filtered and concentrated under reduced pressure.The resulting residue was subjected to column chromatography onsilica gel (PE/Et2O, 99:1 to 8:2) to give (�)-tert-butyl-[2-(iodometh-yl)butoxy]diphenylsilane (1.11 g, 70%) as a colorless oil. 1H NMR(300 MHz, CDCl3): δ = 7.71–7.63 (m, 4 H, Har), 7.46–7.34 (m, 6H, Har), 3.63 (dd, J = 3.9, J = 10.2 Hz, 1 H, CH2OTBDPS), 3.53–3.47 (m, 2 H, CH2OTBDPS and CH2I), 3.39 (dd, J = 4.8, J =
Towards the Synthesis of Restricted Analogues of Peloruside A
A solution of this iodo compound (4.03 g, 8.91 mmol, 1 equiv.) andPPh3 (2.80 g, 10.69 mmol, 1.2 equiv.) in anhydrous toluene (35 mL)was heated to reflux for 96 h. A solid appeared progressively in thereaction mixture, which was subjected to vigorous stirring whencooling to room temperature. After concentration under reducedpressure, the sticky residue was triturated in anhydrous Et2O for14 h. The liquid supernatant was then removed, and resulting hy-groscopic beige solid (�)-13 was obtained (4.74 g, 71%) after dry-ing under vacuum with P2O5 for one week. IR (KBr): ν̃ = 3071,3048, 2959, 2928, 2855, 1483, 1112 cm–1. 1H NMR (300 MHz,CDCl3): δ = 7.71–7.63 (m, 4 H, Har), 7.46–7.34 (m, 6 H, Har), 3.63(dd, J = 3.9, J = 10.2 Hz, 1 H, CH2O), 3.53–3.47 (m, 2 H, CH2Oand CH2P), 3.39 (dd, J = 4.8, J = 9.6 Hz, 1 H, CH2P), 1.42–1.25(m, 3 H, CH and CH2CH3), 1.06 (s, 9 H, tBu), 0.84 (t, J = 7.5 Hz,3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 135.0 (Car), 134.9(Car), 134.8 (Car), 134.4 (Car), 133.2 (Car), 133.0 (Car), 132.9 (Car),132.5 (C(IV)ar), 132.2 (C(IV)ar), 131.5 (Car), 130.2 (Car), 130.1 (Car),129.5 (Car), 128.1 (Car), 128.0 (Car), 127.4 (Car), 127.0 (Car), 118.3(C(IV)ar), 117.2 (C(IV)ar), 64.6 and 64.5 (CH2O), 37.4 (CH), 26.5(tBu), 24.2 + 23.9 + 23.2 (CH2), 18.8 (C(IV) tBu), 10.6 (CH3) ppm.31P{1H} NMR (121 MHz, CDCl3): δ = 23.1 ppm. MS (CI): m/z =587 [M – I]+; 263 [Ph3PH]+.
(S)-{2-[(tert-Butyldiphenylsilyloxy)methyl]butyl}triphenyl-phosphonium Iodide [(–)-13]: Triphenylphosphane (10.22 g,39.0 mmol, 1.5 equiv.), then N-iodosuccinimide (8.77 g, 39.0 mmol,1.5 equiv.) were cautiously added at 0 °C under argon to a solutionof alcohol (+)-12 (8.9 g, 26.0 mmol, 1 equiv.) in anhydrous CH2Cl2(105 mL). The reaction mixture was stirred at room temperaturefor 16 h. After dilution with CH2Cl2, the organic phase was washedwith 10% aqueous Na2S2O3 solution (2�) and brine, then driedwith anhydrous MgSO4, filtered and concentrated under reducedpressure. The resulting beige solid was subjected to columnchromatography on silica gel (PE/Et2O, 98:2 to 8:2) to give (+)-tert-butyl[2-(iodomethyl)butoxy]diphenylsilane (10.7 g, 92%) as acolorless oil. [α]D20 = +3.7 (c = 0.57, CHCl3). MS (CI): m/z = 453[M + H]+; 470 [M + NH4]+.
This iodo compound (10.7 g, 23.7 mmol, 1 equiv.) and PPh3
(7.44 g, 28.4 mmol, 1.2 equiv.) in anhydrous toluene (85 mL) wereheated to reflux for 96 h. A solid appeared progressively in the reac-tion mixture, which was subjected to vigorous stirring when coolingto room temperature. After concentration under reduced pressure,the sticky residue was triturated in anhydrous Et2O for 16 h. Theliquid supernatant was then removed, and the resulting hygroscopicyellowish solid (–)-13 was obtained (11.8 g, 85%) after drying un-der vacuum with P2O5 for several hours, m.p. 53–55 °C (notrecryst.). [α]D20 = –3.4 (c = 0.86, CHCl3). 31P{1H} NMR (121 MHz,CDCl3): δ = 23.1 ppm. HRMS: calcd. for C39H44OPSi [M – I]+
587.2899; found 587.2899.
tert-Butyl [(2R,5S,Z)-2-Ethyl-5-(4-methoxybenzyloxy)octa-3,7-dien-yloxy]diphenylsilane (15) and tert-Butyl [(2S,5S,Z)-2-Ethyl-5-(4-methoxybenzyloxy)octa-3,7-dienyloxy]diphenylsilane (16): Phos-phonium salt (�)-13 (8.0 g, 11.19 mmol, 1.15 equiv.) was intro-duced in dry THF (30 mL) under argon. A commercial KHMDSsolution (0.5 m in THF, 19.5 mL, 9.75 mmol, 1 equiv.) was addeddropwise to this slurry at 0 °C, which was then stirred at room
temperature for 30 min. The mixture became dark red and the ini-tial phosphonium salt dissolved completely. A solution of aldehyde(–)-11 (2.15 g, 9.75 mmol, 1 equiv.) in dry THF (5 mL) was addeddropwise to the reaction mixture at –80 °C. This mixture was thenstirred at the same temperature for 1 h, before being slowly warmedto room temperature, and further stirred at this temperature for16 h. Reaction was quenched with saturated aqueous NH4Cl(10 mL), and the resulting aqueous phase was extracted withCH2Cl2 (3 � 20 mL). The combined organic layers were thenwashed with brine, dried with anhydrous MgSO4, filtered and con-centrated under reduced pressure. The residue was subjected to col-umn chromatography on silica gel (PE/Et2O, 98:2 to 90:10) to givea mixture of compounds 15 and 16 (3.25 g, 63%) as a colorless oil.
For analysis see optically pure compound 15.
(2R,5S,Z)- (17) and (2S,5S,Z)-2-Ethyl-5-(4-methoxybenzyloxy)octa-3,7-dien-1-ol (18): The protected mixture of 15 and 16 (2.93 g,5.38 mmol, 1 equiv.) was dissolved in THF (90 mL). Then TBAF(1 m in THF, 6.92 mL, 6.92 mmol, 1.29 equiv.) was added at 0 °C.The mixture was stirred 48 h and then concentrated under reducedpressure. The crude mixture was subjected to column chromatog-raphy on silica gel (PE/Et2O, 99:1 to 30:70) to give expected pure(2R,5S,Z)-2-ethyl-5-(4-methoxybenzyloxy)octa-3,7-dien-1-ol (17)(0.70 g, 45%). [α]D20 = –1.5 (c = 1.0, CHCl3). IR (KBr): ν̃ = 3438,2959, 2931, 2872, 1612, 1514, 1248, 1037 cm–1. 1H NMR(300 MHz, CDCl3): δ = 7.28–7.25 (m, 2 H, Har), 6.88–6.85 (m, 2H, Har), 5.84 (ddt, J = 6.8, J = 10.0, J = 17.1 Hz, 1 H, CHCH2),5.60 (dd, J = 2.0, J = 9.1 Hz, 1 H, CHCH), 5.34 (t, J = 11.1 Hz, 1H, CHCH), 5.07 (m, 2 H, CHCH2), 4.51 and 4.37 (AB system, J
[(2R,5S,Z)-2-Ethyl-5-(4-methoxybenzyloxy)octa-3,7-dienyloxy]-(tert-butyl)diphenylsilane (15): Imidazole (0.35 g, 5.14 mmol,2 equiv.) and TBDPSCl (1.07 g, 3.89 mmol, 1.5 equiv.) were suc-cessively added to a solution of alcohol 17 (0.76 mg, 2.62 mmol,1 equiv.) in DMF (12 mL). The reaction mixture was stirred atroom temperature for 48 h, before being quenched with saturated
(4S,7R,Z)-7-[(tert-Butyldiphenylsilyloxy)methyl]-4-(4-methoxy-benzyloxy)non-5-en-2-one (6): CuCl (0.25 g, 2.49 mmol, 1.1 equiv.)and PdCl2 (0.08 g, 0.46 mmol, 0.2 equiv.) were added to a solutionof compound 15 (1.18 g, 2.23 mmol, 1 equiv.) in a DMF/H2O sol-vent mixture (7:1, 32 mL). Because of substrate solubility problemsin this solvent mixture, Et2O (1.0 mL) was regularly added to thereaction mixture when stirring. The black slurry was vigorouslystirred at room temperature and in contact with oxygen (bubbling)for 5 days. It was then diluted with 1 n aqueous HCl (50 mL), andthe resulting aqueous phase was extracted with Et2O (5� 20 mL).The combined organic layers were washed with brine, dried withanhydrous MgSO4, filtered and concentrated under reduced pres-sure. 1H NMR spectroscopic data of the resulting residue indicatedformation of the expected ketone along with 8% of the correspond-ing aldehyde. TLC analysis of this green oil showed no separationbetween both formed carbonylated compounds. As a result, thecrude product (1.22 g, quantitative yield) was directly subjected toan aldehyde-oxidation-based purification step.
The crude mixture (8 mol-% aldehyde) was dissolved in tBuOH(3.8 mL) and 2-methyl-2-butene (0.9 mL). An aqueous solution(1.5 mL) of NaClO2 (147 mg, 1.62 mmol) and NaH2PO4·H2O(174 mg, 1.30 mmol) was then added dropwise to the reaction mix-ture, which was stirred at room temperature for 16 h. The volatilesolvents (tBuOH and isoamylene) were then removed under re-duced pressure, and saturated aqueous NaHCO3 solution (10 mL)was added to the oily residue. The resulting aqueous phase wasextracted with CH2Cl2 (3� 15 mL), and the combined organic lay-ers were washed with brine, dried with anhydrous MgSO4, filteredand concentrated under reduced pressure. The residue was sub-jected to column chromatography on silica gel (PE/Et2O, 95:5 to7:3) to give methyl-ketone 6 (990 mg, 82% over two steps) as acolorless oil. [α]D20 = –26.7 (c = 1.2, CHCl3). IR (KBr): ν̃ = 3070,2999, 2958, 2857, 1718, 1514, 1248, 1272 cm–1. 1H NMR(300 MHz, CDCl3): δ = 7.69–7.63 (m, 4 H, Har), 7.42–7.31 (m, 6H, Har), 7.10–7.04 (m, 2 H, Har), 6.81–6.75 (, 2 H, Har), 5.47 (dd,J = 9.3, J = 11.1 Hz, 1 H, CHCH), 5.40 (dd, J = 8.7, J = 11.1 Hz,1 H, CHCH), 4.56 (m, 1 H, CHOPMB), 4.48 and 4.19 (AB system,J = 11.1 Hz, 2 H, CH2Ar), 3.77 (s, 3 H, OCH3), 3.59 (dd, J = 5.7,J = 10.2 Hz, 2 H, CH2OSi), 2.78 (dd, J = 9.0, J = 15.3 Hz, 1 H,CH2COCH3), 2.61–2.48 (m, 1 H, CHCH2OSi), 2.39 (dd, J = 3.9,
(�)-tert-Butyldimethyl[4-(oxiran-2-yl)butoxy]silane [(�)-19]: Com-mercial 5-hexen-1-ol (3.70 g, 37 mmol, 1 equiv.) was dissolved inDMF (38 mL) and tert-butyldimethylsilyl (TBSCl; 6.15 g,40.7 mmol, 1.1 equiv.) with imidazole (2.77 g, 40.7 mmol,1.1 equiv.) were added to the mixture. After 5 h stirring at roomtemperature the reaction was quenched with water (40 mL), andthe aqueous phase was extracted with Et2O (6� 20 mL). The com-bined organic layers were washed with brine (30 mL), dried withMgSO4, filtered and concentrated under reduced pressure. tert-Butyl(hex-5-enyloxy)dimethylsilane was obtained without furtherpurification as a colorless oil. 1H NMR (300 MHz, CDCl3): δ =5.85–5.75 (m, 1 H, CH2CHCH2), 4.98–4.92 (m, 2 H, CH2CHCH2),3.61 (t, J = 6.0 Hz, 2 H, CH2OTBS), 2.05 (q, J = 6.0 Hz, 2 H,CH2CH2OTBS), 1.55–1.47 (m, 4 H, CH2CH2), 0.89 (s, 9 H, tBu),0.05 (s, 6 H, 2� CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 136.9(CH2CHCH2), 112.3 (CH2CHCH2), 61.1 (CH2OTBS), 31.5(CH2CH2), 30.3 (CHCH2CH2), 23.9 (tBu), 20.3 (CH2CH2OTBS),16.3 (C(IV) tBu), –5.3 (2� CH3) ppm.
To a solution of tert-butyl(hex-5-enyloxy)dimethylsilane (8.00 g,37 mmol, 1 equiv.) in CH2Cl2 (150 mL) meta-chloroperoxybenzoicacid (mCPBA) in water (70%, 11.05 g, 44.4 mmol, 1.2 equiv.) wasadded. The mixture was stirred for 14 h at room temperature. Satu-rated aqueous solution of Na2S2O3 (30 mL) followed by aqueoussolution of NaOH 10% were added to the mixture (20 mL). Theaqueous phase was extracted with CH2Cl2 (3 � 100 mL). The com-bined organic layers were then washed with brine (50 mL), driedwith MgSO4, filtered and concentrated under reduced pressure. Thecrude mixture was subjected to column chromatography on silicagel (PE/Et2O, 99:1 to 90:10) to give racemic epoxide (�)-19 (6.09 g,72%) as a colorless oil. For analytical description see optically pure(–)-19.
(R)-tert-Butyldimethyl[4-(oxiran-2-yl)butoxy]silane [(–)-19]: Ja-cobsen (R,R)-CoII-Salen (0.12 g, 0.19 mmol) was placed in toluene(4 mL) and acetic acid (125 μL) was added. The mixture was stirredfor 30 min under an air atmosphere. Toluene was eliminated byevaporation under reduced pressure and racemic epoxide (�)-19(23.45 g, 101 mmol) was added to the complex. Water (930 μL,52 mmol, 0.51 equiv.) was added and the reaction was stirred 16 hat room temperature. The crude mixture was subjected to columnchromatography on silica gel (PE/Et2O, 99:1 to 90:10) to give enan-tiomerically pure epoxide (–)-19 (10.5 g, 45%) as a clear yellowliquid (lit. reported compound[20b]). [α]D20 = –1.5 (c = 1.0, CHCl3).1H NMR (300 MHz, CDCl3): δ = 3.61 (t, J = 6.0 Hz, 2 H,CH2OTBS), 2.95–2.87 (m, 1 H, CHCH2CH2), 2.74 (t, J = 3.0 Hz,1 H, OCH2CH), 2.46 (t, J = 3.0 Hz, 1 H, OCH2CH), 1.60–1.40 (m,6 H, CH2CH2CH2), 0.89 (s, 9 H, tBu), 0.05 (s, 6 H, 2� CH3) ppm.1 3C NMR (75 MHz, CDCl3 ) : δ = 60.9 (CH2 OTBS), 50 .3(CHCH2CH2), 45.0 (OCH2CH), 30.5 (CH2CH2OTBS), 30.2(CH2CH2CH), 23.9 (tBu), 20.3 (CH2CH2CH), 16.3 (C(IV) tBu),–5.3 (2� CH3) ppm. MS (CI): m/z = 231 [M + H]+.
(R)-Oct-7-ene-1,5-diol [(+)-20]: To a solution of CuI (0.48 g,2.50 mmol, 0.22 equiv.) in dry Et2O (70 mL) under argon at –30 °C,
Towards the Synthesis of Restricted Analogues of Peloruside A
commercially available vinylmagnesium bromide (25.1 mL,25.1 mmol, 2.2 equiv., 1 m in THF) was added dropwise and themixture stirred for 1 h at the same temperature. The solution ofepoxide (–)-19 (2.63 g, 11.44 mmol) in Et2O (40 mL) was addedslowly to the mixture through a cannula. After 3 h at –30 °C thereaction was carefully quenched with saturated aqueous solutionof ammonium chloride. The aqueous layer was extracted withCH2Cl2, and the combined organic layers were dried with MgSO4,filtered and solvent was eliminated under reduced pressure. Themixture was subjected to column chromatography on silica gel (PE/Et2O, 99:1 to 90:10) to give (R)-8-(tert-butyldimethylsilyloxy)oct-1-en-4-ol (2.25 g, 76%) as a colorless oil. (lit. enantiomer reportedcompound[30]). [α]D20 = +4.6 (c = 1.0, CHCl3) [lit. (–)-enantiomer:[α]D20 = –4.8 (c = 0.46, CHCl3)]. 1H NMR (300 MHz, CDCl3): δ =5.90–5.76 (m, 1 H, CHCH2), 5.16–5.11 (m, 2 H, CHCH2), 3.66–3.60 (m, 1 H, CHOH), 3.62 (t, J = 6.1 Hz, 2 H, CH2OTBS), 2.35–2.26 (m, 1 H, CH2CHCH2), 2.19–2.09 (m, 1 H, CH2CHCH2), 1.62–1.35 (m, 6 H, CH2CH2CH2), 0.90 (s, 9 H, tBu), 0.05 (s, 6 H,2CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 135.0 (CH2CH),118 .2 (CH 2 CH), 70 .8 (CHOH) , 62 .3 (CH 2 OTBS) , 42 .1(CH2CHCH2), 36.7 (CH2CH2CHOH), 32.9 (CH2CH2OTBDPS),22.1 (CH2), 18.5 (C(IV) tBu), –5.1 (2CH3) ppm. MS (CI): m/z = 259[M + H]+.
This monoprotected diol (300 mg, 1.16 mmol, 1 equiv.) was dis-solved in THF (6 mL), then TBAF (1 m in THF, 2.20 mL,2.20 mmol, 1.9 equiv.) was added at 0 °C. The mixture was stirred16 h at room temperature and the reaction was quenched withwater (5 mL). The aqueous phase was extracted with CH2Cl2 (3�
15 mL), and the combined organic layers were dried with MgSO4,filtered and concentrated under reduced pressure. The crude mix-ture was subjected to column chromatography on silica gel(CH2Cl2/MeOH, 99:1 to 90:10) to give 1,5-diol (+)-20 (139 mg,87%) as a colorless oil. [α]D20 = +7.4 (c = 0.5, CHCl3). IR (KBr): ν̃= 3346, 3075, 2934, 2863, 1825, 1255, 913, 736 cm–1. 1H NMR(300 MHz, CDCl3): δ = 5.90–5.81 (m, 1 H, CHCH2), 5.17–5.12 (m,2 H, CHCH2), 6.69–6.64 (m, 1 H, CHOH), 3.67 (t, J = 6.1 Hz, 2H, CH2OH), 2.35–2.29 (m, 1 H, CH2CHCH2), 2.20–2.10 (m, 1 H,CH2CHCH2), 1.60–1.30 (m, 6 H, CH2CH2CH2) ppm. 13C NMR(75 MHz, C6D6): δ = 134.7 (CH2CH), 118.2 (CH2CH), 70.5( C H O H ) , 6 2 . 8 ( C H 2 O H ) , 4 2 . 0 ( C H 2 C H C H 2 ) , 3 6 . 4(CH2CH2CHOH), 32.6 (CH2CH2OH), 22.2 (CH2) ppm. MS (CI):m/z = 145 [M + H]+.
(R)-6-Allyl-tetrahydropyran-2-one [(–)-21]: To a solution of diol (+)-20 (1.16 g, 8.04 mmol, 1 equiv.) in CH2Cl2 (40 mL), a buffer solu-tion (NaHCO3 (0.5 m)/K2CO3 (0.05 m), 40 mL), Ac-TEMPO(0.17 g, 0.82 mmol, 0.1 equiv.) and tetra-n-butylammonium brom-ide (TBABr; 0.26 g, 0.80 mmol, 0.1 equiv.) were added and thismixture was vigorously stirred at room temperature. Then N-chlo-rosuccinimide (NCS; 3.22 g, 24.1 mmol, 3 equiv.) was added, andthe reaction was stirred for 16 h at the same temperature. The layerswere separated and the aqueous phase was extracted with CH2Cl2(3� 40 mL), dried with MgSO4, filtered and concentrated underreduced pressure. The crude mixture was subjected to columnchromatography on silica gel (PE/Et2O, 99:1 to 40:60) to give vola-tile lactone (–)-21 (1.35 g, with 20% of Et2O) as a yellow liquid.[α]D20 = –4.1 (c = 1.0, CHCl3), lit.[31] [α]D20 = –8.1 (c = 1.0, CHCl3).1H NMR (300 MHz, CDCl3): δ = 5.90–5.75 (m, 1 H, CH2CH),5.19–5.11 (m, 2 H, CH2CH), 4.39–4.29 (m, 1 H, CHOCO), 2.60–2.25 (m, 4 H, 2CH2) 2.0–1.6 (m, 4 H, CH2CH2CHOCO) ppm. 13CNMR (75 MHz, CDCl3): δ = 170.8 (CO), 132.6 (CH2CH), 118.6(CH2CH), 79.8 (CHOCO), 40.0 (CH2CHCH2), 29.5 (CH2CO),27.2 (CH2), 18.4 (CH2CH2CHOCO) ppm. MS (CI): m/z = 158 [M+ NH4]+.
Methyl (–)-2-[(2S,6R)-6-Allyl-tetrahydro-2H-pyran-2-yl]-2-methyl-propanoate [(–)-22]: To a solution of diisopropylamine (2.86 mL,20.3 mmol, 2.9 equiv.) in THF (25 mL) at 0 °C was added slowlyn-butyllithium (2.5 n in hexane, 20.3 mmol, 2.9 equiv.). After15 min the solution was cooled to –78 °C and methylisobutyrate(2.3 mL, 20.3 mmol, 2.9 equiv.) was added dropwise. The mixturewas then stirred for 40 min at –78 °C, warmed up to 0 °C and asolution of (–)-21 (1.0 g, 7 mmol) in THF (10 mL) was added witha cannula. After 1 h at the same temperature the solution wasquenched with the addition of an aqueous solution of HCl (1 n,30 mL). The aqueous layers were extracted with Et2O (3� 100 mL)and the combined organic layers were washed with brine, driedwith MgSO4, filtered, and concentrated under reduced pressure.The crude mixture was quickly subjected to column chromatog-raphy on silica gel (PE/Et2O, 80:20) to furnish a colorless oil. Thisresidue was then dissolved in CH2Cl2 (25 mL) and the solution wascooled to –78 °C, before addition of triethylsilane (2.2 mL,14 mmol) followed by BF3·Et2O (1.0 g, 7 mmol). The mixture wasthen stirred 4 h at –78 °C, warmed up to 0 °C and quenched witha saturated aqueous ammonium chloride solution (50 mL). Theaqueous layer was extracted with CH2Cl2 (3� 100 mL) and thecombined organic layers were dried with MgSO4, filtered and con-centrated under reduced pressure. The crude mixture was subjectedto column chromatography on silica gel (PE/Et2O, 90:10) to affordtetrahydropyran (–)-22 (1.36 g, 86 % over two steps) as a colorlessoil. [α]D20 = –12.7 (c = 1.0, CHCl3). 1H NMR (300 MHz, CDCl3):δ = 5.87–5.73 (m, 1 H, CH2CH), 5.04–4.95 (m, 2 H, CH2CH), 3.65(s, 3 H, OMe), 3.49 [d, J = 1.1, J = 11.3 Hz, 1 H, OCHC(Me)2],3.35–3.27 (m, 1 H, OCHCH2), 2.25–2.05 (m, 2 H, CH2CHCH2),1.87–1.80 (m, 1 H, CH2), 1.55–1.11 (m, 5 H, CH2CH2CH2), 1.17 (s,3 H, CH3), 1.10 (s, 3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3): δ= 177.7 (CO), 135.6 (CH2CH), 116.0 (CH2CH), 82.3 [OCHC-(Me)2], 77.8 (OCHCH2), 51.8 (OCH3), 46.9 [C(Me)2], 40.9(CH2CHCH2), 31.3 (CH2CH–O), 25.3 (CH2), 23.8 [CH2CH(O)-CH2CH], 21.1 (CH3), 20.6 (CH3) ppm. MS (CI): m/z = 227 [M +H]+. HRMS: calcd. for C13H22O3Na [M + Na+] 249.1461; found249.1471.
(–)-2-[(2S,6R)-6-Allyl-tetrahydro-2H-pyran-2-yl]-2-methylpropanal(7): To a solution of ester (–)-22 (480 mg, 2.12 mmol, 1 equiv.) inTHF (20 mL) was added LiAlH4 (85 mg, 2.25 mmol) at –5 °C. Themixture was then stirred 4 h at room temperature. The solution wasquenched with water (2.2 mL) followed by an aqueous solution ofNaOH (1 n, 2.2 mL) and a second addition of water (2.2 mL). Themixture was stirred vigorously for 30 min and then filtered. Theliquid phase was then evaporated under reduced pressure to furnishthe corresponding alcohol (365 mg, 87%) as a colorless oil. [α]D20 =+17.3 (c = 1.0, CHCl3). IR (KBr): ν̃ = 3445, 3075, 2993, 1642,2857, 1087, 1050, 913 cm–1. 1H NMR (400 MHz, CDCl3): δ = 5.87–5.73 (m, 1 H, CH2CH), 5.10–5.04 (m, 2 H, CH2CH), 3.44 (s, 2 H,CH2OH), 3.42–3.34 (m, 1 H, OCHCH2), 3.23 [dd, J = 1.9, J =11.1 Hz, 1 H, OCHC(Me)2], 2.23–2.18 (m, 2 H, CH2CHCH2),1.90–1.84 (m, 1 H, CH2), 1.60–1.19 (m, 5 H, CH2CH2CH2), 0.91(s, 3 H, CH3), 0.85 (s, 3 H, CH3) ppm. 13C NMR (100 MHz,CDCl3): δ = 135.0 (CH2CH), 117.3 (CH2CH), 87.3 [OCHC(Me)2],77.9 (OCHCH2), 73.4 (CH2OH), 41.1 (CH2CHCH2), 38.0[C(Me)2], 31.3 (CH2CHO), 25.6 (CH2), 23.7 [CH2CH(O)CH2CH],22.9, (CH3) 19.2 (CH3) ppm. MS (CI): m/z = 198 [M + H]+.
To a solution of oxalyl chloride (60 mg, 0.48 mmol) in CH2Cl2
(2 mL) at –78 °C was added dropwise a solution of DMSO (70 mg,0.96 mmol) in CH2Cl2 (2 mL). The reaction was stirred 30 min atthe same temperature. A solution of the previous alcohol (80 mg,0.41 mmol) in CH2Cl2 (2 mL) was added slowly through a cannulaand the mixture was stirred for 30 min. Then Et3N (0.32 mL,
J. Lebreton, M. Mathé-Allainmat et al.FULL PAPER2.3 mmol) was added slowly and the reaction was stirred for 1 h at–78 °C, then warmed to 0 °C and stirred for 1 h. The reaction wasquenched with water (5 mL) and diluted with Et2O (5 mL). Theorganic layer was separated and the aqueous layer was extractedwith Et2O (3� 25 mL). The organic layers were combined, washedwith saturated NaCl aqueous solution (20 mL), dried with MgSO4,filtered and concentrated under reduced pressure. The crude mix-ture was subjected to column chromatography (PE/Et2O, 85:15) tofurnish aldehyde 8 in quantitative yield as a yellow liquid. [α]D20 =–18.6 (c = 1.0, CHCl3). IR (KBr): ν̃ = 3076, 2936, 2858, 2711, 1726,1643, 1269, 1196, 1090, 912 cm–1. 1H NMR (400 MHz, CDCl3): δ= 9.59 (s, 1 H, CHO), 5.85–5.73 (m, 1 H, CH2CH), 5.05–4.98 (m,2 H, CH2CH), 3.40 [dd, J = 1.6, J = 11.2 Hz, 1 H, OCHC(Me)2],3.35–3.27 (m, 1 H, OCHCH2), 2.25–2.09 (m, 2 H, CH2CHCH2),1.90–1.85 (m, 1 H, CH2), 1.65–1.15 (m, 5 H, CH2CH2CH2), 1.05(s, 3 H, CH3), 1.02 (s, 3 H, CH3) ppm. 13C NMR (100 MHz,CDCl3): δ = 206.10 (CHO), 135.5 (CH2CH), 116.6, (CH2CH) 82.0[OCHC(Me)2], 78.1 (OCHCH2), 49.9 [C(Me)2], 41.1 (CH2CHCH2),31.1 (CH2CH–O), 25.4 (CH2), 23.8, [CH2CH(O)CH2CH] 19.5(CH3), 17.1 (CH3) ppm. MS (CI): m/z = 214 [M + NH4]+; 197 [M+ H]+. HRMS: calcd. for C12H20O2Na [M + Na+] 219.1356; found219.1354.
(3S,7S,10R,Z)-2-[(2S,6R)-6-allyl-tetrahydro-2H-pyran-2-yl]-10-[(tert-butyldiphenylsilyloxy)methyl]-3-hydroxy-7-(4-methoxybenz-yloxy)-2-methyldodec-8-en-5-one (23): Methyl ketone 6 (300 mg,0.55 mmol, 1 equiv.) was dissolved in anhydrous CH2Cl2/Et2O(2.5 mL:1.5 mL), and aldehyde 7 (216 mg, 1.10 mmol, 2 equiv.) wasdissolved in anhydrous Et2O (1.5 mL), both under argon. Both sub-strate solutions were stirred for 30 min in the presence of 1–3 CaHpellets. The solution of 6 was transferred by cannula into a flame-dried flask. A commercial (c-Hex)2BCl hexanes solution (1.0 m,1.55 mL, 1.55 mmol, 3 equiv.) was added dropwise to the ketonesolution at 0 °C, followed by freshly distilled Et3N (210 μL,1.54 mmol, 3 equiv.). The solution was then stirred for 1.5 h at 0 °Cbefore the addition of the solution of 7 by a cannula at –85 °C. Themixture was then stirred 3.5 h at –78 °C and the reaction mixturewas poured onto NaHCO3 solution (5 %, 5 mL). The aqueousphase was extracted with CH2Cl2 (3� 15 mL) and the combinedorganic layers were washed with brine, dried with anhydrousMgSO4, filtered and concentrated under reduced pressure. Thecrude mixture was then subjected to column chromatography onsilica gel (PE/Et2O, 99:1 to 90:10) to give a mixture of 1,5-anti-23and 1,5-syn-23 with a dr of 7:3 in favor of anti-23 (160 mg, 83%)as a colorless oil. 1H NMR (400 MHz, CDCl3): (two isomers): δ =7.68–7.66 (m, 4 H, Har), 7.38–7.35 (m, 6 H, Har), 7.09 (d, J =8.6 Hz, 2 H, Har), 6.78 (d, J = 8.6 Hz, 2 H, Har), 5.84–5.73 (m, 1H, CH2CH), 5.50–5.39 (m, 2 H, CHCH), 5.08–5.00 (m, 2 H,CH2CH), 4.66–4.59 (m, 1 H, CHOPMB), 4.31 (d, J = 10.9 Hz, 1H, CH2OPMB), 4.10–4.01 (m, 2 H, CHOH and CH2OPMB), 3.88(d, J = 5.1 Hz,1 H, OH), 3.78 (s, 3 H, OCH3), 3.60–3.57 (m, 2 H,CH2OTBDPS), 3.39–3.27 (m, 1 H, CH2CHCH2CHO), 3.22 [dd, J
= 1.4, J = 11.4 Hz, 1 H, CH(Me)2], 2.91–2.83 [m, 1 H, O–CHCH2C(O)], 2.60–2.41 [m, 4 H, O–CHCH2C(O) and CHCH2Oand C(O)CH2CH(OH)], 2.21–2.16 (m, 2 H, CH2CHCH2), 1.91–1.84 (m, 1 H, CH2), 1.74–1.64 (m, 1 H, CH2CH3), 1.55–1.22 (m, 6H, CH2CH3 and CH2CH2CH2), 1.06 (s, 9 H, tBu), 0.89 (s, 0.9 H,CH3 syn isomer), 0.86 (s, 2.1 H, CH3 anti isomer), 0.85 (s, 2.1 H,CH3 anti isomer), 0.84 (t, J = 7.5 Hz, 3 H, CH2CH3), 0.70 (s, 0.9H, CH3 syn isomer) ppm. 13C NMR (100 MHz, CDCl3): δ = 209.6(CO, syn isomer), 208.7 (CO, anti isomer), 159.2 (Car), 135.8 (Car),135.6 (CH=CH, syn isomer), 135.5 (CH=CH, anti isomer), 135.1(CH=CH2, syn isomer), 131.0 (CH=CH, anti isomer), 130.9(CH=CH, syn isomer), 135.0 (CH=CH2, anti isomer), 134.0 (C(IV)
), 133.9 (2C(IV)), 130.8 (C(IV)), 129.8 (Car), 129.6 (Car), 127.9 (Car),127.8 (Car), 117.4 (CH=CH2, anti isomer), 117.1 (CH=CH2, syn
isomer), 113.8 (Car), 85.8 {[OCHC(Me)2], syn isomer}, 85.6{[OCHC(Me)2], anti isomer}, 78.3 (CH2CHCH2CH–O, anti iso-mer), 77.9 (C6 pyran, syn isomer), 75.2 (CHOH, syn isomer), 74.7(CHOH, anti isomer), 71.8 (CHOPMB, anti isomer), 71.7(CHOPMB, syn isomer), 70.4 (CH2Ar, anti isomer), 70.3 (CH2Ar,s y n i s o m e r ) , 6 7 . 3 ( C H 2 OT B D P S ) , 5 5 . 4 ( O C H 3 ) , 5 0 . 3(CH2CHOPMB, anti isomer), 49.6 (CH2CHOPMB, syn isomer),47.2 (CH2CHOH, anti isomer), 46.7 (CH2CHOH, syn isomer), 42.2(CHEt), 41.2 (CH2CHCH2, syn isomer), 41.1 (CH2CHCH2, anti
isomer), 40.5 [C(Me)2, syn isomer], 40.1 [C(Me)2, anti isomer], 31.3(O–CHCH2CH2, anti isomer), 31.2 (O–CHCH2CH2, syn isomer),27.1 (C tBu, two isomers), 25.3 (CH2CH3, syn isomer), 25.2(CH2CH3, anti isomer), 24.7 (CH2CH2CH2), 23.9 (CH2CH2CH2,syn isomer), 23.8 (CH2CH2CH2, anti isomer), 21.3 (CH3), 21.2(CH 3 ) , 19 .5 (C ( I V ) tBu) , 16 .04 (CH 3 , one isomer ) , 11 .8(CH2CH3) ppm. HRMS: calcd. for C46H64O6SiNa [M + Na+]763.4364; found 763.4362. HPLC (C18, MeOH/H2O = 95:5 v/v):tR = 21.76 (70%, anti isomer), 23.69 min (30%, syn isomer).
(3S,5S,7S,10R,Z)-2-[(2S,6R)-6-Allyl-tetrahydro-2H-pyran-2-yl]-10-[(tert-butyldiphenylsilyloxy)methyl]-7-(4-methoxybenzyloxy)-2-methyldodec-8-ene-3,5-diol (24): Acetic acid (3.5 mL) was added toa solution of both aldol 24 and its diastereomer (dr 7:3; 150 mg,0.20 mmol, 1 equiv.) in dry CH3CN (3.5 mL) under argon. Themixture was stirred 2 min at –20 °C before fast addition ofMe4NHB(OAc)3 (220 mg, 0.84 mmol, 4.1 equiv.). The resultingmixture was then stirred for 8 h under argon at the same tempera-ture. The reaction was quenched with addition of saturated aque-ous NaHCO3 solution (10 mL) and the aqueous phase was ex-tracted with CH2Cl2 (3 � 20 mL). The combined organic layerswere washed with brine, dried with anhydrous MgSO4, filtered andconcentrated under reduced pressure. The crude mixture was thensubjected to column chromatography on silica gel (PE/Et2O, 98:2to 50:50) to give pure anti-1,3-diol 24 (97 mg, 65%) as a colorlessoil. [α]D20 = –58.5 (c = 1.0, CHCl3). 1H NMR (400 MHz, C6D6): δ= 7.82–7.78 (m, 4 H, Har), 7.26–7.22 (m, 8 H, Har), 6.77–6.74 (m,2 H, Har), 5.82–5.68 (m, 1 H, CH2CH), 5.55–5.37 (m, 2 H, CHCH),5,08–4.98 (m, 2 H, CH2CH), 4.59–4.48 (m, 2 H, CHOPMB andCHOH), 4.51 and 4.14 (AB system, J = 11.1 Hz, 2 H, CH2Ar),4.16–4.12 (m, 2 H, CHOH), 3.92 (d, J = 5.5 Hz, 1 H, OH), 3.71–3.60 (m, 2 H, CH2OTBDPS), 3.12–3.06 [m, 1 H, C(Me)2CH–O],3.03–2.95 (m, 1 H, CH2CHCH2CH–O), 2.65–2.53 (m, 1 H, CHEt),2.25–2.13 (m, 1 H, PMBO–CHCH2) , 2 .00–1.80 (m, 2 H,CH2CHCH2), 1.85–1.80 (m, 1 H, PMBO–CHCH2), 1.70–1.65 [m,2 H, CH(OH)CH2CH(OH)], 1.20–0.85 (m, 8 H, CH2CH2CH2 andCH2CH3), 1.18 (s, 9 H, tBu), 0.93 (s, 3 H, CH3), 0.89 (s, 3 H, CH3),0.89 (t, J = 7.3 Hz, 3 H, CH2CH3) ppm. 13C NMR (100 MHz,C6D6): δ = 159.7 (C(IV)ar), 135.2 (CH2CH), 134.9 (CHCH), 134.1(C(IV)ar), 132.6 (CHCH), 131.2 (C(IV)ar), 130.2 (Car), 130.1 (Car),129.6 (Car), 128.2 (Car), 128.1 (Car), 117.2 (CH2CH), 114.2 (Car),85.9 [C(Me)2CH–O], 78.1 (CH2CHCH2CH–O), 76.0 (CHOPMB),74.9 (CHOH), 70.3 (CH2Ar), 68.8 [C(Me)2CHOH], 67.7 (CH2-OSiTBDPS), 54.8 (OCH3), 44.2 (PMBOCHCH2), 42.3 (CHEt),41.1 (CH2CHCH2), 40.2 [C(Me)2], 39.8 [CH(OH)CH2CH(OH)],31.3 (CH2CH–O), 27.2 (C tBu), 25.2 (CH2CH2CH2), 25.0(CH2CH3), 23.9 (CH2CH2CH2), 21.6 (CH3), 21.5 21.6 (CH3), 19.6(C(IV) tBu), 11.9 (CH2CH3) ppm. MS (CI): m/z = 744 [M + H]+.HRMS: calcd. for C29H38O4Na [M + Na]+ 765.4521; found765.4514. HPLC (C18, MeOH/H2O = 95:5 v/v): tR = 19.76 (98.5%,1,5-anti), 24.12 min (1.5%, minor product).
Towards the Synthesis of Restricted Analogues of Peloruside A
oxybenzyloxy)hex-3-enyloxy](tert-butyl)diphenylsilane (25): Atroom temperature under argon, 2,2-dimethoxypropane (2,2-DMP;166 mg, 1.59 mmol, 10 equiv.) followed by pyridinium p-toluene-sulfonate (PPTS; 40 mg, 0.159 mmol, 1 equiv.) were added to diol24 (118 mg, 0.159 mmol, 1 equiv.) dissolved in dry CH2Cl2. Theresulting mixture was then stirred for 14 h at the same temperature.After this time the solvent was evaporated and the crude mixturewas subjected to column chromatography on silica gel (PE/Et2O,98:2 to 80:20) to give pure diastereomer 25 (101 mg, 81%) as acolorless oil. [α]D20 = –44.4 (c = 1.0, C HCl3). 1H NMR (400 MHz,C6D6): δ = 7.82–7.79 (m, 4 H, Har), 7.30–7.28 (m, 2 H, Har), 7.26–7.21 (m, 6 H, Har), 6.83–6.81 (m, 2 H, Har), 5.97–5.87 (m, 1 H,CH2=CH), 5.59 (dd, J = 9.4, J = 11.0 Hz, 1 H, CHCH), 5.45 (t, J
(2S,5R,Z)-1-((4R,6S)-6-{2-[(2S,6R)-6-Allyl-tetrahydro-2H-pyran-2-yl]propan-2-yl}-2,2-dimethyl-1,3-dioxan-4-yl)-5-[(tert-butyldi-phenylsilyloxy)methyl]hept-3-en-2-ylacrylate (26): To a cold solu-tion of acetonide 25 (205 mg, 0.262 mmol, 1 equiv.) in CH2Cl2
(2.4 mL) and phosphate buffer (pH = 7.0, 1.2 mL) was added DDQ(71 mg, 0.313 mmol, 1.2 equiv.). The reaction mixture was stirredfor 2.5 h at 0 °C before a second addition of DDQ (30 mg,0.132 mmol, 0.5 equiv.) and the mixture was stirred for a further1 h. The reaction was diluted with CH2Cl2 (3 mL) quenched withsaturated aqueous NaHCO3 solution (3 mL), and diluted withwater. The layers were separated and the aqueous layer extractedwith CH2Cl2 (3 � 5 mL). The combined organic layers were driedwith anhydrous MgSO4, filtered and concentrated under reducedpressure. The resulting residue was subjected to column chromatog-raphy on silica gel (PE/Et2O, 99:1 to 70:30) to give the expectedC15 hydroxy compound (139 mg, 80%) as a colorless liquid. [α]D20
= –25.0 (c = 1.0, CHCl3). 1H NMR (400 MHz, C6D6): δ = 7.89–7.80 (m, 4 H, Har), 7.27–7.24 (m, 6 H, Har), 5.98–5.85 (m, 1 H,CH2CH), 5.83–5.76 (m, 1 H, CHCH), 5.21 (t, J = 10.5 Hz, 1 H,CHCH), 5.09–5.02 (m, 2 H, CH2CH), 4.80–4.74 (m, 1 H, CHOH),4.24 [dd, J = 6.4, J = 10.3 Hz, 1 H, C(Me)2CH–O–acetonide], 4.08–3 . 9 9 ( m , 1 H , C H – O – a c e t o n i d e ) , 3 . 6 6 – 3 . 5 4 ( m , 2 H ,CH2OTBDPS), 3.42 [dd, J = 1.2, J = 10.8 Hz, 1 H, C(Me)2CH–O], 3.25–3.18 (m, 2 H, OH and CH2CHCH2CH–O), 2.80–2.72 (m,1 H, CHEt), 2.36–2.24 (m, 1 H, CH2CHCH2), 2.20–2.11 (m, 1 H,CH2CHCH2), 2.07–1.97 [m, 1 H, CH(OH)CH2], 1.78–1.61 [m, 3
(1S,7S,9S,11R,13R,E)-7-{(R,Z)-3-[(tert-Butyldiphenylsilyloxy)meth-yl]pent-1-enyl}-9,11-dimethyl-1,3-dioxan-12,12-dimethyl-6,17-di-oxabicyclo[11.3.1]heptadec-3-en-5-one (27): Acrylate 26 (31 mg,0.043 mmol, 1 equiv.) was dissolved in degassed CH2Cl2 (35 mL).Grubbs II catalyst (10 mg) was quickly added and argon wasbubbled through the solution for 10 min before heating to reflux.After 2 h, the temperature was lowered to room temperature andair was bubbled through the solution to destroy excess catalyst. Thesolvent was evaporated and the resulting residue was subjected to
(1R,7S,9S,11R,13S,E)-7-{(R,Z)-3-[(tert-Butyldiphenylsilyloxy)meth-yl]pent-1-enyl}-9,11-dihydroxy-12,12-dimethyl-6,17-dioxabicyclo-[11.3.1]heptadec-3-en-5-one (28): Acetonide-protected macrocycle27 (7 mg, 0.011 mmol, 1 equiv.) was dissolved in acetone/H2O (9:1,3 mL), and PPTS was added (2 mg, 0.008 mmol, 0.74 equiv.). Theresulting reaction mixture was gently heated to reflux for 1 h butthe reaction was not complete. Acetone/H2O (9:1 1 mL) was addedand the mixture was heated for 2 h until completion of the reactionand then cooled to room temperature and diluted with buffer solu-tion (pH = 7.0, 5 mL). It was then extracted with CH2Cl2 (3�
1 equiv.) was dissolved in THF (6 mL), then freshly opened TBAFreagent (1 m in THF, 0.06 mL) was added and the reaction mixturewas stirred for 24 h. To drive the reaction to completion a secondportion of TBAF (1 m in THF, 0.06 mL) was added and after 8 hthe solvent was evaporated under reduced pressure. The resultingresidue was subjected to column chromatography on silica gel(Et2O then Et2O/MeOH, 9:1) to give triol 8 (7 mg, 92 %) as color-less oil. [α]D20 = –8 (c = 0.1, CHCl3). 1H NMR (500 MHz, C6D6): δ= 7.2 [m, 1 H, (CO)CHCH], 6.09 [dtd, J = 0.97, J = 7.08, J =8.18 Hz, 1 H, CHOC(O)], 5.8 (ddd, J = 0.69, J = 8.2, J = 11.29 Hz,1 H, CHCH), 5.67 [d, J = 16.25 Hz, 2 H, C(O)CHCH], 5.21 (dd,J = 1.08, J = 11.67 Hz, 1 H, CHCH), 4.52 [m, 1 H, CH(OH)], 3.62(m, 1 H, CH2OH), 3.53 [t, J = 10.88 Hz, 1 H, 1 H, CH(OH)], 3.39(m, 1 H, CH2OH), 3.07 (d, J = 9.9 Hz, 1 H, OH), 2.95 (dd, J =2.32, J = 10.36 Hz, 1 H, CH–O pyran), 2.85 (m, 1 H, CHEt), 2.78(m, 1 H, OH), 2.60 (tt, J = 2.13, J = 11 Hz, 1 H, CH–O pyran),2.12 [ddd, J = 4.19, J = 7.66, J = 14.72 Hz, 1 H, CH2CHOC(O)],1.96 [ddd, J = 1.6, J = 4.11, J = 14.75 Hz, 1 H, CH2CHOC(O)],1.75–1.60 {m, 2 H, CH2[CH(OH)CMe2 and C(O)CHCHCH2]},1.5–0.89 [m, 7 H, CH2CH2CH2 and C(O)CHCHCH2], 1.10 (s, 3H, CH3), 0.81 (t, J = 7.43 Hz, 3 H, CH2CH3), 0.63 (s, 3 H,CH3) ppm. 13C NMR (125 MHz, C6D6): δ = 165.28 (CO), 148.86[C(O)CHCH], 136.07 (CHCH), 129.69 (CHCH), 123.37 [C(O)-CHCH], 84.84 (CH–O pyran), 82.09 (CH–O pyran), 79.17[CH(OH)], 69.71 [CHOC(O)], 66.82 (CH2OH), 66.22 [CH(OH)],43.81 (CHEt), 42.72 [CH2CHOC(O)], 40.83 (CH2), 40.71 (C(IV)),37.19 (CHCHCH2), 31.45 (CH2CH2CH2), 25.71 (CH2CH2CH2),24.75 (CH2CH3), 24.02 (CH2CH2CH2), 23.36 (CH3), 20.82 (CH3),11.99 (CH2CH3) ppm. MS (CI): m/z = 411.19 [M + H]+. HRMS:calcd. for C23H38O6Na [M + Na+] 433.2561; found 433.2569.
Supporting Information (see footnote on the first page of this arti-cle): 1H NMR and 13C NMR spectra for all key intermediates andfinal products as well as the NOESY spectrum and geometry opti-mization for 27.
Acknowledgments
The authors are grateful to V. Silvestre and J. Graton working inthe laboratory for NMR and modelisation supports and to R.Le Guével (ImPACcell-SFR BIOSIT, Rennes, France) for bio-logical evaluations. This work was supported by grants fromCNRS – Région Bretagne-Pays de Loire and financial contri-butions from the Cancéropôle Grand-Ouest, the Ligue contre lecancer and Institut National du Cancer (INCa).
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Received: December 21, 2012Published Online: March 5, 2013
