Reported herein is the total synthesis of zincophorin methyl ester, a polyketide ionophore. Of particular interest is the use of sterically hindered nucleophiles to surmount the unfavorable stereochemical outcome, leading to acetate aldol adducts, in nucleophilic addition to the aldehyde derived from propionates. The approach is based on the addition of an enoxysilane (bearing a removable phenylselenide moiety) to generate selectively FelkineAnh adducts in a BF3,OEt2-mediated Mukaiyama aldol reaction. Subsequent reduction of the selenide group led to the corresponding syn-aldol acetate motif, and this approach was applied to induce selectively the C12eC13 relationship of zincophorin.
耐士科技400-188-0725www.rysstech.comTetrahedron 71 (2015)709-726 耐士科技400-188-0725www.rysstech.comE Godin et al. / Tetrahedron 71 (2015) 709-726710 Contents lists available at ScienceDirect 国Tetrahedron Tetrahedron ELSEVIER journalhomepage: www.elsevier.com/locate/tet Total synthesis of zincophorin methyl ester. Stereocontrol of 1,2-induction using sterically hindered enoxysilanes Francois Godin, Philippe Mochirianab, Gabrielle St-Pierre a., Yvan Guindona.b.c* Institut de recherches cliniques de Montreal (IRCM), Bio-organic Chemistry Laboratory, 110 avenue des Pins Ouest, Montreal,Quebec H2W 1R7, Canada Departement de chimie, Universite de Montreal, C.P. 6128, succursale Centre-ville, Montreal, Quebec H3C 3J7, Canada ‘Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, Quebec H3A 2K6, Canada ARTICLEINFO ABSTRACT Article history:Received 19 September 2014Received in revised form 21 November 2014Accepted 24 November 2014Available online 28 November 2014 1. Introduction Polyketides, such as zincophorin 1 or salinomycin 2 (Scheme 1)are an important class of biologically active molecules,partly be-cause a large proportion displays ionophore properties. Indeed,the pseudo-cyclic conformation adopted by their tertiary structureallows for the creation of a cavity capable of coordinating certainmetal cations, in order to facilitate their transport across lipophilicmembranes. This permeability can lead to a disruption of the cel-lular potential, hence supporting why many polyketides havefound commercial applications as antibiotics, antiparasitics andinsecticides. The scarce availability and structural complexity ofthese compounds have attracted1numerous groups to designstrategies towards their synthesis.5Recently, identification of theantitumoral activity of salinomycin 2 against cancer stem cells(CSCs) has greatly intensified the interest of the scientific com-munity towards polyether ionophores. Following this importantdiscovery, several compounds of this class were investigated, aswell as analogs thereof, by a derivatization of the natural product.In order to increase the diversity of the compounds being evaluatedand possibly identify the pharmacophores, de novo synthetic ap-proaches also need to be considered. ( * C orresponding author. T el.: +1 5 14 9 87 5786; fax: + 1 514 9 8 7 5789; e-mail address:y van.guindon@ i rcm.qc.ca (Y . Guindon). ) Scheme 1. Representative polyketide ionophores. The total synthesis of these molecules bearing polypropionatemotifs is, however, not trivial although numerous methodologieswere developed over the years to access these sequences of con-tiguous stereogenic centers. Indeed, not all isomers can be selec-tively accessed by a single methodology and, more importantly, it issomewhat difficult to predict cases of mismatched double dia-stereoselectivity induction as the complexity of the substrate in-creases. To address this issue, our group has developed a robustiterative approach that allows an easily predictable elaboration ofpropionate units based on a Mukaiyama aldol reaction and a dia-stereoselective radical reduction (Scheme 2). At each step, thestereochemistry (anti or syn) of the center being created is simply = stereocenter controlled Scheme 2. Methodology for the synthesis of polypropionate motifs and application tozincophorin fragment 8. dictated by the choice of Lewis acid (L.A.). Furthermore, we havedemonstrated that the reaction sequence can be used iteratively toaccess all 16 polypropionate stereopentads,0 and we have appliedthis methodology to the synthesis of zincophorin fragment C1-C138 from aldehyde 4. Recently, we have also reporteda DFT analysisof the transition states for the hydrogen transfer step. Zincophorin 1a was first isolated in 1984 from strains of Strep-tomyces griseus and its structure was confirmed by crystallographicanalysis of the zinc-magnesium salt.From a biological perspec-tive, it shows a strong in vivo antibiotic activity against Gram-positive bacteria and Clostridium welchii, as well as for type Iher-pes simplex virus (HSV). The methyl ester of zincophorin 1b wasalso reported active against influenza virus A/WSN, and displayedsignificantly less cytotoxicity than the free carboxylic acid 1a.Since its discovery, many groups have reported the synthesis ofvarious fragments,but only four total syntheses of the target werecompleted. Herein, we describe the total synthesis of zincophorin methylester 1b by employing a sterically hindered nucleophile, bearinga phenylselenide, to introduce selectively the stereogenic center atC13. A systematic study on the aldehydes of simplified propionatesrevealed that an excellent stereocontrol is achieved under mono-dentate Lewis acid activation,and leads to the corresponding 3,4-syn aldol acetate motifs after cleavage of the phenylselenide group.The synthesis of zincophorin fragment C17-C25 is also presented. 2. Results and discussion Our retrosynthetic analysis for 1b is presented in Scheme 3. Weenvisioned a disconnection at the C16-C17 trans olefin, which couldbe obtained by a Julia-Kocienski couplingof fragments 9 and 10.We intended to generate the 18,19-anti relationship of 10 by takingadvantage of the MgCl2-catalyzed anti-aldol developed by Evans18on the a,p-unsaturated aldehyde 11. The sulfone 9 could in turnarise from a functionalization of the homoallylic alcohol 12 obtainedby an allylation reaction under Felkin-Anh control. Finally, the stereogenic center at C12 of 13 could be introduced by a Bu2BOTf-mediated diastereoselective radical reduction of halide precursor 8,previously obtained selectively via a Mukaiyama aldol reaction. The completion ofthe synthesis begins with the radical reductionof 10,11-anti β-hydroxyester 8.As expected, the desired 11,12-antiproduct 13 or its 11,12-syn isomer 14 were obtained selectively fol-lowing a L.A. pre-complexation, with either Bu2BOTf or Me3Al(Scheme 4). Having most of the polypropionate sequence com-pleted, we decided to introduce the remaining C12-C13 syn re-lationship of zincophorin by an allylation reaction in presence ofa monodentate Lewis acid. Our goal was to take advantage of thematched 1,2- and 1,3-asymmetric induction originating from therelative anti-relationship of substituents, on the corresponding al-dehyde,20 to favor formation of the Felkin-Anh product. Using thecommon precursor 16 prepared from fragment 13 (Scheme 5), twoaldehyde substrates were considered, either benzyl-protected 17 oras an acetonide 19. In both cases, a similar disappointing result wasnoted. Indeed, an equinolar mixture of homoallylic alcohols 20a,bor 21a,b were obtained with allylstannane and BF3·OEt2, althoughprevious reports yielded selectively the desired product on a simpleraldehyde.20b.21 Scheme 4. Radical reduction of β-hydroxyester 8. Another approach was then evaluated with enoxysilane 22 ina Mukaiyama aldol reaction of 17 using a monodentate Lewis acid,which should give the corresponding syn β-hydroxyester 23a, a use-ful intermediate. Unfortunately, once again no diastereoselectivitywas noted. These results were surprising, and the causes at the originof this lack of stereocontrol remains unknown. Scheme 5. Synthesis of aldehydes 17 and 19-Reagents and conditions: (a) BnOC(NH)C,1 h; (c) DMP,NaHCO3, CH2Cl2, rt, 1 h; (d) 2-methoxypropene, PPTS, CH2Cl2, 0 °C, 3 h, (e) (COCl)2,DMSO, Et3N, -78°C,1 h. We decided to further investigate this reaction, in search of a so-lution to access the desired syn acetate motif. Simpler propionatefragments 24 and 25 were first studied (Table 1). Under the sameallylation reaction conditions, substrate 24 leads to the exclusiveformation of Felkin product 28a (entry 1), while 25 affords the anti-Felkin isomer 32b in a modest 4.9:1 ratio (entry 5)." This poor se-lectivity originates from competing 1,2-and 1,3-induction for 2,3-synaldehyde 25. The stereochemistry of the major product can be ra-tionalized by a dominant control exerted by the βstereocenter in thiscase. Our solution to this problem originated from previous work byour group and others.20bWe previously demonstrated that BF3·OEt2-mediatedMukaiyama aldol reactioni using tetrasubstitutedenoxysilane 3 led to high levels of diastereoselectivity (entries 2 and6).Replacing the silylated enolate by nucleophile 26 proved to yieldalso the desired isomer selectively (entries 3 and 7). Clearly, thepresence of substituents on the olefin increases the steric effects ofthe nucleophile hence, the resulting 1,2-induction and stereofacialselectivity. This observation also suggested an alternative pathway tocircumvent the lack of diastereoselectivity noted when preparing23a. Indeed, we hypothesized that an enoxysilane bearing a bulkyterminal substituent, which could eventually be removed at a laterstep, would also favor a reaction controlled uniquely by 1,2-induction. Based on previous studies by our group for the elabora-tion oftertiary centers,23 we envisioned that the use oftrisubstitutedenoxysilane 27, bearing a phenylselenide,couldprovide high ratios inthe presence of BF3·OEt2. To our delight, aldehydes 24 and 25 sub-mitted to these conditions also led to excellent diastereoselectivity infavor of Felkin adducts 31a²4 and 35a (entries 4 and 8). In a subsequent step, the resulting a-phenylselenide adductswere cleaved by radical reduction, to yield acetate aldol products36 and 37 from their corresponding precursors 31a and 35a (Scheme 6). Moreover, we demonstrated that the aldol-reductionreaction sequence can also be applied to other functionalized al-dehydes in order to generate exclusively the 3,4-syn isomer 39 and41 from elaborate fragments of zincophorin (38 and 40).1 Table 1Nucleophilic addition on aldehydes 24 and 25 a Product ratios were determined by 'H NMR analysis of the crude reactionmixture."Yields of isolated products.‘ Yield based on recovered starting material.d Reference 10. Our next objective was to apply these conditions onto an ad-vanced substrate of zincophorin (Scheme 7) by taking advantage ofthe sterical bias imposed by the nucleophile to remove possiblemismatched situations. We were able to isolate the desiredC12-C13 syn isomer 42a with a good selectivity (dr13:1) in theBF3·OEt2-promoted Mukaiyama aldol of aldehyde 17 in the pres-ence of enoxysilane 27, therefore completing the introduction ofthe necessary stereogenic centers after reduction to the corre-sponding acetate aldol 23a. Having the key motif in hand, the nextchallenge was to complete the synthesis of fragment 9 necessaryfor the coupling reaction. The aldehyde 45 was obtained easily after Scheme 7. Synthesis of C1-C16 fragment 9-Reagents and conditions: (a) 27, BF3·OEt2, CH2Cl2, -78°C, 1 h;(b) BuzSnH, Et3B, air, CH2Cl2, rt, 18 h; (c) BnOC(NH)CCl3, TfOH, cHex/CH2Cl2(2:1), 0°C,18h; (d) DIBAL-H,CH2Cl2,-40°C, 1 h;(e)DMP,NaHCO, CH2Cl2, rt, 1 h; (f) MePPh3Br,nBuLi,;(g) 1. 9-BBN, THF, 0 °C, 6 h; 2.NaOH,H202,0 °C to rt, 18 h; (h) PivCl,pyridine, CHzCl2, rt, 18 h;(i) TBAF, THF, 0 °C to rt, 18 h;(j) 1. NaClo2, NaH2PO4,2-methyl-2-butene, tBuOH, rt, 18 h; 2. TMSCHN2, MeOH/toluene (2:3), rt, 2 h;(k) H2, Pd/C, MeOH, rt,18 h; (1) TBSOTf, 2,6-lutidine, CH2Cl2, rt, 36 h; (m) K2C03, MeOH, rt, 36 h;(n) DIAD, PPh3, 54, THF, rt, 3 h;(o)(NH4)6Moz0244H20,H202, EtOH, rt, 18 h. Scheme 8. Synthesis of C17-C25 fragment 10-Reagents and conditions: (a) MgCl2,EtgN,TMSCl,57, EtOAc,rt, 18h;(b)TFA, MeOH,0°C,1h;(c)PMBOC(NH)CCl,TfOH,cHexCH2Cl2(2:1),0°C,18h;(d)LiBH4,MeOH,Et20,0°C,18h;(e)DMP,NaHCO3,CH2Cl2,rt, 1 h Scheme 9. Coupling of fragments 9 and 10-Reagents and conditions: (a) KHMDS,DME, -55 °C to-40°C,1.5 h; (b) DDQ, buffer pH 7, rt, 30 min;(c) TBAF, THF,rt, 68 h. The synthesis of the other fragment of zincophorin was realizedusing aldehyde 11,28 obtained from chiral alcohol 56 (Scheme 8).The C18-C19 anti relationship was introduced using Evans' anti-aldol conditions, yielding product 58 selectively. Subsequentdesilylation and protection of the secondary alcohol 59 with a PMB(60), cleavage of the auxiliary and oxidation to the aldehyde pro-vided fragment C17-C25 10, whose NMR spectra (1H and 13c) wereidentical to those previously reported.16d Coupling of fragments 9 and 10 was realized using the[ulia-Kocienski conditions,1 and led us to the selective formationof trans olefin 61a (Scheme 9). Finally, cleavage of the PMB, fol-lowed by desilylation of 62 with TBAF completed the sequenceleading to zincophorin methyl ester 1b, whose spectroscopicanalysis revealed to be identical to the compound reported byCossy.16b In summary, we have reported the total synthesis of zincophorinmethyl ester 1b. An important contribution of this work is the se-lective induction of the C13 stereocenter via a Mukaiyama aldolreaction through the use of a hindered silylated enolate. The latterbears a removable group that increases the dominance of 1,2-induction and avoids mismatch situations. In other previous re-ports of the target molecule, introduction of the C13 stereocenterwas either accomplished on simple substrates early in the syn-thesis, through fragment coupling or required an important num-ber of steps if performed on an advanced intermediate. The synthesis of the C1-C16 fragment 9 was achieved hereinusing a single methodology in a linear sequence of 44 steps, with anoverall yield of 0.2% from 4. One of the most notable features of ourapproach is the versatility to generate all four propionate isomersfrom a common intermediate by only varying the nature of Lewisacid at each step. While prior total syntheses of zincophorin methylester required fewer steps, our methodology facilitates the access toany isomers of the natural target in the perspective of a structure-activity optimization. Work aimed at improving the efficiency bydecreasing the number of steps per stereocenter (e.g., througha more convergent approach) and evaluating the generality of thismethodology, to access other polyether ionophores, is currentlyunder investigation and will be reported in due course. 4. Experimental 4.1. General comments Silylated enol ether 27 was prepared according to a procedurepreviously described by our group.a Experimental methods andphysical characterization of products 8, 18, 38, 40 a as well as 24and 25d have already been reported by our group. All proceduresrequiring anhydrous conditions were carried out under a positiveargon atmosphere (ornitrogen, for radical reductions) in oven-driedglassware using standard syringe techniques. All reaction solvents(HPLC grade) were dried using activated 4 A molecular sieves (48 h at180 °C under vacuum) according to the procedure described byWilliams et al.2 Crude products were purified by flash chromatog-raphy on silica gel (porosity: 60 A, size: 40-75 um) using HPLC-gradesolvents and compressed air, or using Biotage Isolera One (v1.3.6).Chemical shifts in ppm for H (400 or 500 MHz) and cspectra (100or 125 MHz) were referenced to residual solvent peak (oH and oc). For'H NMR data, the associated coupling constants (J, Hz), integrationvalue and multiplicity are reported. All ratios of products weremeasured from crude H spectra. Infrared spectra in cmwererecorded on a FTIR spectrophotometer (ABB Bomen, MB) on a NaClsupport. Optical rotations were measured on a PerkinElmer 343polarimeter at 25 °C from the sodium D line (589nm) with a cell of1.0 mL measuring 9.998 cm in length, and concentration c is reportedin g/100 mL. Mass spectra were recorded through electrospray ion-ization (ESI) on a LTQ Orbitrap XL instrument (Thermo Fisher) op-erating at 70 eV, and coupled to an ion trapt. 4.2. General experimental procedures 4.2.1. Procedure A-protection of alcohol with benzyl ether or PMBether. To a cooled (0 °C) solution of alcohol (1 equiv) in a solventmixture of dry cyclohexane and CH2Cl2 (2:1, 0.1 M) was addedsuccessively 2,2,2-benzyltrichloroacetimidate (Bn, 1.5 equiv) or 4-methoxybenzyl 2,2,2-trichloroacetimidate (PMB, 1.5 equiv) andTfOH(0.1 equiv), followed by stirring overnight at 0°C. The reactionmixture was treated with Et3N (0.15 equiv), and concentrated invacuo. The residue was solubilized in hexanes, filtered onto a pad of Celite@,washed thoroughly with hexanes and the filtrate concen-trated in vacuo. 4.2.2. Procedure B-reduction ofester to primary alcohol with DIBAL-H. To a cooled (-40°C) solution of ester (1 equiv) in dry CH2Cl2(0.1 M) was added a 1 M solution of DIBAL-H in hexanes (3 equiv). Themixture was stirred for 1 h at -40 °C or until ester was completelyconsumed, as verified by TLC. The reaction mixture was treated firstwith the dropwise addition of MeOH at -40 °C until gas evolutionceased, followed by a saturated potassium sodium tartrate solution(Rochelle’s salt). Mixture was stirred 1 h at rt (or until clarification ofphases) followed by separation of the organic phase. The aqueouslayer was extracted with Et20 (3x) and the combined organic frac-tions were dried (MgSO4), filtered and concentrated in vacuo 4.2.3. Procedure C-oxidation of primary alcohol with Dess-Martin pe-riodinane. To a solution of alcohol (1 equiv) in dry CH2Cl2(0.1 M) at itwas added successively NaHCO3 (10 equiv) and Dess-Martin peri-odinane (1.5 equiv). The reaction mixture was stirred for 1 h at rt andthen concentrated in vacuo. Resulting white solid residue wasdigested in hexanes, filtered onto a pad of Celite, washed thoroughlywith hexanes and the filtrate concentrated in vacuo. 4.2.4. ProcedureD-nucleophilic addition on aldehyde using BF3·OEt2. Toi cooled(-78 °C) solution of aldehyde (1 equiv) in dry CH2Cl2(0.1 M)was added successively the appropriate nucleophile (2 equiv) andBF3·OEt2 (1.5 equiv). After stirring for 1.5 h at -78 °C, the reactionmixture was treated with a saturated aqueous solution of NH4Cl at78°C,followed by separation of the organic phase at rt. The aqueouslayer was then extracted with CH2Cl2 (3×) and the combined organicfractions were dried (MgSO4), filtered and concentrated in vacuo. 4.2.5. ProcedureE-hydrogenolysis ofbenzylether with palladium. Toa solution of benzyl ether (1 equiv) in MeOH (0.1 M) at rt was added10% wt. Pd on activated carbon (0.1 equiv). Inert gas atmospherewas purged by 3 cycles of vacuum-H2 gas before stirring reactionmixture at rt until reaction was judged completed by TLC. Mixturewas then filtered onto a pad of Celite, washed thoroughly withMeOH and the filtrate concentrated in vacuo. 4.2.6. Procedure F-radical reduction ofphenylselenide. To a solutionof phenylselenide in dry CH2Cl2 (0.1 M) at rt was added successivelyBu3SnH (2 equiv), a 1 M solution of Et3B in CH2Cl2 (0.2 equiv) andair (syringe), followed by stirring overnight at rt. The mixture wastreated successively with 1,4-dinitrobenzene (0.2 equiv), a satu-rated aqueous solution of NH4Cl, and then concentrated in vacuo.The aqueous layer was extracted with Et20 (3x) and combinedorganic fractions were washed (2x) with a saturated aqueous so-lution of KF and brine, then dried (MgSO4), filtered and concen-trated in vacuo. 4.3. (+)-(2R,3R,4S,5S,6S)-Methyl 5-(benzyloxy)-6-((2S,3S,6S)-6-((R)-1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)-3-methyltetrahydro-2H-pyran-2-yl)-3-hydroxy-2,4-dimethylheptanoate (13) To a cooled (-78C) solution of bromide precursors ga(117 mg, 0.15 mmol) in dry CH2Cl2 (0.1 M, 1.5 mL) was added suc-cessively DIEA (1.5 equiv, 40 pL) and a 1M solution of Bu2BOTf inCH2Cl2 (1.3 equiv, 200 pL). After stirring for 1 h at -78°C, themixture was successively treated with BuzSnH (2 equiv, 82 uL),a 1 M solution of Et3B in CH2Cl2 (0.2 equiv,30 pL) and air via syringe(~3 mL). Supplementary addition of Et3B solution and air wererealized each 30 min until reaction was judged completed by TLC(3-4 h). Reaction mixture was treated with the addition of 1,4-dinitrobenzene (0.2 equiv, 5 mg) and stirring for 15 min at -78°C, before being treated by a saturated aqueous solution ofNH4Cl.Organic phase was separated at rt and the aqueous layer wasextracted with Et20(3x). Combined organic fractions were washed(2x) with a saturated aqueous solution of KF and brine, then dried(MgSO4), filtered and concentrated in vacuo. The residue was sol-ubilized in MeOH (0.1 M, 1.5 mL), cooled to 0°C, and treated witha 35% wt. solution of H202 in water (3 equiv, 40 pL). After stirring for2 h at O°C, the mixture was treated with water, diluted with Et20and the organic phase separated. The aqueous layer was extractedwith Et20 (3x) and the combined organic fractions were dried(MgSO4), filtered, and concentrated in vacuo. lH NMR analysis ofthe crude product indicated a ratio >20:1 of product 11,12-anti (13):11,12-syn(14). The residue was purified by flash chromatography onsilica gel (hexanes/EtOAc, 90:10) to give 11,12-anti product 13 asa pale yellow oil (99.2 mg, yield=77%). R 0.25 (hexanes/EtOAc,85:15);[c]+18.2(c 1.69, CH2Cl2); C42H60O6Si; MW 689.01 g/mol;IR (liquid film) Vmax3517,2955,2930,2857,1716,1459,1428,1380,1197, 1170,1112,1091, 1066 cm-; 1H NMR (500 MHz, CDCl3) 6H7.69-7.63 (m, 4H), 7.44-7.33(m, 6H), 7.29-7.22 (m, 3H), 7.21-7.16(m,2H), 4.42 (d,J=12.2 Hz,1H), 4.40(d,J=12.2 Hz, 1H), 3.68 (s,3H),3.74-3.61 (m, 4H), 3.51 (br s, 1H), 3.47 (dd,J=7.3, 4.2 Hz,1H), 3.35(dd,J=7.7,3.7Hz,1H), 2.76(qd,J=7.1, 3.5 Hz,1H), 2.23-2.14(m,1H),2.06-1.97(m, 1H), 1.97-1.88 (m,1H), 1.75-1.68(m,1H), 1.68-1.60(m,2H), 1.61-1.49(m,2H), 1.25 (d,J=7.1 Hz, 3H), 1.04 (s, 9H), 0.92(d,J=6.9 Hz, 3H), 0.88(d,J=6.9 Hz, 3H), 0.87 (d,J=7.0 Hz,3H), 0.86(d, J=6.4 Hz, 3H) ppm; 13C NMR (125MHz, CDCl;) òc 176.2,138.7,135.89, 135.87,134.2, 134.1, 129.65,129.60,128.4,127.71,127.69,127.5,127.4,86.3,76.6,76.4,74.4,71.8,65.9,51.7,42.3,39.1,38.1,37.1,30.1,28.0,27.1,24.7,19.5,18.6,16.6,15.2,13.5,11.8 ppm; MS (ESI) m|z227.0(3), 360.3(4),689.4(11,M+H+), 706.5(2,M+NH4), 711.4(100,M+Na+), 712.4(50),713.4(12); HRMS calcd for C42H61O6Si[M+H+]:689.4232, found: 689.4250)(2.6ppm);calcd forC42H6406NSi[M+NH4]: 706.4497, found: 706.4514(2.3ppm); calcdfor C42H60O6NaSi [M+Na+]: 711.4051, found: 711.4072 (3.0ppm). 4.4. (+)-(2S,3R,4S,5S,6S)-Methyl 5-(benzyloxy)-6-((2S,3S,6S)-6-((R)-1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)-3-methyltetrahydro-2H-pyran-2-yl)-3-hydroxy-2,4-dimethylheptanoate (14) To acooled(-78°C)solution of a mixture of bromide precursors81la (26.6 mg, 35 umol) in dry CH2C2 (0.1 M, 350 pL) was addeda 2 M solution of Me3Al in hexanes (2.5 equiv, 44 pL). After stirringfor 1 h at -78°C, the mixture was sticcessively treated with BuzSnH(2 equiv,19 uL), a 1M solution of Et3B in CH2Cl2(0.2 equiv,7uL)andair via syringe (~1 mL). Supplementary addition of Et3B solutionand air were realized each 30 min until reaction was judged com-pleted by TLC (3-4 h). Reaction mixture was treated with the ad-dition of 1,4-dinitrobenzene (0.2 equiv, 2 mg) and stirring for15 min at -78°C. To the mixture was added MeOH dropwise untilgas evolution ceased, followed by a saturated aqueous solution ofpotassium sodium tartrate (Rochelle's salt) and stirring overnight atrt before separation of the organic phase. The aqueous layer wasextracted with Et20 (3x) and combined organic fractions werewashed (2x) with a saturated aqueous solution of KF and brine,then dried (MgSO4), filtered and concentrated in vacuo. lH NMRanalysis of thecrude product indicated a ratio >20:1 of product11,12-syn (14): 11,12-anti (13). The residue was purified by flashchromatography on silica gel (hexanes/EtOAc, 90:10) to give 11,12-syn product 14 as a colorless oil (11.9 mg, yield=50%).R 0.33(hexanes/EtOAc, 85:15); [α]+26.6 (c 1.19, CH2Cl2); C42H6006Si;MW 689.01 g/mol; Vmax (liquid film) 3526,2953,2930,2857,1733,1589, 1459,1428,1382,1200,1112,1063 cm-1;1H NMR(500MHz,CDCl3) 8H 7.70-7.63 (m,4H), 7.44-7.33 (m,6H), 7.30-7.23 (m,3H),7.20-7.16 (m, 2H), 4.44 (d,J=11.4 Hz, 1H), 4.39 (d,J=11.4 Hz, 1H),4.04(dd,J=9.2,2.9 Hz,1H), 3.73-3.67(m,2H),3.70(s,3H), 3.61 (dd, J=9.6, 4.1 Hz, 1H), 3.47 (dd,J=7.1, 4.5Hz,1H), 3.35(dd,J=7.4, 3.9 Hz,1H), 3.30 (br s, 1H), 2.60 (qd,J=7.0, 3.1 Hz, 1H), 2.21-2.11 (m,1H),1.97-1.85(m,2H), 1.74-1.68(m,1H), 1.68-1.60 (m,1H), 1.60-1.49(m,2H), 1.31-1.23(m,1H),1.14(d,J=7.1 Hz, 3H), 1.04(s,9H), 0.94(d,J=7.0 Hz, 3H), 0.88(d,J=6.9 Hz, 3H), 0.86(d,J=6.6 Hz, 3H), 0.82 (d,J=7.1 Hz, 3H) ppm; 13c NMR (125 MHz, CDCl3) oc 176.3, 138.5,135.90, 135.88, 134.16,134.15,129.7, 129.6,128.4,127.72,127.70,127.6,127.5,86.6,76.42,74.3,74.1,71.8,65.8,51.9,42.3,38.4,37.9,37.1, 30.1, 27.1,27.0,24.6,19.5,18.6,16.5,13.5,11.8,9.2ppm; MS (ESI)m|z 227.0 (6), 338.3(4),360.3(7),689.4(10, M+H+), 711.4(100,M+Na+),712.4(50); HRMS calcd for C42H6106Si [M+H+]:689.4232,found: 689.4232 (-0.02 ppm); calcd for C42H6006NaSi [M+Na+]:711.4051, found: 711.4057 (0.8 ppm). 4.5. (+)-(2R,3R,4R,5S,6S)-Methyl 3,5-bis(benzyloxy)-6-((2S,3S,6S)-6-((R)-1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)-3-methyltetrahydro-2H-pyran-2-yl)-2,4-dimethylheptanoate (15) Product 15 (181 mg, yield=86%) as a colorless oil was obtainedfrom alcohol 13 (186 mg, 0.27 mmol) according to general procedureA, and purification by flash chromatography on silica gel (hexanes/EtOAc, 90:10). Rr 0.34 (hexanes/EtOAc, 90:10); [x]25+22.1 (c1.31,CH2Cl2); C49H6606Si; MW 779.13 g/mol; IR (liquid film) Vmax 3068,3031,2950,2929,2857,1737,1455,1428,1380,1202,1111,1091,1066 cm-1,H NMR (500 MHz, CDCl3) 0n 7.66-7.60 (m, 4H),7.42-7.31(m, 6H),7.29-7.16 (m,10H), 4.56 (d,J=11.5 Hz,1H), 4.52(d,J=11.5Hz,1H), 4.42 (d,J=11.7 Hz, 1H), 4.35(d,J=11.7Hz,1H),3.90(dd,J=7.4,4.8 Hz,1H),3.72-3.66(m,2H), 3.66-3.61(m,1H), 3.63 (s,3H), 3.45 (dd,J=7.4,3.8Hz,1H), 3.39 (dd,J=7.9,3.4Hz,1H), 2.90(qd,J=6.9, 4.7 Hz, 1H), 2.23-2.08(m, 2H), 2.00-1.90 (m, 1H), 1.67-1.46(m,5H), 1.18(d,J=7.1Hz,3H), 1.03 (s,9H), 0.89(d,J=7.0 Hz,3H), 0.87(d,J=6.9 Hz,3H),0.85 (d.J=7.2 Hz,3H),0.66 (d,J=6.4 Hz, 3H) ppm;13c NMR (125 MHz, CDCl3) 6c 175.5, 139.6, 139.1, 135.91, 135.86,134.16,134.12,129.60, 129.58,128.24, 128.19,127.72,127.68, 127.4,127.3,127.13,127.09,84.6,82.8,76.5,73.8,72.7,71.9,66.0,51.6, 42.1,37.8,37.3,36.5,30.4,27.2,27.1,24.9,19.5,18.4,15.4,13.6,12.6,11.4 ppm; MS (ESI) m|z 227.0(2),360.3(7),779.5(16,M+H*),780.5(9),781.5(2),796.5 (3,M+NH4), 801.5 (100, M+H+), 802.5 (59),803.5 (18); HRMS calcd for C49H6706Si [M+H+]: 779.4701, found:779.4704 (0.3 ppm); calcd for C49H7006NSi [M+NH4]: 796.4967,found: 796.4970 (0.3 ppm); calcd for C49H66O6NaSi [M+Na+]:801.4521,found: 801.4528 (0.9 ppm). 4.6.(+)-(2S,3S,4S,5S,6S)-3,5-bis(Benzyloxy)-6-((2S,3S,6S)-6-((R)-1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)-3- methyltetrahydro-2H-pyran-2-yl)-2,4-dimethylheptan-1-ol(16) Primary alcohol 16 (26.2 mg, yield=94%) as a colorless oil wasobtained from ester 15 (29.0 mg, 37 pmol) according to generalprocedure B, and purification by flash chromatography on silica gel(hexanes/EtOAc, 85:15).R0.15 (hexanes/EtOAc, 85:15);[a]+28.2(c1.60, CH2Cl2); C48H6605Si; MW 751.12 g/mol; IR (liquid film) Vmax3447, 3069,3030,2959,2929,2857,1455,1428,1380,1111, 1091,1066,1028 cm-1; 1HNMR (500 MHz, CDCl3) 8q 7.69-7.62 (m,4H),7.44-7.32 (m,6H), 7.31-7.17 (m, 10H), 4.73 (d,J=11.4Hz, 1H), 4.47(d,J=11.4 Hz, 1H), 4.42 (s,J=11.6 Hz, 2H), 3.87 (dt,J=11.1, 3.4 Hz,1H), 3.75-3.68 (m,2H), 3.66 (dd,J=9.5, 3.9 Hz, 1H), 3.62(dd,J=7.1,3.2Hz,1H), 3.54(ddd,J=10.8,7.3,4.7 Hz,1H), 3.46(dd,J=7.6,3.7 Hz,1H), 3.36 (dd,J=8.0, 3.5 Hz, 1H), 2.93 (dd,J=7.3, 3.9 Hz, 1H), 2.25(ddq,J=3.7, 7.0, 6.9 Hz, 1H), 2.12(ddq,J=3.9, 7.0, 6.9 Hz, 1H),2.01-1.90(m, 2H), 1.67-1.50(m, 4H), 1.25-1.16 (m, 1H), 1.07 (d,J=7.1 Hz, 3H), 1.04 (s, 9H), 0.94 (d,J=3.1 Hz, 3H), 0.93 (d,J=2.9 Hz,3H), 0.88 (d,J=6.8 Hz, 3H), 0.68 (d, J=6.5 Hz, 3H) ppm; 13c NMR(125 MHz, CDCl3) oc 139.4, 138.6,135.90,135.86,134.13,134.09,129.66,129.60,128.5,128.3,127.72,127.69,127.6,127.5,127.2,127.0, 86.2,85.0,76.4,74.3,73.8,71.9,66.0,65.8,37.9,37.6,36.6,36.5,30.3,27.2,27.1,24.9,19.5,18.4,16.8,16.0,13.6,11.5 ppm; MS (ESI) m/z338.3(10),360.3(4),643.4(8),751.5(74,M+H+), 752.5(41),753.5(12), 754.5(3),768.5(3,M+NH4), 773.5(100,M+Na+),774.5 (59),775.5(17),776.5(3); HRMS calcd for C48H6705Si[M+H+]: 751.4752,found: 751.4751 (-0.2 ppm); calcd for C48H7005NSi [M+NH4]:768.5018, found: 768.5011(-0.8 ppm); calcd for C48H6605NaSi[M+Nat]: 773.4572, found: 773.4571(-0.1 ppm). 4.7. (2R,3R,4R,5S,6S)-3,5-bis(Benzyloxy)-6-((2S,3S,6S)-6-((R)-1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)-3- methyltetrahydro-2H-pyran-2-yl)-2,4-dimethylheptanal (17) Aldehyde 17 as a colorless oil was obtained from primary alcohol16(12.0 mg, 16 umol) according to general procedure C, and was usedas crude without purification. Re 0.42 (hexanes/EtOAc, 85:15);C48H6405Si; MW 749.10 g/mol; IR (liquid film) Vmax 3069, 3031,2959,2929,2857,1701,1686,1588,1455,1363,1264,1239,1112,1092,1027 cm-1; 1H NMR (500 MHz, CDCl3) on9.79 (d,J=2.3 Hz, 1H),7.68-7.60 (m, 4H), 7.43-7.32 (m,6H), 7.31-7.16(m, 10H), 4.61 (d,J=11.6 Hz,1H), 4.46(d,J=11.6Hz,1H), 4.40 (d,J=11.6Hz,1H), 4.36(d,J=11.6Hz,1H), 3.83 (dd,J=6.4,2.5 Hz, 1H), 3.73-3.67 (m,2H), 3.65(dd,J=9.5, 3.9 Hz,1H), 3.44(dd,J=7.4, 3.8 Hz, 1H), 3.33 (dd,J=7.9,3.6 Hz,1H), 2.79-2.73(m,1H), 2.24-2.19(m,1H),1.98-1.89(m,1H),1.66-1.48(m,5H),1.25-1.19(m,1H),1.11(d,J=7.0Hz,3H),1.04(s,9H),0.90 (d,J=6.8 Hz,3H), 0.89 (d,J=7.1 Hz, 3H), 0.88 (d,J=6.6Hz,3H)0.72(d,J=6.4Hz,3H)ppm;13cNMR(125MHz,CDCl3)6c205.2,139.2,138.7,135.89,135.85, 134.10, 134.06,129.65,129.61,128.38,128.30,127.73,127.68,127.5,127.4,127.3,127.1,84.7,82.4,76.4,74.4,72.6,71.9,65.9,48.9,37.6,37.4,36.7,30.2,27.1,24.9,20.5,19.5,18.4,15.3,13.6,12.4,11.3 ppm; MS(ESI) m|z 195.1(4),264.9(7),286.9(19),338.3(13),533.3(10),641.4(9),749.5(11,M+H+),750.5(6),766.5(4,M+NH4)771.4(100, M+Na+), 772.4(58),773.4(17);HRMS calcd forC48H65OsSi [M+H+]: 749.4596, found: 749.4597(0.2ppm); calcd forC48H6805NSi[M+NH4]:766.4861,found:766.4847(-1.8ppm); calcdfor C48H6405NaSi[M+Nat]:771.4415, found: 771.4418 (0.4 ppm). 4.8. (+)-(S)-2-((4S,5S,6R)-6-((R)-1-((2S,3S,6S)-6-((R)-1-((tert-Bu-tyldiphenylsilyl)oxy)propan-2-yl)-3-methyltetrahydro-2H-pyran-2-yl)ethyl)-2,2,5-trimethyl-1,3-dioxan-4-yl)propyl pivalate (S1) To a cooled (0°C) solution of diol 18 (478 mg, 0.73 mmol) in DMF(0.1 M, 7.3 mL) was added successively 2-methoxypropene (6 equiv,410 pL) and PPTS (0.1 equiv, 17 mg). After stirring for 3 h at rt, re-action mixture was poured in a separatory funnel containing hex-anes and a saturated brine solution. The aqueous layer was extractedwith hexanes (3×) and combined organic fractions were washed(2×) with brine, then dried (MgSO4), filtered and concentrated invacuo. The residue was purified by flash chromatography on silicagel (hexanes/EtOAc,90:10) to give acetonide-protected product S1as a colorless oil (0.49 g,yield=96%).R0.34(hexanes/EtOAc, 90:10);[c]+17 (c 0.14, CDCl3); C42H66O6Si; MW 695.06 g/mol; IR (liquidfilm) Vmax 2962,1728,1155,1111 cm-1HNMR(400MHz,CDCl3)oH7.67-7.63 (m,4H), 7.43-7.32 (m,6H), 4.21(dd,J=11.0, 5.7 Hz, 1H),3.86 (dd,J=11.0, 7.3 Hz,1H), 3.71 (dd,J=9.8, 5.5 Hz, 1H), 3.65 (dd,J=9.8,4.7 Hz,1H), 3.60(td,J=8.2,3.8 Hz,1H), 3.40 (dd,J=7.4, 4.5 Hz,1H), 3.32 (dd,J=10.0, 3.1 Hz, 1H), 3.26 (dd,J=10.2, 2.1 Hz, 1H),2.15-2.05(m,2H), 1.94-1.85 (m,1H), 1.83-1.76(m,1H), 1.72-1.59(m, 2H), 1.55-1.47 (m, 1H), 1.42-1.30 (m, 2H), 1.23 (s, 3H), 1.20 (s,3H), 1.19 (s, 9H), 1.05(s,9H), 0.98 (d,J=7.0 Hz, 3H),0.97(d,J=6.8 Hz,3H), 0.95 (d,J=7.1 Hz,3H), 0.88 (d,J=6.9 Hz, 3H), 0.77 (d,J=6.5 Hz,3H)ppm;13cNMR(100MHz, CDCl3)oc 178.8,135.88,135.86,134.26,134.24, 129.6,129.5,127.66,127.65,97.7,77.9,77.5,77.3,70.9,65.8,65.6,38.9,38.5,36.8,34.1,33.3,30.1,29.8,27.4,27.1,26.2,23.5,19.5,19.4,18.6,15.9,13.9,13.3,13.1 ppm; MS (ESI) m/z 395.2(85),637.4(30),695.5(100,M+H*); HRMS calcd for C42H6606NaSi [M+Na+]: 717.4526, found: 717.4518(1.2ppm); Analysis calcd for C42H6606Si:C, 72.58; H, 9.57; found: C, 72.31; H, 9.70. 4.9. (+)-(S)-2-((4S,5S,6R)-6-((R)-1-((2S,3S,6S)-6-((R)-1-((tert-Bu-tyldiphenylsilyl)oxy)propan-2-yl)-3-methyltetrahydro-2H-py-ran-2-yl)ethyl)-2,2,5-trimethyl-1,3-dioxan-4-yl)propan-1-o1(S2) Primary alcohol S2 (413 mg,yield=98%) as a colorless oil wasobtained from ester S1 (0.48 g, 0.69 mmol) according to generalprocedure B, and purification by flash chromatography on silica gel(hexanes/EtOAc, 85:15). Rr 0.22 (hexanes/EtOAc, 80:20); []+18(c 0.65, CDCl3); C37H5805Si; MW 610.94 g/mol; IR (liquid film) Vmax3457,2859,1461,1428,1379,1254 cm-1;1H NMR(400MHz, CDCI3)8H 7.68-7.63 (m,4H), 7.44-7.31(m,6H), 3.94 (dd,J=4.0, 11.0 Hz,1H), 3.69 (dd,J=6.3,11.0 Hz, 1H), 3.66-3.57 (m,2H), 3.51-3.43 (m,1H), 3.43-3.31(m,3H), 2.88 (br s,1H), 2.14-2.03 (m,1H),1.97-1.87(m, 1H), 1.87-1.74 (m, 2H), 1.75-1.60 (m, 2H), 1.60-1.48 (m, 1H),1.45-1.29(m,2H), 1.25(s, 3H), 1.20 (s, 3H), 1.11 (d,J==7.0 Hz, 3H),1.05(s,9H), 0.98 (d,J=7.0 Hz, 3H), 0.97 (d,J=6.8 Hz, 3H), 0.88 (d,J=6.9 Hz, 3H), 0.73 (d,J=6.5 Hz, 3H) ppm; 13c NMR (100 MHz,CDCl3)oc 135.9 (2C),134.23,134.19,129.62,129.55,127.7(2C),98.1,80.2,77.8,77.4,71.1,65.8,63.9,38.1,36.8,34.3,34.2,30.3,30.0,27.1,26.3,23.6,19.5,19.0, 18.6,15.6,14.1,13.3,13.2 ppm; MS (ESI) m/z553.4(25),611.4(40,M+H+), 633.3(100,M+Na+); HRMS calcd for(C37H59O5Sii[M+H+]: 611.4132, found: 611.4130 (0.2 ppm). 4.10. (+)-(R)-2-((4R,5R,6R)-6-((R)-1-((2S,3S,6S)-6-((R)-1-((tert-Butyldiphenylsilyl)oxy)propan-2-yl)-3-methyltetrahydro-2H-pyran-2-yl)ethyl)-2,2,5-trimethyl-1,3-dioxan-4-yl)propanal (19) To a cooled(-78°C)solution of oxalyl chloride (1.2 equiv, 67 pL)in dryCH2Cl2 (3.5 mL) was added dropwise anhydrous DMSO(2.4 equiv, 110 pL). After stirring for 5 min at -78 °C, a solution ofprimary alcohol S2 (0.41 g, 0.67 mmol) in dry CH2Cl2(0.2 M, 3.5 mL)was cannulated into the reaction flask, and the mixture wasallowed to stir for an additional 30 min at -78°C before addition ofdry EtsN (5 equiv, 0.47 mL). Mixture was stirred 1 h at -78 °C,before addition of a saturated aqueous solution of NH4Cl. Theaqueous layer was extracted with Et20 (3x) and combined organicfractions were washed(2×) with brine, then dried (MgSO4),filteredand concentrated in vacuo. The residue was purified by flashchromatography on silica gel (hexanes/EtOAc, 90:10) to give alde-hyde 19 as a colorless oil (0.36 g, yield=88%). R 0.21 (hexanes/EtOAc, 90:10);[c] +13 (c 0.35, CDCl3); C37H5605Si;:MW608.92 g/mol; IR (liquid film) Vmax 2858,1725,1379,1202 cm-1;1HNMR (400 MHz, CDCl3) oH 9.73 (d,J=2.6 Hz,1H), 7.68-7.63 (m,4H),7.44-7.33 (m, 6H), 3.71 (dd,J=9.7, 5.4 Hz, 1H), 3.64 (dd,J=9.7,4.5 Hz,1H), 3.62 (td,J=8.2, 4.2 Hz,1H), 3.50 (dd,J=10.4, 2.0 Hz,1H),3.39-3.33 (m,2H),2.50 (ddq,J=2.3, 2.3, 6.8 Hz, 1H), 2.10-2.00(m,1H), 1.97-1.87 (m, 1H), 1.81-1.72 (m, 1H),1.72-1.60(m, 2H),1.59-1.48(m,1H),1.46-1.37(m,1H),1.38-1.27(m,1H),1.23 (s,3H),1.21 (s,3H), 1.16(d,J=7.0 Hz,3H), 1.05(s, 9H), 0.95 (d,J=6.7 Hz, 3H),0.95 (d,J=7.1 Hz, 3H), 0.89 (d,J=6.9 Hz, 3H), 0.77 (d,J=6.5 Hz,3H)ppm;13cNMR(100 MHz, CDCl3)oc 205.2,135.9 (2C),134.24,134.21,129.6, 129.5,127.7 (2C), 98.0,77.7,77.2,76.9,71.2,65.8,47.5,37.9,36.8,34.3, 30.1,30.0,27.1,26.4,23.7,19.5, 19.0, 18.6,13.9,13.3,13.1,11.9 ppm; MS (ESI) m|z277.2(100),395.3(50),533.4(50),609.5(70,M+H+); HRMS calcd for C37H5605NaSi [M+Na+]: 631.3795, found:631.3781(2.2ppm); Analysis calcd for C37H56O5Si: C, 72.98; H, 9.27;found: C, 72.95; H, 9.51. ( 4.11. (+)-(2S,3R)-2-((4S,5S,6R)-6-((R)-1-((2S,3S,6S)-6-((R)-1- ((tert-Butyldiphenylsilyl)oxy)propan-2-yl)-3-methyltetrahydro- 2H-pyran-2-yl)ethyl)-2,2,5-trimethyl-1,3-dioxan-4-yl)hex-5-en- 3-0l(20a);(+)-(2S,3S)-2-((4S,5S,6R)-6-((R)-1-((2S,3S,6S)-6-((R)-1- ) ((tert-Butyldiphenylsilyl)oxy)propan-2-yl)-3-methyltetrahydro-2H-pyran-2-yl)ethyl)-2,2,5-trimethyl-1,3-dioxan-4-yl)hex-5-en-3-ol (20b) Homoallylic alcohols 20a and 20b were obtained from aldehyde19 (0.25 g, 0.41 mmol) according to general procedure D usingallyltributylstannane as the nucleophile. H NMR analysis of thecrude product indicated a ratio 1:1 of product 12,13-syn(20a): 12,13-anti (20b). The residue was purified by flash chromatography onsilica gel (hexanes/EtOAc, 85:15)to give products 20a (70 mg,yield=26%) and 20b (73 mg,yield=27%) as colorless oils. 20a; R0.20(hexanes/EtOAc,90:10);[α]+38 (c0.15, CDCl3); C40H62O5Si; Mw651.00 g/mol; IR (liquid film) Vmax 3484,2960,2859,1460,1428 cm-1; 1H NMR (500 MHz, CDCl) 6H 7.68-7.63 (m, 4H),7.43-7.33(m, 6H), 5.89 (dddd, J=16.8, 10.3,7.7, 6.1 Hz, 1H),5.14-5.07 (m,2H), 3.72 (dd,J=9.7, 5.3 Hz,1H), 3.75-3.59(m, 2H),3.63 (dd,J=9.8, 4.5 Hz, 1H), 3.39 (dd,J=6.8, 5.0 Hz, 1H), 3.35-3.30(m, 2H), 2.91 (br s, 1H), 2.47-2.39 (m, 1H), 2.21-2.10 (m, 1H),2.10-2.00 (m, 1H), 1.96-1.88 (m, 1H), 1.88-1.73 (m,3H), 1.71-1.60(m, 1H), 1.55-1.47 (m, 1H), 1.46-1.28 (m, 2H), 1.25 (s, 3H), 1.20 (s,3H), 1.05(s,9H),0.97 (d,J=7.1Hz,3H),0.95 (d,J=6.9Hz, 3H), 0.94(d,J=7.1 Hz,3H), 0.89(d,J=6.9 Hz, 3H), 0.77 (d,J=6.4Hz, 3H) ppm; 13cNMR(125MHz,CDCl3)8c 136.2, 135.87,135.85,134.25,134.22,129.6,129.5,127.67,127.66,117.1,97.9,79.8,77.6,77.4,73.4,71.1,65.7,39.9,39.0,38.1,36.8,35.4,30.3,30.0,27.1,26.4,23.7,19.5,19.1,18.6,16.8,14.0,13.7,13.3 ppm; MS (ESI) m/z 343.1 (60),381.2(52),637.2(65)651.3 (60, M+H+), 673.3(100, M+Na*); HRMS calcdforC40H6205NaSi [M+Na*]:673.4264, found: 673.4274 (1.4ppm). 20b;Re 0.33 (hexanes/EtOAc, 90:10); [a]6 +24 (C 0.20, CDCl);C40H62O5Si; MW 651.00 g/mol; IR (liquid film) max 3520, 30712859,1461,1428,1379cm-1;1HNMR(500MHz, CDCl:)oH 7.68-7.64(m,4H), 7.43-7.34 (m,6H), 5.80 (dddd,J=16.8, 10.2, 7.7, 6.4Hz,1H),5.14-5.05(m,2H), 4.02 (dd,J=7.5,6.9Hz,1H),3.71(dd,J=9.7,5.4Hz,1H), 3.64(dd,J=9.9, 4.7 Hz,1H),3.66-3.58(m,2H),3.40(dd,J=10.4,1.6 Hz, 1H), 3.38-3.34 (m,2H), 2.39-2.30 (m, 1H), 2.12-2.04(m,2H), 1.96-1.87 (m, 1H), 1.83-1.71 (m, 2H), 1.71-1.63 (m, 1H),1.59-1.50 (m,2H), 1.45-1.38(m,1H), 1.38-1.30(m,1H), 1.25 (s,3H),1.20 (s,3H), 1.05 (d,J=2.8 Hz, 9H), 1.00 (d,J=7.1 Hz, 3H), 0.97 (d,I-69J=6.8 Hz, 3H), 0.96(d,J=7.1 Hz, 3H), 0.90 (d,J=6.9 Hz, 3H), 0.70(d,j=6.5 Hz, 3H) ppm; 13c NMR (125 MHz, CDCl3) òc 135.87, 135.86,135.6,134.3, 134.2,129.62,129.55,127.68,127.67,117.0,98.3,81.1,77.9,77.2,71.1,69.7,65.8,39.3,38.2,37.0,35.0,33.6,30.2,30.1,27.1,26.3,23.6,19.5,19.0,18.7,14.1,13.3,12.9,11.0 ppm; MS(ESI) m|z381.2(65),637.2(100),651.3(20,M+H+),673.3(80,M+Na*); HRMS calcdfor C40H620sNaSi [M+Na+]: 673.4264, found: 673.4260 (0.6 ppm). 4.12. (5S,6S,7S,8S,9S)-6,8-bis(Benzyloxy)-9-((2S,3S,6S)-6-((R)-1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)-3-methyltetrahydro-2H-pyran-2-yl)-5,7-dimethyldec-1-en-4-o1(21a;21b) Homoallylic alcohols 21a and 21b were obtained from aldehyde17 (12 mg, 16 pmol) according to general procedure D using allyl-tributylstannane as the nucleophile. HNMR analysis of the crudeproduct indicated a ratio 1.3:1 of alcohols 21a and 21b. The twodiastereoisomers were separated by flash chromatography on silicagel (hexanes/EtOAc,90:10) to yield 21a (6.3 mg, yield=50% over 2steps) and 21b (5.6 mg, yield=44% over 2 steps) as colorless oils.21a;R0.35(hexanes/EtOAc,90:10); C51H7005Si; MW 791.18 g/mol;IR (liquid film) Vmax 3503,3069,2962,2929,2857,1456,1428,1380,1112, 1092, 1065, 1028 cm-; H NMR (500 MHz, CDCl3) 0H7.69-7.61(m,4H), 7.42-7.31(m,6H), 7.28-7.17(m, 10H), 5.76(ddt,J=17.2, 10.2, 7.3 Hz, 1H), 5.05 (dd,J=24.8, 13.7 Hz, 2H), 4.80 (d,J=11.3 Hz, 1H), 4.48 (d,J=11.3 Hz,1H), 4.42 (d,J=11.7 Hz, 1H), 4.38(d,J=11.7 Hz, 1H), 4.10 (app t,J=7.0 Hz, 1H), 3.80 (s, 1H), 3.74-3.69(m, 2H), 3.67-3.62 (m, 2H), 3.45 (dd,J=8.6, 2.4 Hz, 1H), 3.37 (dd,J=9.0, 2.1 Hz,1H), 2.35-2.25(m,2H), 2.09-2.00(m,2H), 2.00-1.92 (m,1H),1.88-1.80(m,1H),1.61-1.54(m,4H),1.22-1.12(m,1H),1.03(d, J=6.9 Hz, 3H), 1.03 (s, 9H), 0.92 (d,J=7.0 Hz, 3H), 0.87 (d,J=7.0 Hz,2x3H), 0.59 (d,J=6.4 Hz,3H) ppm;13c NMR (125 MHz,CDCl3) oc 139.5,138.4,135.92,135.86,135.7,134.14, 134.10, 129.66,129.59, 128.56,128.3,127.73,127.70,127.6,127.23,127.22,127.0,116.8,87.3,85.6,76.0,74.6,74.5,72.3,70.6,66.0,39.4,38.7, 37.0,36.9,35.9, 30.7,27.5,27.1,25.4,19.5,18.3,17.1,13.8,12.1,11.3 ppm;MS (ESI) m/z 227.0(6),360.3(5), 791.5 (25, M+H+), 792.5 (25),793.5(5),808.5(3,M+NH4), 813.5(100,M+Na+),814.5(60),815.5(17); HRMS calcd for C51H7105Si [M+H+]:791.5065, found:791.5058 (-0.9 ppm); calcd for C51H7405NSi [M+NH4]: 808.5331,found: 808.5320 (-1.4 ppm); calcd for C51H7005NaSi [M+Na+]:813.4885, found: 813.4900(1.9ppm). 21b; Rf0.24 (hexanes/EtOAc,90:10); C51H70O5Si; MW 791.18 g/mol; IR (liquid film) Vmax 3462,3070,2959,2929,2857,1496,1455,1428,1382,1111,1091,1065,1028 cm-1; 1H NMR (500 MHz, CDCl3) H 7.67-7.61 (m,4H),7.42-7.31(m,6H), 7.26-7.18 (m, 10H), 5.92-5.83(m,1H), 5.07 (dd,J=13.0, 9.3 Hz, 2H), 4.66 (d,J=11.4 Hz, 1H), 4.51 (d,J=11.5 Hz, 1H),4.41-4.40 (m,2H), 3.74-3.62(m, 4H), 3.59 (dd,J=6.5, 4.6 Hz, 1H),3.46 (dd,J=7.1, 4.2 Hz, 1H), 3.35 (dd,J=7.7, 3.9 Hz, 1H), 3.14 (d,J=2.6 Hz, 1H), 2.41-2.35(m,1H),2.25-2.20(m,1H), 2.19-2.14(m,1H), 2.12-2.04 (m, 1H), 1.99-1.90(m, 2H)1.67-1.55(m, 4H),1.24-1.14(m, 1H), 1.03 (s, 9H), 0.96 (d,J=7.2 Hz, 3H), 0.91 (d,J=7.0Hz, 3H), 0.88(d,J=7.4 Hz, 3H), 0.87 (d,J=7.6 Hz, 3H),0.68 (d,T=60.5 Hz,3H)ppm;13cNMR(125MHz,CDC3)6c 139.5,138.7,136.0,135.90, 135.87, 134.15,134.10,129.65,129.61, 128.4,128.2, 127.72,127.69,127.61,127.56,127.18,127.13,117.0,85.6,84.8,76.5,74.0, 73.5,73.2,71.8,66.0,40.7,39.0,38.8,37.6,36.8,30.2,27.1,27.0,24.8,19.5,18.4,115.9,15.8,13.6,11.55 ppm; MS (ESI) m/z 227.0 (5),360.3 (7),791.5(16,M+H+), 792.5(10),793.5(3),808.5(3,M+NH4), 813.5(100,M+Na*), 814.5(59),815.5(18),816.5(3); HRMS calcd forC51H710sSi [M-H]: 791.5065, found: 791.5061 (-0.5 ppm); calcdfor calcd forC51H7405NSi [M+NH4]: 808.5331, found: 808.5325(-0.7 ppm); calcd for C51H7005NaSi [M+Na+]: 813.4885, found:813.4903(2.2 ppm0). 4.13. (±)-(4R,5S,6R,7R)-6,8-bis(Benzyloxy)-5,7-dimethyloct-1-en-4-ol (28a) ( Homoallylic alcoho l 28 a was obtained from aldehyde 24 ( 19. 5 mg, 60 u mol) according t o g e neral p r ocedure D u sing allyl-tributylstannane as the nucleophile. ' H N M R ana l ysis of the cru d e product i ndicated a ratio >20:1 of products 4 ,5-syn (28a): 4,5-anti (28b). The residue was purified by flash chromatography on silica gel (hexanes/EtOAc, 8 5:15) t o y ield 28a a s a colorless oil (18.9 mg, yield=86%). 2 2 Rg 0.32 (hexanes/EtOAc, 85:15) ; C24H3203 ; MW 368.51 g/mol; IR(liquid film)Vmax 3499,2970,2908,2876,1496,1454, 1354, 1 088 cm-1 ; 1 H NMR (500 MHz,CDCl3) 8H 7.30-7.14 (m,10 H ), 5.70(dddd,J=6. 8 ,7.5, 10.2,17 . 1 H z ,1H ) , 5.05-4.94 (m, 2H), 4.53 (d, J =10.8 Hz, 1H), 4.48 (d,J=10.8 H z , 1H), 4.42 (s, 2H), 3.97 (app t , J =7.0Hz,1H), 3.56(dd,J=8.9,5.0 Hz,1H), 3.45 (td,J=8.6,3.2 H z,2H),3.41 (s,1H), 2.31-2.20(m,1H), 2.12-1.99 (m,2H), 1.77-1.69(m,1H), 1.01 (d,J=7.1 Hz, 3H), 0.93 (d,J=7.0Hz,3H)pp m ;13cNMR(125MHz, CDClz)oc 138.6,138.2,135.5,128.6,128.5,127.9,127.82,127.77,127.69,117.0, 87.1,76.0,73.3,72.4,69.9,39.3,37.0, 36.9,15.2, 11.5 ppm; MS (ESI) m/z 369. 2 (35, M+H+ ) , 391.2(100,M+Na*), 481.3(19); HRMS calcd for C24H3303[M+H+]: 3 6 9.2424, f o und: 3 6 9.2429 (1.2 ppm); calcd for C24H3203Na[M +N a+]:391.2244,found:391.2249(1.2ppm). ) ( 4.14. (±)-(3S,4S,5R,6R)-Methyl 5,7-bis(benzyloxy)-3-hydroxy- 2,2,4,6-tetramethylheptanoate (30a) ) ( β-Hydroxyester 30a was obtained f rom aldehyde 24 (154 mg, 0.47 mmol) according to general p rocedure D using 1 - methoxy-2-methyl-1-(trimethylsiloxy)propene 26 as the nucleophile. H NMR analysis of the crude product indicated a ratio > 20:1of product 3,4- ) syn (30a): 3,4-anti (30b). The residue was purified by flash chroma-tography on silica gel (hexanes/EtOAc, 90:10) to yield unreacted al-dehyde 24 (70.2 mg,yield=45%) and 3,4-syn product 30a (86.1 mg,yield=43%, 78% brsm) as colorless oils. Rf 0.22 (hexanes/EtOAc,90:10); C26H3605; MW 428.56g/mol; IR (liquid film) Vmax 3495, 3029,2973, 2932,2877,1731,1454, 1257,1141, 1073 cm-1; 1H NMR(500 MHz, CDCl3) oH 7.44-7.20 (m,10H), 4.61 (d,J=11.2 Hz,1H), 4.58(d,J=11.1 Hz, 1H), 4.53(d,J=12.3Hz,1H),4.50(d,J=12.3Hz,1H), 4.03(d,J=3.2 Hz, 1H), 3.68 (s, 3H), 3.63 (dd,J=8.8, 5.4 Hz, 1H), 3.56 (dd,J=8.9, 3.5 Hz,1H), 3.40 (dd,J=8.2, 3.3 Hz, 1H), 3.20(d,J=3.3 Hz,1H),2.16-2.07(m,1H),1.97-1.90(m,1H),1.22(s,3H),1.21(s,3H),1.040(d,J=6.6Hz, 3H),1.038 (d,J=7.0Hz,3H)ppm;13cNMR(100MHz, CDCl;)oc 178.0,138.6,138.4,128.6,128.5,127.91,127.89,127.74,127.66,88.1,76.1, 74.7,73.3,72.2,52.0,46.9,36.6,35.3,22.9,22.8,15.5, 13.3 ppm;MS (ESI) m|z 213.1(4),321.2(4),411.3(17),429.3(86,M+H), 451.2(100, M+Na*), 519.3 (14), 541.3(22),879.5 (17); HRMS calcd forC26H3705[M+H+]:429.2636, found: 429.2629(-1.6ppm); calcd forC26H3605Na [M+Na+]: 451.2455, found: 451.2448(-1.6 ppm). 4.15. (±)-(3S,4S,5R,6R)-Methyl 5,7-bis(benzyloxy)-3-hydroxy-4,6-dimethyl-2-(phenylselanyl)heptanoate (31a-1; 31a-2) 0.30 mmol) according to general procedure F, and purification byflash chromatography on silica gel (hexanes/EtOAc, 80:20). R0.22(hexanes/EtOAc, 80:20); C24H3205; MW 400.51 g/mol; IR (liquidfilm) Vmax 3494, 3030, 2965,2913,2879,1737,1454,1355,1173,1089 cm-1, 1H NMR (500 MHz, CDCl3) oH 7.38-7.23 (m, 10H), 4.60(d,J=10.9 Hz,1H),4.58 (d,J=10.9 Hz, 1H), 4.51(s, 2H), 3.69 (s,3H),3.65(dd,J=8.9,5.0 Hz, 1H), 3.68-3.59(m,1H),3.62(s,1H), 3.55(dd,J=8.5, 3.4 Hz, 1H), 3.53(dd,J=9.0, 3.7 Hz, 1H), 2.59 (dd,J=15.4,8.3 Hz, 1H), 2.35 (dd,J=15.3, 5.4 Hz, 1H), 2.25-2.15 (m, 1H),1.86-1.79(m,1H), 1.09 (d,J=7.1Hz,3H), 1.06 (d,J=7.0Hz, 3H) ppm;13cNMR(125MHz, CDCl3)c 172.6, 138.6,138.1,128.6,128.5,128.0,127.9,127.8,127.7,86.6,76.0,73.3,72.3,67.3,51.8,39.7,37.5,36.8,15.3, 11.7 ppm; MS (ESI) m/z 401.2(7,M+H+), 423.2(100,M+Na+),513.3 (17),603.3(3),823.4(13); HRMS calcd for C24H3305[M+H+]:401.2323, found: 401.2317 (-1.4 ppm); calcd for C24H3205Na[M+Na+]: 423.2142, found: 423.2134(-1.9ppm). 4.17. (±)-(4R,5S,6S,7S)-6,8-bis(Benzyloxy)-5,7-dimethyloct-1-en-4-ol (32a); (±)-(4S,5S,6S,7S)-6,8-bis(Benzyloxy)-5,7-dimethyloct-1-en-4-ol (32b) β-Hydroxyesters 31a-1 and 31a-2 were obtained from aldehyde24 (50.2 mg,0.15 mmol) according to general procedure D usingenoxysilane 27 as the nucleophile. H NMR analysis of the crudeproduct indicated a ratio >20:1 of products 3,4-syn (31a): 3,4-anti(31b) and a mixture ~3:1 of C2-phenylselenides 31a-1 and 31a-2The two diastereoisomers were separated by flash chromatographyon silica gel(hexanes/EtOAc, 80:20)to yield products 31a-1 and 31a-2 (76.6 mg, combined yield=92%) as pale yellow oils. The relativestereochemistry of compounds 31a-1 and 31a-2 was not de-termined. 31a-1; Rf 0.21 (hexanes/EtOAc, 85:15); C30H3605Se; MW555.56 g/mol; IR (liquid film) Vmax 3467,3060,3029,2968,2877,1728,1454,1436,1258,1087 cm-1;1H NMR (500 MHz, CDCl3)6H7.66-7.61(m,2H), 7.38-7.18(m,13H),4.58 (d,J=10.8 Hz,1H), 4.55(d,J=10.8 Hz, 1H), 4.49 (s, 2H), 4.33 (d,J=10.6 Hz, 1H), 3.98 (s,1H),3.93 (d,J=10.5 Hz,1H), 3.66(dd,j-8.9, 4.5 Hz,1H), 3.54(dd,J=9.0,2.5 Hz, 1H), 3.47 (dd,J=9.0, 3.5 Hz, 1H), 3.45 (s, 3H), 2.15-2.06 (m,1H), 1.90-1.80(m, 1H), 1.11 (d,J=7.1 Hz,3H), 0.98 (d,J=7.0 Hz,3H)ppm;13c NMR(125MHz, CDCs) 6c 171.3,138.6,137.9,136.5,129.0,128.8, 128.6,128.5,128.0,127.9,127.8,127.7,127.5,86.8,77.4, 76.1,73.3,69.8,51.8,48.9,37.0,36.2,14.7,11.7ppm;MS(ESI)mjz195.1(8)338.3(8),449.1(9),539.2(9),557.2(19,M+H*),579,2(100,M+Na),595.1(5),669.2 (16); HRMS calcd for C30H3705Se[M+H*]:557.1801found: 557.1800(-0.2 ppm); calcd for C30H3605SeNa [M+Na*]:579.1620, found: 579.1630 (1.7ppm).31a-2;Rr0.20(hexanes/EtOAc,85:15); C30H360sSe; MW 555.56 g/mol; IR (liquid film) Vmax 3457,3065,3021,2963,2882, 1732, 1454,1436,1270 cm-1; 1H NMR(500 MHz,CDCl3) oH 7.61-7.56(m,2H),7.36-7.18(m, 13H), 4.55(d,J=11.4Hz,1H), 4.53(d,J=11.5 Hz,1H),4.51(s,2H),4.43(d,J=10.7 Hz,1H), 3.88 (s, 1H), 3.71-3.66 (m, 2H), 3.64 (s, 3H), 3.57 (dd,J=9.0,2.8 Hz,1H), 3.52(dd,J=8.9,3.4Hz,1H), 2.43-2.34(m,1H),2.22-2.12(m, 1H), 1.10(d,J=7.0 Hz,3H), 0.90 (d.J=7.1 Hz,3H) ppm; 13c NMR(125 MHz, CDCl3) 8c 172.8,138.6,134.0,135.3, 129.4, 128.7, 128.6,128.5,128.02,127,98,127.90,127.81,127.74,86.9,76.2,73.3,72.3,71.4,52.4,47.9,36.9,34.5,15.2,11.5 ppm; MS(ESI)m|z182.2(17),227.0(6),337.1 (27),365.1(30),391.2(35),421.2(17),457.3(11),539.2(9),579.2(100,M+Nat),595.2(9),656.3(16),669.2(12); HRMS calcd forC30H3705Se [M+H*]; 557.1801, found: 557.1806(0.9 ppm);calcd forC30H3605SeNa [M+Na*]: 579.1620, found: 579.1634 (2.4ppm). ( 4.16. (±)-(3R,4S,5R,6R)-Methyl 5,7-bis(benzyloxy)-3-hydroxy- 4,6-dimethylheptanoate (36) ) ( Product 3 6 (72.4 mg,yield=60%) as a colorless oil was obtained from a a mixture of p henylselenid e 31a-1 ; 31a-2 ( (168 3I mg, ) Homoallylic alcohols 32a and 32b were obtained from aldehyde259d(62.7 mg, 0.19 mmol) according to general procedure D usingallyltributylstannane as the nucleophile. H NMR analysis of thecrudeproduct indicated a ratio 1:4.9 of products 4,5-syn (32a): 4,5-anti(32b). The residue was purified by flash chromatography onsilica gel (hexanes/EtOAc, 85:15) to yield 32aand 32b (52.3 mg,combined yield=74%)as colorless oils. 32a; Rr0.29(hexanes/EtOAc,85:15);C24H3203; MW 368.51 g/mol; IR (liquid film) Vmax 3447,3030, 2971,2914,1640,1454,1361,1207 cm-1;1HNMR (500 MHz,CDCl3) oH 7.36-7.25 (m, 10H), 5.84 (dddd,J=6.3, 8.2, 9.3, 20.0 Hz,1H),5.18-5.13(m,2H),4.66(d,J=11.5 Hz,1H),4.55(d,J=11.5Hz,1H),4.50(d,J=12.0Hz,1H), 4.48(d,J=12.1Hz,1H), 3.82(dd,J=9.0,1.9 Hz,1H), 3.62-3.55(m,1H), 3.57 (dd,J=8.8, 3.7 Hz,1H), 3.53 (dd,J=8.8,5.9Hz,1H), 2.49-2.42(m,1H), 2.18-2.10(m,2H), 2.10-2.02(m,1H),1.77-1.69(m,1H),0.99(d,J=6.9Hz,3H), 0.93 (d,J=7.0Hz,3H)ppm;CNMR(125 MHz,CDCl3)oc 139.3,138.9,135.1,128.5,128.4,127.8,127.7,127.6,127.5,118.5,80.3,74.0,73.3,73.0,72.4,40.07,40.05,37.0,15.1,10.6 ppm; MS (ESI) m|z 391.2 (100,M+Na*), 481.3(4); HRMScalcd for C24H3203Na [M+Na*]: 391.2244, found: 391.2242(--0.5 ppm). 32b; Rf 0.23 (hexanes/EtOAc, 85:15); C24H3203; MW368.51 g/mol; IR (liquid film) Vmax 3447, 3030,2969,2922,1496,1455,1361,1207 cm-1;1HNMR(500 MHz, CDCl3)8H 7.37-7.25 (m,10H), 5.79(tdd,J=7.0.10.0, 17.1 Hz, 1H), 5.13-5.04 (m, 2H),4.62 (d,J=11.1Hz,1H), 4.56(d,J=11.0Hz,1H),4.52(d,J=12.0Hz,1H), 4.49(d,J=12.0 Hz,1H), 3.88-3.83 (m,1H), 3.63 (dd,J=7.9, 3.3 Hz, 1H), 3.60(dd,J=9.1, 5.2 Hz,1H), 3.51(dd,J=9.0, 4.3 Hz,1H), 2.88(d,J=1.7 Hz,1H), 2.33-2.23(m,1H), 2.23-2.09(m,2H),1.79 (dd,J=6.6,3.5 Hz,1H), 1.02 (d,J=7.0 Hz, 3H), 0.96 (d, J=7.1 Hz, 3H) ppm; 13c NMR(125 MHz, CDCl3) oc 138.6,138.4,135.6,128.6,128.5,127.83 (2C),127.82,127.7,117.4,85.2,74.7, 74.1,73.4,72.4,39.8, 38.4,36.8,15.0,7.0 ppm; MS (ESI) m/z 391.2 (100,M+Na+), 481.3(13); HRMS calcdfor C24H3203Na[M+Na*]: 391.2244, found: 391.2242(-0.5 ppm). 4.18. (±)-(3S,4S,5S,6S)-Methyl 5,7-bis(benzyloxy)-3-hydroxy-2,2,4,6-tetramethylheptanoate (34a) ( -Hydroxyester 34a was obtained from aldehyde 25 (198 m g, 0.61 mmol) according to general p rocedure D using 1-methoxy-2- methyl-1-(trimethylsiloxy)propene 26 as the nucleophile. lH N MR analysis ofthe crude product indicated a ratio >20:1 of product 3,4- syn (34a):3,4-anti (34b). The residue was purified b y flash c h ro-matography on silica gel (hexanes/EtOAc, 90:10) to yield unreacted aldehyde25(99.8 mg,yield=51%) and 3,4-synproduct 34a(78.5 mg, yield=30% over 2 steps, 61% brsm) as colorless oils. R0.10 (hexanes/ EtOAc, 9 0:10); C 26H3605; M W 428 . 56 g/mol; IR ( l iq u id fil m ) Vmax ) 400-188-0725 as the nucleophile. HNMR analysis of the crude product indicateda ratio >20:1 of product 3,4-syn (S3): 3,4-anti. The residue was pu-rified by flash chromatography on silica gel (hexanes/EtOAc, 90:10)toyield product S3 as a pale yellow oil (137 mg, yield=68%). R 0.19(hexanes/EtOAc,90:10); C28H3805Se; MW 533.56 g/mol; IR (liquidfilm)vmax 3440,2950,2929,2858,1729,1455,1437,1089,1018 cm;H NMR (500 MHz, CDCl3) 8H 7.70-7.66(m,2H), 7.41-7.24(m,8H),4.58(d,J=11.9 Hz,1H), 4.53 (d,J=11.9 Hz,1H), 4.14(dd,J=9.6,1.9 Hz,1H), 4.11(s,1H),3.97(d,J=9.5Hz,1H),3.71(dt,J=10.2,3.8Hz,1H),3.55(dd,J=9.1,3.2Hz,1H),3.49(s,3H),3.44(dd,J=9.1,6.3Hz,1H),3.40(dd,J=9.4,2.8Hz,1H), 2.31-2.21(m,1H),1.86-1.77(m,1H),1.71-1.65(m,2H), 1.64-1.52(m,2H), 1.29-1.18(m,1H), 0.95(d,J=7.1 Hz, 3H),0.93(d, J=6.8 Hz,3H), 0.77 (d,J=6.5 Hz, 3H) ppm; 1’c NMR (125 MHz,CDCl3) oc 171.9,138.9,136.4,129.0,128.7,128.5,127.84,127.81,127.5,80.9, 74.8,74.4,73.4,72.6,51.9,48.7, 36.1,32.2,31.6,26.9,25.7,17.7,14.9,5.6 ppm; MS (ESI) m/z 247.2(5),517.2(11),535.2(27,M+H*557.2 (100, M+Na+), 1091.4 (41, 2M+Na+); HRMS calcd forC28H3905Se[M+H+]: 535.1957, found: 535.1953(-0.9ppm); calcd forC28H3805SeNa [M+Na+]: 557.1777, found: 557.1774(-0.4ppm). 4.19. (±)-(3S,4S,5S,6S)-Methyl 5,7-bis(benzyloxy)-3-hydroxy-4,6-dimethyl-2-(phenylselanyl)heptanoate (35a) Product 37 (129 mg,yield=54%) as accolorless oil was obtainedfrom phenylselenide 35a (333 mg, 0.60 mmol) according to generalprocedure F, and purification by flash chromatography on silica gel(hexanes/EtOAc,80:20). R0.18 (hexanes/EtOAc,80:20); C24H3205;MW 400.51 g/mol; IR (liquid film) Vmax 3512, 3063,3030,2965,2916,28,79,1736,1454,1172,1091 cm-1;1HNMR(500 MHz, CDCl3)oH 7.41-7.25(m,10H), 4.62 (d,J=11.1 Hz,1H), 4.57(d,J=11.2Hz,1H),4.53 (d,J=12.2 Hz, 1H), 4.50 (d,J=12.4 Hz, 1H), 4.24 (dt,J=8.6,3.8 Hz,1H), 3.70 (s, 3H), 3.65 (dd,J-7.3, 3.6Hz,1H),3.58(dd,J=9.0,5.2 Hz, 1H), 3.54 (dd,J=9.1, 4.6 Hz, 1H), 3.25 (br s, 1H), 2.54 (dd,J=15.7,8.8 Hz, 1H), 2.43 (dd,J=15.7,4.2 Hz,1H), 2.22-2.12(m,1H),1.85-1.77 (m,1H),1.03(d,J=7.0Hz,3H), 1.00 (d,J=7.0 Hz, 3H) ppm;1c NMR (125 MHz, CDCl3) oc 173.1, 138.5,138.4,128.53, 128.47,127.75(2C),127.74,127.7,84.0,74.0,73.3,72.3,71.3,51.8,39.7,39.2,36.7, 15.0, 7.9 ppm; MS (ESI) m|z 401.2 (16, M+H+), 423.2 (100,M+Na+),513.3(8),823.4(30),913.5(3); HRMS calcd for C24H3305[M+H+]:401.2323,found:401.2329(1.66ppm); calcdforC24H3205Na [M+Na*]: 423.2142,found: 423.2144(0.4ppm). 4.21. (±)-(3S,4S)-Methyl 4-((2S,3S,6S)-6-((R)-1-(benzyloxy) ( propan-2-yl)-3-methyltetrahydro-2H-pyran-2-yl)-3-hydroxy-2-(phenylselanyl)pentanoate (S3) ) B-Hydroxyester S3 was obtained from aldehyde 38 (116 mg,0.38 mmol) according to general procedure D using enoxysilane 279a 4.22. (±)-(3R,4S)-Methyl 4-((2S,3S,6S)-6-((R)-1-(benzyloxy)propan-2-yl)-3-methyltetrahydro-2H-pyran-2-yl)-3 hydroxypentanoate(39) Product 39(72.9mg,yield=75%) as a colorless oil was obtainedfrom phenylselenide S3 (137 mg,0.26 mmol) according to generalprocedure F, and purification by flash chromatography on silica gel(hexanes/EtOAc,80:20). Re0.31 (hexanes/EtOAc,80:20); C22H3405;MW 378.50 g/mol; IR (liquid film)Vmax 3472, 2952, 2929,2858,1739,1455,1438,1171,1089,1017 cm-1;1H NMR(500MHz, CDCl3)oH 7.40-7.24(m,5H),4.56(d,J=11.9 Hz,1H), 4.51 (d,J=11.9 Hz, 1H),4.28 (ddd,J=7.5, 5.9, 1.4 Hz, 1H), 3.76 (br s, 1H), 3.71 (s, 3H),3.73-3.68 (m, 1H), 3.60 (dd,J=9.0, 3.2 Hz,1H), 3.48 (dd,J=9.6,2.7 Hz,1H),3.43 (dd,J=9.0, 6.7 Hz,1H), 2.61 (dd,J=15.3, 7.9 Hz,1H),2.42(dd,J=15.3,5,8 Hz,1H), 2.40-2.31 (m,1H), 1.81-1.74(m, 1H),1.74-1.68 (m,2H), 1.67-1.53 (m, 2H), 1.34-1.23 (m, 1H), 0.95 (d,J=7.0Hz,3H), 0.93 (d,J=7.3 Hz, 3H), 0.81 (d,J=6.5 Hz, 3H) ppm; 13CNMR(125MHz, CDCl3)8c 172.6,138.9,128.4,127.8,127.5,81.4,74.6,73.4,72.7, 72.6,51.7,39.9,37.1,32.0,31.8,27.1,25.8,17.7,15.0,5.2 ppm; MS (ESI) m/z 289.2 (4), 379.2 (42, M+H+), 401.2(100,M+Na+),415.2(7),779.5(14,2M+Na); HRMS calcd for C22H3505[M+H+]:379.2479, found:379.24866(2.0ppm); calcdforC22H3405Na [M+Na+]: 401.2298, found: 401.2303 (1.0 ppm). 4.23. (±)-(3S,4S,5S,6S)-Methyl 5-(benzyloxy)-6-((2S,3S,6S)-6-((R)-1-(benzyloxy)propan-2-yl)-3-methyltetrahydro-2H-pyran-2-yl)-3-hydroxy-4-methyl-2-(phenylselanyl)heptanoate (S4) -Hydroxyester S4 was obtained from aldehyde 401a(18.3 mg,40 umol) according to general procedure D using enoxysilane 27=as the nucleophile. lH NMR analysis of the crude product indicateda ratio >20:1 of product 3,4-syn (S4): 3,4-anti. The residue waspurified by flash chromatography on silica gel (hexanes/EtOAc,85:15) to yield product S4 as a pale yellow oil (11.4 mg,yield=40%).R0.25 (hexanes/EtOAc, 85:15);C28H5006Se; MW 681.76 g/mol; IR(liquid film) Vmax 3457, 2950,2925,2856,1729,1455,1437,1086,1022 cm-1; 1H NMR (500 MHz, CDCl3) 8H 7.68-7.63 (m, 2H),7.34-7.23 (m, 13H), 4.60 (d,J=10.9 Hz, 1H), 4.52 (d,J=10.9 Hz,1H),4.49 (d,J=12.7 Hz, 1H),4.46 (d,J=12.8 Hz,1H), 4.31(d,J=10.4 Hz,1H), 4.25(s,1H), 3.94(d,J=10.5Hz,1H), 3.68 (dd,J=8.6, 3.3 Hz,1H),3.54 (dd,J=9.3, 4.5 Hz, 1H), 3.50 (dd,J=8.9, 2.1 Hz,1H), 3.48-3.45(m,1H), 3.46(s,3H), 3.29(dd,J=8.5, 7.7 Hz,1H), 2.13-2.05(m,1H),2.06-1.97 (m,1H), 1.85-1.77 (m, 1H), 1.69-1.58 (m, 4H), 1.26-1.18(m, 1H), 1.13 (d, J=7.1 Hz, 3H), 0.91 (d, J=6.7 Hz, 3H), 0.82 (d,J=6.4 Hz, 3H), 0.77 (d, J=7.0 Hz, 3H) ppm; 13c NMR (125 MHz,CDCl3) oc 171.3, 138.7,138.0,136.5,129.0,128.7,128.6,128.4,127.9, 127.78,127.76,127.60,127.57,87.5,76.1,75.7,73.6,73.5,73.4,70.0,51.9,48.8,36.2,34.7,30.5,29.9,27.4,25.6,18.6,14.5,12.2, 9.7 ppm;MS (ESI) m|z 360.3(7),475.3(7),683.3 (5, M+H*), 705.3 (100,M+Na+), 719.3(6); HRMS calcd for C28H5106Se [M+H*]: 683.2845,found: 683.2847 (0.2 ppm); calcd for C28H5006SeNa [M+Na*]:705.2665, found: 705.2687 (3.1 ppm). 4.24. (±)-(3R,4S,5S,6S)-Methyl 5-(benzyloxy)-6-((2S,3S,6S)-6-((R)-1-(benzyloxy)propan-2-yl)-3-methyltetrahydro-2H-py-ran-2-yl)-3-hydroxy-4-methylheptanoate (41) Product 41 (6.8 mg,yield=38%) as a colorless oil was obtainedfrom phenylselenide S4 (23 mg, 33 umol) according to generalprocedure F, and purification by flash chromatography on silica gel(hexanes/EtOAc,85:15). R0.20 (hexanes/EtOAc, 85:15); C32H4606;MW 526.70 g/mol; IR (liquid film) Vmax 3489, 2952,2925,1737,1454,1380,1172,1084,1020 cm-1; 1H NMR (500 MHz, CDCl3) 8H7.33-7.24(m,10H), 4.62(d,J=10.8Hz, 1H),4.55-4.51 (m,1H), 4.50(d,J=12.1 Hz, 1H), 4.48 (d,J=12.1 Hz, 1H), 3.81 (s, 1H), 3.72 (dd,J=8.6, 3.3 Hz, 1H), 3.74-3.64 (m,1H), 3.69 (s,3H), 3.57 (dt,J=9.4,4.9 Hz,1H), 3.52(dd,J=8.8,2.3Hz, 1H), 3.50 (dd,J=9.0, 2.1 Hz, 1H),3.32 (dd,J=8.5, 7.7 Hz, 1H), 2.59 (dd,J=15.0, 8.2 Hz, 1H), 2.34 (dd,J=14.9, 5.4 Hz,1H), 2.17-2.10 (m,2H), 1.84-1.76(m,1H), 1.73-1.60(m, 4H), 1.33-1.22(m,1H), 1.11 (d,J=7.2 Hz, 3H), 0.93 (d,J=6.8 Hz,3H), 0.86 (d, J=7.0 Hz, 3H), 0.85 (d, J=6.4 Hz, 3H) ppm; 13c NMR(125 MHz, CDCl3) oc 172.5, 138.7,138.2,128.6,128.4,127.9,127.8,127.60,127.59,87.3,75.92,75.86,73.52,73.45,73.35,67.4,51.8,39.9,37.7,37.3,34.7,30.6,27.3,25.5,18.6,14.4,12.2,10.4 ppm; MS (ESI)m/z 527.3 (9, M+H+), 549.3(100,M+Na+), 639.4(12); HRMS calcdfor C32H4706[M+H+]: 527.3367, found: 527.3370 (0.5 ppm); calcdfor C32H4606Na [M+Na*]: 549.3187, found: 549.3192(1.0ppm). 4.25. (3S,4S,5S,6S,7S,8S)-Methyl 5,7-bis(benzyloxy)-8-((2S,3S,6S)-6-((R)-1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)-3-methyltetrahydro-2H-pyran-2-yl)-3-hydroxy-4,6-dimethyl-2-(phenylselanyl)nonanoate (42a) β-Hydroxyester 42aa was obtained from crude aldehydee 17(52 mg, 69umol))accordingtogeneral procedure D usingenoxysilane 27 as the nucleophile.. HNMR analysis of the crudeproduct indicated a ratio 13:1 of product 12,13-syn (42a): 12,13-anti(42b).1 The major diastereoisomer was separated by flash chro-matography on silica gel (hexanes/EtOAc, 90:10) to yield an in-separable mixture (~9:1) of C14-phenylselenide 42a as a colorlessoil (50 mg,yield=74% over 2 steps). The relative stereochemistry ofcompound 42a was not determined. Rf 0.13 (hexanes/EtOAc, 95:5);C57H7407SeSi; MW 978.24 g/mol; IR (liquid film) Vmax 3461, 3068,2951,2929,2857,1728,1455,1428,1381,1092,1065,1027 cm-1; 1HNMR (500 MHz, CDCl3) H7.71-7.61(m,6H), 7.42-7.12 (m, 19H),4.84(d,J=11.4Hz,1H), 4.48(d,J=11.4Hz,1H), 4.42 (d,J=11.8 Hz,1H),4.34(d,J=11.9Hz,1H),4.28(s,1H),3.88(d,J=10.6Hz,1H), 3.76-3.70(m,2H), 3.66-3.59(m,2H),3.45(s,3H), 3.46-3.41(m,1H), 3.35 (dd,J=9.0, 1.2 Hz,1H), 2.26-2.17(m, 1H), 2.10-2.00 (m, 1H), 2.00-1.91(m,1H), 1.84(d,J=7.1 Hz,1H), 1.62-1.50 (m, 4H), 1.33-1.24(m,1H),1.20-1.11(m, 1H), 1.07((d,J=7.1 Hz, 3H), 1.03 (s, 9H), 0.91 (d,J=7.0 Hz, 3H), 0.877(d,J=6.8 Hz, 3H), 0.80 (d,J=7.2 Hz,3H), 0.54(d,j=6.4Hz,3H)ppm;CNMR(125MHz, CDCl3)oc 171.4,139.5,138.1,136.9,135.89,135.85,134.2,134.0, 129.69,129.67,128.94, 128.89,128.6,128.3,127.73,127.72,127.69,127.17,127.16,127.15,126.8,87.6,86.1,75.9,74.8,74.6,72.3,69.8,65.9,51.8,48.2,38.9,36.7,36.3,35.6,30.8,27.5,27.1,25.4,19.5,18.2,17.3,13.8,12.1, 11.4 ppm; MS (ESI) m|z193.6(18),261.1(23),300.9(8),338.3(100),360.3(92),408.3(21),457.3(14),480.9(5),536.6(11),594.0(12),979.4(10,M+H+), 1001.4(59, M+Na); HRMS calcd for C57H7507SeSi [M+H+]: 979.4442,found: 979.4440 (-0.2 ppm); calcd for C57H7407SeSiNa [M+Na+]:1001.4261, found: 1001.4258 (-0.3ppm). 4.26. (3R,4S,5S,6S,7S,8S)-Methyl5,7-bis(benzyloxy)-8-((2S,3S,6S)-6-((R)-1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)-3-methyltetrahydro-2H-pyran-2-yl)-3-hydroxy-4,6-dimethylnonanoate (23a) Product 23a (37.2 mg,yield=88%) as a colorless oil was obtainedfrom phenylselenide 42a (49.9 mg, 51 pmol) according to generalprocedure F, and purification by flash chromatography on silica gel(hexanes/EtOAc, 85:15). Note: Reaction was repeated from a largerscale of crude aldehyde 17 (721 mg, 0.96 mmol), providing 12,13-syn product 23a with similar results (514 mg, yield=65% over 3steps). Rf 00..22.(hexanes/EtOAc, 85:15);C51H7007Si;MW823.18 g/mol; IR (liquid film) Vmax 3489,3069,3030,2957,2928,2857, 1739,1457,1428,1379,1171,1092,1016 cm-1; 1H NMR(500 MHz, CDCl3) oH 7.73-7.65 (m, 4H), 7.48-7.35(m, 6H),7.33-7.21 (m, 10H), 4.84 (d,J=11.3 Hz, 1H),4.59 (appt,J-6.8 Hz,1H), 4.51 (d, J=11.3 Hz, 1H), 4.46 (d, J=11.6 Hz, 1H), 4.42 (d,J=11.6 Hz, 1H), 3.87 (br s, 1H), 3.79-3.73 (m, 2H), 3.71 (s, 3H),3.73-3.67 (m, 2H), 3.50 (dd, J=8.3, 2.5 Hz, 1H), 3.43 (dd,J=8.7,2.2 Hz, 1H), 2.59 (dd,J=15.1,8.0 Hz, 1H), 2.40-2.34(m, 1H), 2.30(dd, J=15.2, 5.9 Hz, 1H), 2.13-2.05(m, 1H), 2.05-1.96 (m, 1H),1.96-1.89(m,1H), 1.72-1.59 (m, 4H), 1.27-1.16 (m,1H), 1.072 (d,J=6.8Hz, 3H), 1.070 (s,9H), 0.97 (d,J=6.8Hz, 3H),0.97 (d,J=7.5 Hz,3H), 0.92 (d,J=6.8 Hz, 3H), 0.65 (d,J=6.4 Hz, 3H) ppm; 13c NMR(125MHz, CDCl3) c 172.4, 139.4, 138.2,135.88,135.83, 134.09,134.01,129.64,129.62,128.5,5,1128.2,127.71,127.70,127.69,127.3,127.2, 127.0,87.0,85.6,76.0,74.6,74.4,72.2,67.9,66.0,51.7,39.8,38.5,37.5,36.9,36.0,30.6,27.4,27.1,25.3,19.5,18.3,17.7,16.9,12.2,11.4 ppm; MS (ESI) m/z 179.0(10),338.3(14),360.3(17),625.2(5),823.5(21,M+H+),824.5(12),825.4(4),845.5(100,M+Na*),846.5(60),847.5(18),848.5 (4); HRMS calcd for C51H7107Si [M+H*]:823.4969, found: 823.4960(-0.5 ppm); calcd for C51H7007NaSi[M+Na*]: 845.4783, found: 845.4796 (1.5 ppm). 4.27.(:(3S,4S,5S,6S,7S,8S)-Methyl 5,7-bis(benzyloxy)-8-((2S,3S,6S)-6-((R)-1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)-3-methyltetrahydro-2H-pyran-2-yl)-3-hydroxy-4,6- dimethylnonanoate (23b) -Hydroxyesters 23a and 23b were obtained from aldehyde 17(22.5 mg, 30 umol) according to general procedure D using 1(tert-butyldimethylsilyloxy)-1-methoxyethene 22 as the nucleophile. HNMR analysis of the crude product indicated a ratio ~1:1 of alco-hols 12,13-syn (23a): 12,13-anti (23b). The two diastereoisomerswere separated by flash chromatography on silica gel (hexanes/EtOAc, 85:15) to yield products 23a and 23b as colorless oils(combined yield; 17.2 mg, 70% over 2 steps). 23b;R 0.17 (hexanes/EtOAc,85:15); C51H7007Si; MW 823.18 g/mol; IR (liquid film) Vmax3499, 3068, 3031,2929,2857,1737,1456,1428,1380,1171,1111,1092,1066 cm-1;1H NMR(500 MHz, CDCl3) oH 7.67-7.60(m, 4H),7.42-7.32(m,6H), 7.26-7.17 (m, 10H), 4.67 (d,J=11.7 Hz, 1H), 4.48(d,J=11.6 Hz, 1H), 4.41-4.40 (m,2H), 4.23-4.17(m,1H), 3.92 (br s,1H), 3.69 (s, 3H), 3.71-3.66(m,2H), 3.64 (dd,J=9.5, 3.9 Hz,1H),3.58 (dd,J=6.8, 4.4 Hz, 1H), 3.45 (dd,J=7.2, 4.0 Hz, 1H), 3.35 (dd,J=7.8, 3.7 Hz, 1H), 2.60 (dd,J=15.7, 2.7 Hz, 1H), 2.35 (dd,J=15.8,10.0 Hz, 1H), 2.24-2.18 (m, 1H), 2.16-2.09 (m, 1H), 2.05-1.97 (m,1H),1.97-1.89(m,1H), 1.63-1.45(m, 4H), 1.24-1.17(m,1H), 1.03 (s,9H), 0.96 (d, J=7.2 Hz, 3H), 0.899 (d,J=6.9 Hz, 3H), 0.897 (d,J=7.1 Hz, 3H), 0.87 (d,J=6.8 Hz, 3H), 0.66(d,J=6.4Hz,3H) ppm; 13cNMR (125 MHz,CDCl3) òc 173.9, 139.5,138.8,135.90,135.87,134.15,134.10, 129.65, 129.62,128.4,128.3,127.72, 127.69,127.52,127.47,127.2,127.1,84.9,84.3,76.5,74.1,73.4,71.8,69.9,66.0,51.8,40.7,39.0,38.2,37.7,36.7,30.3,27.9,27.1,24.8,19.5,18.4,16.0,14.5,14.3,11.5 ppm; MS (ESI) m/z 192.9 (4),227.0(8),338.3(14),360.3(21),755.4(6),823.5(12,M+H+),824.5(7),825.5(2),840.5(3,M+NH4),845.5 (100, M+Na+), 846.5(63),847.5(21),848.5(5),935.5(4); HRMS calcd for C51H7107Si [M+H+]: 823.4969, found: 823.4955(-1.0 ppm); calcd for C51H7407NSi [M+NH4]:840.5229, found:840.5220(-1.0 ppm); calcd for C51H7007NaSi[M+Na*]: 845.4783,found: 845.4792 (1.1ppm). 4.28. (3R,4S,5S,6S,7S,8S)-Methyl 3,5,7-tris(benzyloxy)-8-((2S,3S,6S)-6-((R)-1-(tert-butyldiphenylsilyloxy)propan-2-yl)-3-methyltetrahydro-2H-pyran-2-yl)-4,6-dimethylnonanoate (43) Product 43 (451 mg,yield=92%) as a colorless oil was obtainedfrom primary alcohol 23a (443 mg, 0.54 mmol) according to gen-eral procedure A, and purification by flash chromatography onsilica gel (hexanes/EtOAc, 90:10). R 0.29 (hexanes/EtOAc, 90:10);C58H7607Si; MW 913.31 g/mol; IR (liquid film) Vmax 3069,3029,2954,2929,2857,1737,1496,1454,1428,1378,1361,1112,1066,1028 cm-1; 1H NMR (500 MHz, CDCl3) oH 7.67-7.61 (m, 4H),7.41-7.32 (m,8H), 7.26-7.17(m, 13H), 4.61 (d,J=11.7 Hz, 1H), 4.46(d,J=11.5 Hz, 1H), 4.44 (d,J=11.7 Hz, 1H), 4.43 (d,J=11.8 Hz, 1H),4.42 (d,J=11.6 Hz,1H), 4.40 (d,J=11.4 Hz, 1H), 4.28 (ddd,J=7.7, 5.5,2.3 Hz,1H), 3.70-3.57(m, 4H), 3.59 (s, 3H), 3.47 (app t,J=6.0 Hz,1H), 3.42 (app t,J=6.0 Hz, 1H), 2.66 (dd,J=15.0, 7.4 Hz, 1H), 2.43(dd,J=15.1, 5.5 Hz, 1H), 2.34-2.27 (m, 1H), 2.27-2.20 (m, 1H),1.98-1.91 (m, 1H), 1.90-1.83(m, 1H), 1.77-1.68 (m, 1H),1.67-1.59(m,1H), 1.54-1.47(m,1H), 1.44-1.36(m,1H), 1.31-1.23(m,1H),1.04(s, 9H), 1.02 (d,J=7.1 Hz, 3H), 0.97 (d, J=6.8 Hz, 3H), 0.96(d,J=6.9Hz,3H), 0.87(d,J=6.9 Hz, 3H),0.81 (d,J=6.8 Hz, 3H)ppm;3NMR (125 MHz, CDCl3) oc 172.7,139.44, 139.41,139.2,135.9 (2C),134.16,134.14,129.63,129.61,128.30,128.27,128.25,127,70,127.68,127.49,127.44,127.31,127.24,127.21,127.17,84.2,83.4,77.7,76.3,73.5,73.2,72.2,70.8,65.9,51.7,40.8,39.0,38.5,38.0,36.6,29.4,27.126.3, 23.7, 19.5,18.5,15.5,13.2,12.4,12.3 ppm; MS (ESI) mjz227.0(24), 338.3 (50),408.3(15),675.7(8),913.5(19,M+H+), 930.6 (5,M+NH4), 935.5 (100, M+Na+), 1012.6(13); HRMScalcd forC58H7707Si [M+H+]: 913.5433, found: 913.5409 ((-2.6 ppm); calcdfor C58H8007NSi[M+NH4]:930.5699, found: 930.5671(-2.9ppm);calcd for C58H7607NaSi [M+Na*]:935.5253,1found:935.5234(-2.0ppm). 4.29. (3R,4S,5S,6S,7S,8S)-3,5,7-tris(Benzyloxy)-8-((2S,3S,6S)-6-((R)-1-(tert-butyldiphenylsilyloxy)propan-2-yl)-3-methyltetrahydro-2H-pyran-2-yl)-4,6-dimethylnonan-1-ol(44) Alcohol 44 (879 mg,yield=98%)as a colorless oil was obtained from ester 43 (934 mg, 1.0 mmol)according to general procedure B,and purification by flash chromatography on silica gel (hexanes/EtOAc, 75:25). R 0.14 (hexanes/EtOAc, 80:20); C57H7606Si; MW885.30 g/mol; IR (liquid film) Vmax 3435, 3067,3030,2958,2930,2857, 1496, 1454, 1428,1378,1111,1091,1066,1028 cm-1; 1H NMR(500 MHz, CDCl3) H 7.68-7.61 (m, 4H), 7.41-7.32 (m, 7H),7.26-7.18 (m,14H), 4.62 (d,J=11.6Hz,1H),4.51(d,J=11.4Hz, 1H),4.45 (d,J=11.5 Hz, 1H), 4.42 (d.J=11.4 Hz, 1H),4.41 (d,J=11.6 Hz,1H), 4.40 (d, J=11.6 Hz, 1H), 3.86 (ddd,J=7.7, 6.0, 2.6 Hz, 1H),3.72-3.52(m,7H),3.49 (appt,J-5.8Hz,1H), 3.43 (appt,J=5.9 Hz,1H), 2.35-2.27 (m, 1H), 2.27-2.20 (m, 1H), 2.00-1.92 (m, 1H),1.92-1.84(m,1H),1.84-1.79 (m, 1H), 1.79-1.72 (m,1H), 1.70-1.60(m, 2H), 1.54-1.49 (m, 1H), 1.47-1.38 (m, 1H), 1.34-1.24(m,1H),1.04(s, 9H), 1.03 (d,J=7.1 Hz, 3H), 0.99 (d,J=6.9Hz, 3H),0.95 (d,J=7.1Hz, 3H), 0.87 (d,J=6.8 Hz, 3H), 0.84 (d,J=6.7 Hz, 3H)ppm; 13cNMR (125MHz, CDCl3)8c 139.5,139.3,139.2,135.88,135.87,134.16,134.15,129.63,129.60,128.42,128.33,128.28,127.70,127.68,127.66,127.62,127.5,127.3,127.22,127.18, 84.4, 83.4,77.8,77.6,73.5, 73.1,72.1,70.9,65.9,60.9,40.5,38.4,37.9,36.7,36.0,29.5,27.1,26.4,23.8,19.5,18.5, 15.6,13.3,12.6,12.3 ppm; MS (ESI) m/z 192.8 (9), 228.2(7),338.3(100),360.3(73),408.3(18),675.7(18),697.7(8),885.5(26, M+H+), 902.6 (7,M+NH4), 907.5 (88, M+Na*), 997.6 (11);HRMS calcd for C57H7706Si [M+H+]: 885.5484, found: 885.5464 ( (-2.2 ppm); c alcd f or C57H8006NSi [M+NH4]: 90 2 .5749, fo u nd:902.5730(-2.2ppm); calcd for C57H7606NaSi [M+Na+]: 907.5303, found: 907.5293 ( - 1.2 ppm). ) ( 4.30. (3R,4S,5S,6S,7S,8S)-3,5,7-tris(Benzyloxy)-8-((2S,3S,6S)-6- ((R)-1-(tert-butyldiphenylsilyloxy)propan-2-yl)-3- methyltetrahydro-2H-pyran-2-yl)-4,6-dimethylnonanal (45) ) Aldehyde 45 as a colorless oil was obtained from alcohol 44(857 mg, 0.97 mmol) according to general procedure C, and wasused as crude without purification. Rf0.53 (hexanes/EtOAc,80:20);C57H7406Si; MW 883.28 g/mol; H NMR (500 MHz, CDCl3) 8H 9.65(t, J=2.2 Hz, 1H), 7.67-7.61 (m, 4H), 7.41-7.32 (m, 7H), 7.26-7.15(m, 14H), 4.63 (d,J=11.7 Hz, 1H), 4.50 (d,J=11.3 Hz, 1H), 4.41 (d,J=11.8 Hz,1H), 4.41 (d,J=11.4Hz, 1H), 4.39(d,J=10.1 Hz,1H), 4.37(d,J=11.5 Hz, 1H), 4.34-4.29 (m,1H), 3.71-3.59(m,4H),3.48 (dd,J=6.5,5.2 Hz, 1H), 3.42 (appt,J=5.9 Hz, 1H), 2.71 (ddd,J=16.3, 7.3,2.5 Hz, 1H), 2.45 (ddd,J=16.3, 5.1, 1.9 Hz, 1H), 2.37-2.29 (m, 1H),2.28-2.20(m,1H), 1.98-1.91 (m,1H), 1.91-1.83 (m,1H),1.79-1.71(m, 1H), 1.71-1.62 (m, 1H), 1.53-1.48 (m,1H), 1.44-1.36 (m, 1H),1.33-1.27(m, 1H), 1.05 (s, 9H), 1.00 (d, J-8.0 Hz, 3H), 0.99 (d,J=7.4Hz, 3H), 0.97 (d,J=7.2 Hz, 3H), 0.87 (d,J=6.9 Hz,3H), 0.85(d,J=6.8 Hz,3H) ppm; 13c NMR (125 MHz, CDCl3) oc 201.8, 139.30,139.28,138.83,135.87,135.86, 134.15,134.13,129.64,129.61,128.39,128.37,128.29,127.70,127.68,127.54, 127.50,127.47,127.36,127.32,127.27,84.3,83.5,77.8,74.3,73.5,73.3,72.0,70.7,65.8,48.4,41.3,38.7,38.0,36.4,29.9,29.3,27.1,26.2,23.6,19.5,18.5,15.6,13.2,12.5 ppm. 4.31. (+)-tert-Butyl-((R)-2-((2S,5S,6S)-5-methyl-6- ((2S,3S,4S,5S,6S,7R)-3,5,7-tris(benzyloxy)-4,6-dimethyldec-9-en-2-yl)tetrahydro-2H-pyran-2-yl)propoxy)diphenylsilane(46) To a cooled (0C) solution of methyltriphenylphosphoniumbromide (3.1 equiv, 1.08 g) in dry THF (0.1 M, 10 mL) was addeda 2.5 M solution of nBuLi in hexanes (3 equiv, 1.17 mL), and themixture was stirred for 40 min at 0 °C. To the mixture was addeda solution of crude aldehyde 45 (863 mg, 0.98 mmol) in dry THF(0.1 M, 10 mL) and the mixture was stirred at 0 °C for 18 h or untilstarting material was completely consumed, as verified by TLC(hexanes/EtOAc, 80:20). Reaction mixture was then treated drop-wise with a saturated aqueous solution of NH4Cl at 0 °C, followedby separation of the organic phase at rt. The aqueous layer wasextracted with Et20(3×) and the combined organic fractions werewashed with a saturated brine solution, then dried (MgSO4), fil-tered and concentrated in vacuo. The residue was purified by flashchromatography on silica gel (hexanes/EtOAc, 95:5) to yieldhomoallylic product 46 as a pale yellow oil (661 mg,yield=78% over2 steps). R 0.40 (hexanes/EtOAc, 95:5);[a]6+4.6(c0.50, CH2Cl2);C58H7605Si; MW: 881.31 g/mol; IR (liquid film) Vmax 3068,3029,2959,2929,2857,1495,1454,1427,1111,1092,1067,1028 cm-1;1HNMR (500 MHz, CDCl3) oH 7.57-7.51 (m, 4H), 7.32-7.21 (m, 8H),7.15-7.08(m, 13H), 5.61 (ddt,J=17.2,10.2, 7.1 Hz, 1H), 4.88 (ddd,J=13.7, 11.1, 1.1 Hz,2H), 4.46 (d,J=11.4 Hz, 1H), 4.44 (d,J=11.3 Hz,1H), 4.36 (s, 2H), 4.29 (d,J=11.7 Hz, 1H), 4.22 (d,J=11.7 Hz, 1H),3.72-3.67 (m,1H), 3.60-3.48 (m, 4H), 3.37 (dd,J=6.6, 5.1 Hz, 1H),3.34 (app t, J=5.9 Hz, 1H), 2.38-2.30 (m, 1H), 2.28-2.19 (m,1H),2.16-2.06(m, 2H), 1.91-1.83 (m, 1H), 1.80-1.71(m,1H), 1.69-1.61(m, 1H), 1.59-1.50 (m, 1H), 1.43-1.36 (m, 1H), 1.32-1.17 (m, 2H),0.94 (s,9H),0.91 (d,J=7.0 Hz, 3H), 0.88 (d,J=6.9 Hz, 3H), 0.85 (d,J=7.2 Hz, 3H), 0.77 (d,J=6.6 Hz, 3H), 0.75(d,J=6.4Hz,3H)ppm; 13cNMR (125 MHz, CDCl3) oc 139.64, 139.58, 139.50,135.87, 135.86,135.7, 134.2, 134.0,129.61, 129.58,128.30, 128.24, 128.21, 127.69,127.67,127.46,127.42,127.23,127.21,127.15,127.12,116.8,84.0,83.2,78.5,78.0,73.2,73.1,71.5,70.7,65.9,39.6,38.8,38.2,37.1,36.4,30.5,29.3,27.1,26.2,19.5,18.5,15.3,13.2,12.5,11.6 ppm; MS (ESI) m/z 192.8(6),228.2(9), 338.3 (61),411.4(7),675.7(13),881.5(100,M+H+), 898.6(8,M+NH4),903.5(5,M+Na+),971.6(6),988.6(5);HRMS calcd for C58H7705Si [M+H+]: 881.5535, found: 881.5529(-0.7 ppm); calcd for C58H80O5NSi [M+NH4]: 898.5800,found:898.5782 (-2.0 ppm); calcd for C58H7605NaSi [M+Na+]: 903.5354,found: 903.5337 (-1.9 ppm). 4.32. (+)-(4R,5S,6S,7S,8S,9S)-4,6,8-tris(Benzyloxy)-9-((2S,3S,6S)-6-((R)-1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)-3- methyltetrahydro-2H-pyran-2-yl)-5,7-dimethyldecan-1-ol(47) To a cooled (0C) solution of homoallylic product 46 (11.5 mg,13 pmol) in dry THF (0.1 M, 13 pL) was added dropwise a 0.5 Msolution of 9-BBN in THF (3 equiv, 78 pL), turning the pale yellowsolution to colorless. After stirring for 6 h at 0 °C, the reactionmixture was treated successively at 0°C with MeOH (40 uL), a 3 Msolution of NaOH (25 pL) and a 35% wt. solution of H202 in water(15 pL). The mixture was stirred and allowed to warm overnightfrom 0 °C to rt before addition of a saturated brine solution anddilution with Et20 (1 mL). The aqueous layer was then extractedwith Et20 (3×), and the combined organic fractions were dried(MgSO4), filtered and concentrated in vacuo. The residue was pu-rified by flash chromatography on silica gel (hexanes/EtOAc, 95:5)toyield product 47 (12.8 mg, quantitative yield) as a colorless oil. Note:Reaction was repeated on a larger scale of homoallylic olefin 46(150-200 mg) with similar results.Rr0.20 (hexanes/EtOAc,80:20);[o]6+0.9(c1.28, CH2Cl2); C58H7806Si; MW 899.32g/mol; IR(liquidfilm)Vmax 3408,3066,3029,2929,2857,1496,1454,1426,1378,1111,1091,1066,1028 cm-1;1H NMR (500 MHz,CDCl3)67.67-7.61(m,4H), 7.42-7.31(m,7H), 7.27-7.18(m,14H), 4.59 (d,J=11.8Hz,1H),4.51(d,J=11.6Hz,1H), 4.46(d,J=11.9 Hz,1H), 4.46(d,J=11.8Hz,1H),4.40 (d,J=11.7 Hz, 1H), 4.35 (d,J=11.7 Hz, 1H), 3.71-3.64(m, 3H),3.64-3.58(m,2H),3.53-3.42(m,5H),2.39-2.29(m,1H), 2.25-2.18(m, 1H), 2.02-1.94 (m,1H), 1.90-1.82 (m, 1H), 1.82-1.74 (m, 1H),1.71-1.62(m,2H),1.51-1.35(m,4H),1.34-1.25(m,2H),1.04(s,9H),1.00 (d,J=7.1Hz, 3H), 0.99 (d,J=71Hz,3H), 0.97 (d,J=7.4 Hz, 3H),0.88 (d,J=6.9 Hz, 3H), 0.87 (d,j=6.8 Hz, 3H) ppm;13c NMR(125 MHz, CDCl3) oc 139.62,139.60,139.58,135.88,135.87,134.23,134.22,129.63,129.60,128.33,128.30,128.24,127.70,127.68,127.49,127.48,127.29,127.24,127.16,127.11,84.2,83.8,78.8,78.0,77.4, 73.3,71.6,70.8,65.9,63.2,40.0,39.0,38.1,36.5,35.0,29.4,28.9,27.6,27.1,22.9,19.5, 18.5,15.8,13.2,12.7,11.9 ppm; MS (ESI) m/z 195.1(13)338.3(9),791.5(5),899.6(100,M+H+), 916.6(14,M+NH4),921.5(57,M+Na); HRMS calcd for C58H79O6Si [M+H+]: 899.5640,found:899.5654 (1.5 ppm); calcd for C58H8206NSi [M+NH4]:916.5906,found: 916.5896(-1.0 ppm); calcd for C58H7806NaSi [M+Na+]:921.5460, found: 921.5465 (0.6 ppm). 4.33.(+)-(4R,5S,6S,7S,8S,9S)-4,6,8-tris(Benzyloxy)-9-((2S,3S,6S)-6-((R)-1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)-3- methyltetrahydro-2H-pyran-2-yl)-5,7-dimethyldecyl pivalate (48) To a cooled (0°C) solution of alcohol 47 (468 mg, 0.52 mmol) indry CH2Cl2 (0.2M,2.6 mL) was added successively pyridine (5 equiv,210 pL) and pivaloyl chloride (2.5 equiv, 160 pL). After stirring for18 h at rt, the opaque white mixture was treated with a saturatedaqueous solution of NH4Cl and concentrated in vacuo.The resultingwhite paste was extracted with Et20 (3x), and the combined or-ganic fractions were washed with a saturated brine solution, thendried (MgSO4), filtered and concentrated in vacuo. The residue waspurified by flash chromatography on silica gel (hexanes/EtOAc,90:10) to yield product 48 as a colorless oil (461 mg,yield=90%). Rf0.36(hexanes/EtOAc, 90:10);[α]65+1.4(c1.60,CH2Cl2);C63H8607Si;MW 983.44 g/mol; IR (liquid film) Vmax 3068, 3029,2958,2930,2857,1727,1454,1428,1363,1284,1155,1111,1067, 1028 cm-1; 1HNMR (500 MHz, CDCl3) on 7.67-7.62 (m, 5H), 7.41-7.32(m, 7H), 7.25-7.20(m,13H), 4.59 (d,J=11.7 Hz, 1H), 4.50 (d,J=11.4 Hz, 1H),4.45(d,J=11.6 Hz, 1H), 4.44 (d,J=11.5 Hz, 1H), 4.38 (d,J=11.7 Hz,1H), 4.32 (d,J=11.7 Hz, 1H), 3.98-3.91(m,2H), 3.72-3.58 (m,5H),3.51-3.43 (m,2H), 2.40-2.32 (m,1H), 2.24-2.17 (m,1H), 1.96-1.89(m, 1H), 1.89-1.82(m, 1H), 1.82-1.75 (m, 1H), 1.71-1.62 (m,2H),1.53-1.43 (m,4H), 1.39-1.27 (m, 2H), 1.18 (s, 9H), 1.04 (s, 9H), 0.99(d,J=6.8 Hz, 3H), 0.98(d,J=7.2 Hz, 3H), 0.97 (d,J=7.6 Hz, 3H), 0.88(d,J=6.4 Hz, 3H), 0.87 (d,J=6.5 Hz, 3H) ppm; 13C NMR (125 MHz,CDCl3) oc 178.7, 139.55,139.54, 139.4, 135.88,135.87, 134.16 (2C),129.62,129.59,128.32,128.30,128.24,127.69,127.67,127.5,127.4,127.27, 127.23,127.17,127.16, 84.0,83.4,78.6,78.1,73.2,73.1, 71.5,70.6,65.8,64.5,39.9,39.0,38.8,38.1,36.3, 30.1,29.9,29.2,28.8,27.4,27.1,23.4,19.5,18.5,15.5,13.1,12.6,11.7 ppm; MS (ESI) m|z 195.1(8),338.3(16),983.6 (100,M+H+), 1000.6(41,M+NH), 1005.6(20,M+Na), 1082.7 (36); HRMS calcd for C63H8707Si [M+H]:983.6216, found: 983.6208(-0.7 ppm); calcd for C63H9007NSi[M+NH4]: 1000.6481, found: 1000.6463(-1.8 ppm); calcd forC63H8607NaSi [M+Na+]: 1005.6035, found: 1005.6016(-(-1.9 ppm). 4.34.(-)-(4R,5S,6S,7S,8S,9S)-4,6,8-tris(Benzyloxy)-9-((2S,3S,6S)-6-((R)-1-hydroxypropan-2-yl)-3-methyltetrahydro-2Hpyran-2-yl)-5,7-dimethyldecyl pivalate (49) To a cooled(0°C) solution of TBDPS ether 48 (390 mg, 0.40 mmol)in dry THF(0.1M, 2.1 mL) was added dropwise a 1 M solution of TBAFin THF (1.5 equiv, 310 pL), followed by stirring overnight at rt. Thereaction mixture was then treated with a saturated aqueous solutionof NH4Cl, and concentrated in vacuo. The aqueous layer was extrac-ted with Et20 (3×) and combined organic fractions were dried(MgSO4), filtered and concentrated in vacuo. The crude product waspurified by flash chromatography on silica gel (hexanes/EtOAc,85:15)) to give primary alcohol 49 as a colorless oil (264 mg,yield=89%). R 0.17 ((hexanes/EtOAc, 85:15);[α]65-8.0(c 0.70,CH2Cl2); C47H6807; MW 745.04 g/mol; IR (liquid film) Vmax 3435,2957,2928,2873,1727,1455,1376,1284,1157,1090,1067 cm-1; 1HNMR(500 MHz,CDCl3)oH 7.32-7.19(m,15H), 4.64(d,J=11.8 Hz,1H),4.59 (d,J12.0Hz,1H), 4.58 (d,J=11.7 Hz, 1H), 4.44(d,J=11.8 Hz,1H),4.41 (d, J=11.8 Hz, 1H), 4.25 (d,J=11.8 Hz, 1H), 3.99-3.91 (m, 2H),3.76-3.72 (m,1H), 3.66 (dd,J=8.4, 2.9 Hz,1H), 3.63-3.59 (m, 1H),3.56-3.52(m,3H), 3.50-3.44(m,1H), 3.38-3.34(m,1H), 2.36-2.27(m,2H), 1.95-1.85(m, 2H), 1.85-1.76(m, 1H), 1.72-1.64 (m, 2H),1.62-1.55 (m,2H), 1.52-1.43 (m, 3H), 1.40-1.32 (m, 1H), 1.18(s,9H),1.11 (d,J=7.0 Hz, 3H), 1.02 (d,J=7.2 Hz, 3H), 0.98 (d,J=7.0 Hz, 3H),0.95 (d,J=6.8Hz,3H), 0.78(d,J=6.9Hz, 3H)ppm;13cNMR(125MHz,CDCl3) oc 178.7, 139.55,139.54,139.4,128.35,128.33,128.32,127.64,127.61,127.34,127.31,127.28,127.27,84.2,78.4,77.8,77.4,76.6,73.5,72.9, 71.4, 68.4,64.5,39.9,38.9,38.3,38.1,35.6,29.9,29.6,28.3,27.4,25.8,25.5,25.4,18.7,14.0,13.3, 11.2 ppm; MS (ESI) m/z 338.3 (12),360.3(8),745.5(47, M+H+), 762.5(5,M+NH4), 767.5(100,M+Na*),790.6(50),844.6(8),857.5(13),880.6(6); HRMS calcd for C47H6907[M+H+]:745.5038, found: 745.5034 (-0.5i ppm); calcd forC47H7207N[M+NH4]:762.5303, found: 762.5291 (-1.6ppm); calcdfor C47H6807Na [M+Na+]: 767.4857,found: 767.4866(1.2ppm). 4.35. (4R,5S,6S,7S,8S,9S)-4,6,8-tris(Benzyloxy)-5,7-dimethyl-9-((2S,3S,6S)-3-methyl-6-((S)-1-0xopropan-2-yl)tetrahydro-2H-pyran-2-yl)decyl pivalate (S5) Aldehyde S5 as a colorless oil was obtained from alcohol 49(30 mg, 40 pmol) according to general procedure C, and was used ascrudewithout purification. Rf 0.24 (hexanes/EtOAc, 90:10);C47H6607; MW 743.02 g/mol; 1H NMR (500 MHz, CDCl3) 8g 9.74(d,J=2.8Hz, 1H), 7.34-7.21 (m, 15H), 4.62 (d,J=12.5 Hz,1H), 4.61 (S,2H), 4.46 (d,J=11.7 Hz, 1H), 4.45 (d, J=11.6 Hz, 1H), 4.35 (d,J=11.7 Hz,1H),4.00-3.95(m,2H), 3.87-3.81(m,1H),3.73-3.69(m,1H), 3.64(dd,J=7.0,4.7Hz,1H), 3.59(app t,J=5.9 Hz,1H), 3.54(dd,400-188-0725 J=6.6,5.4 Hz, 1H), 2.62-2.53(m,1H),2.33-2.23(m,2H), 1.99-1.91(m, 1H), 1.84-1.76 (m, 1H), 1.75-1.66 (m, 2H), 1.55-1.37 (m, 6H),1.20 (s, 9H), 1.04 (d,J=7.0 Hz, 3H), 1.03 (d,J=7.1 Hz, 3H), 1.03 (d,J=6.8 Hz, 3H), 0.98 (d,J=7.0 Hz, 3H), 0.91 (d,J=6.8 Hz, 3H) ppm. 4.36. (4R,5S,6S,7S,8S,9S)-4,6,8-tris(Benzyloxy)-9-((2S,3S,6S)-6-((S)-1-methoxy-1-oxopropan-2-yl)-3-methyltetrahydro-2H-pyran-2-yl)-5,7-dimethyldecyl pivalate (50) 4.37. (4R,5S,6S,7S,8S,9S)-4,6,8-Trihydroxy-9-((2S,3S,6S)-6-((S)-1-methoxy-1-oxopropan-2-yl)-3-methyltetrahydro-2H-pyran-2-yl)-5,7-dimethyldecyl pivalate (51) Triol 51 as a colorless oil was obtained from tris-benzyl product 50(31 mg, 40 pmol) according to general procedure E, and was used ascrude without purification. Rf <0.05 (hexanes/EtOAc, 85:15);C27H5008; MW 502.68 g/mol; IR (liquid film) Vmax 3421,3365,2958,2934,2874,1728,1459,1439,1381,1284,1161,1121,1083 cm-1;1HNMR(500 MHz, CDCl3)On 4.42(d,J=7.9Hz,1H),4.20(s,1H),4.16-4.04(m, 4H), 3.71 (S,3H), 3.72-3.68(m,1H), 3.64(dd,J=8.8, 1.6 Hz,1H),3.44 (td,J=8.6,3.0 Hz,1H), 3.11 (dq,J=10.7,7.0 Hz, 1H), 2.08-1.98(m,2H),1.88-1.76(m,1H),1.78-1.58(m,8H),1.42-1.35(m,1H),1.28-1.21(m,1H), 1.19(s,9H), 1.08(d,J=7.1Hz,3H),1.08(d,J=7.1 Hz,3H), 1.06(d,J=7.2 Hz,3H), 0.83 (d,J=6.5 Hz,3H), 0.68 (d,J=6.8 Hz,3H) ppm; 13cNMR(125MHz, CDCl3)8c 178.8,175.5,84.2,83.9,76.4,74.7,70.1, 64.7,52.5,40.1,38.9,38.4,37.2,34.4,31.7,31.3,27.4,26.6,25.6,25.1,18.0, 14.8, 13.6, 11.5,11.3 ppm; MS (ESI) m/z 227.0(6),360.3(10),503.4(13,M+H+), 525.3 (100,M+Na+), 551.3 (3); HRMS calcd for C27H510g[M+H+]: 503.3578, found: 503.3591 (2.5 ppm); calcd for C27H50OgNa[M+Na+]:525.3398, found: 525.3419 (4.0 ppm). ( 4.38. (+)-(4R,5S,6S,7R,8R,9R)-4,6,8-tris(tert-Butyldimethylsily-loxy)-9-((2S,3S,6S)-6-((S)-1-methoxy-1-oxopropan-2-yl)-3- methyltetrahydro-2H-pyran-2-yl)-5,7-dimethyldecylpivalate(52) ) To a cooled (0°C) solution of crude triol 51 (40 pmol) in dryCH2Cl2 (0.1 M, 0.4 mL) was added successively2,6-lutidine(40 equiv, 190 uL) and TBSOTf (20 equiv, 190 uL). The reactionmixture was stirred for 36 h at rt or until alcohol was completelyconsumed, as verified by TLC (hexanes/EtOAc,95:5). The reactionmixture was treated with a saturated aqueous solution of NH4Cl,followed by separation of the organic phase at rt. The aqueous layerwas then extracted with CH2Cl2 (3×), and the combined organicfractions were dried (MgSO4), filtered and concentrated in vacuo.The residue was purified by flash chromatography on silica gel(hexanes/EtOAc, 95:5) to yield 52 as a pale yellow oil (21 mg, 62%over 2 steps). R 0.45 (hexanes/EtOAc, 95:5), [x]+0.5(c 2.17,CH2Cl2); C45H9208Si3; MW 845.46 g/mol; IR (liquid film) Vmax 2956,2931,2858,1733,1472,1463,1376,1284,1257,1160,1052 cm-1;1HNMR(500 MHz, CDCl3) 8H 4.08-3.98 (m, 2H), 3.98-3.93 (m,1H),3.92-3.84 (m,2H), 3.68(s, 3H), 3.68-3.62 (m, 1H), 3.57 (app d,j-9.3Hz, 1H), 2.51 (dq, J=7.1, 7.1 Hz, 1H), 2.25-2.17 (m, 1H),2.01-1.92 (m, 1H), 1.91-1.76(m,2H), 1.71-1.64 (m, 1H), 1.62-1.53(m,4H), 1.49-1.41(m,3H), 1.19(s,9H), 1.08(d,J=7.0 Hz,3H), 1.07 (d,J=6.5 Hz, 3H), 0.94 (d,J=6.9 Hz, 3H), 0.91 (s, 9H), 0.87 (s, 2x9H),0.85(d,J=7.0Hz,3H),0.85(d,J=7.4Hz,3H), 0.12 (s, 3H), 0.11(s, 3H),0.09 (s,3H), 0.08 (s,3H), 0.06 (s, 3H), 0.05 (s, 3H) ppm; 13c NMR(125MHz, CDCl3)oc 178.7,175.9, 79.7, 74.1, 72.03, 72.02, 71.2,64.8,51.7,45.7,39.6,38.88,38.87, 33.07, 30.11,29.1,27.8,27.36,26.35,26.27,26.24,25.3,24.5,23.9,23.2,18.7,18.53,18.46,18.41,13.2,11.9,-3.0,-3.33.,--3.5,3.7,-3.85,-3.87 ppm; MS (ESI) m|z 227.0 (13),390.3(21),393.1(7),498.9(4),566.9(4),634.9(3),753.5(4),845.6(2,M+H)862.6(3, M+NH4), 867.6 (100, M+Na*), 944.7(5);HRMS calcd for C45H93OgSi3 [M+H+]: 845.6173, found: 845.6190(2.11Pppm); calcd for C45H960gNSi3 [M+NH4]: 862.6438, found:862.6454 (1.8 ppm); calcd for C45H920gNaSi3 [M+Na]:867.5992,found: 867.6014(2.5 ppm). 4.39. (+)-(S)-Methyl2-((2S,5S,6S)-5-methyl-6-((2R,3R,4R,5S,6S,7R)-3,5,7-tris(tert-butyldimethylsilyloxy)-10-hydroxy-4,6-dimethyldecan-2-yl)tetrahydro-2H-pyran-2-yl)propanoate (53) To a cooled(0°C) solution of pivaloyl ester 52 (43.2 mg,51 umol)in MeOH (0.1 M, 0.5 mL) was added K2CO3(1.2 equiv, 8.5 mg).Afterstirring for 36 h at rt, the reaction mixture was treated with water(1mL) and diluted with EtOAc (3 mL). The aqueous layer was thenextracted with EtOAc (3×), and the combined organic fractionswere dried (MgSO4), filtered and concentrated in vacuo. The resi-due was purified by flash chromatography on silica gel (hexanes/EtOAc, 90:10) to yield starting material 52 (14.9 mg, yield=31%) andproduct 53(19.7 mg,yield=51%, 78% brsm) as colorless oils. R0.28(CH2Cl2/EtOAc, 95:5);[x]+1.4 (c1.36,CH2Cl2); C40H8407Sis; MW761.35 g/mol; IR (liquid film) Vmax 3456, 2953,2929,2857,1742,1472,1462,1376,1256,1053 cm-1; 1H NMR (500 MHz, CDCl3) on3.99-3.95 (m, 1H), 3.92-3.86 (m, 2H), 3.68 (s, 3H), 3.69-3.64(m,2H), 3.64-3.60(m,2H), 3.55 (app d,J=8.7 Hz, 1H), 2.52(dq,J=7.4,7.4Hz,1H), 2.25-2.15(m,1H), 2.00-1.92(m,1H),1.92-1.86(m,1H),1.86-1.77(m, 1H), 1.77-1.70 (m, 1H), 1.61-1.39 (m, 7H), 1.08 (d,J=6.9 Hz, 3H), 1.07 (d,J=7.0 Hz, 3H), 0.94 (d,J=7.0 Hz, 3H), 0.91 (s,9H), 0.88 (s, 9H), 0.88 (s, 9H), 0.87 (d, J=7.1 Hz, 3H), 0.85 (d,J=7.4 Hz, 3H), 0.11 (s,2x3H), 0.10 (s,3H), 0.09 (s, 3H), 0.07 (s,3H),0.06 (s, 3H) ppm; 13C NMR (125 MHz, CDCl3) 6c 176.1,79.8,77.7, 400-188-0725 76.8,74.4, 71.4,63.5,51.9,42.4,33.0,30.0,28.6,27.8, 26.43, 26.40,26.37,26.35,26.32,26.30,25.4,23.2,18.88,18.85,18.61,18.55,18.53,18.52,13.3,-3.2,-3.45,-3.55,-3.65,-3.8(2C) ppm; MS (ESI) m/z193.0(12),338.3(14),360.3(35),497.4(6),595.5(6),669.5(18),761.6(2, M+H*), 783.5 (100,M+Na+), 860.7(7); HRMS calcd forC40H8507Si3[M+H+]:761.5598, found: 761.5610 (1.6 ppm); calcdfor C40H8407NaSi3 [M+Na*]:783.5417, found: 783.5432 (1.9 ppm). 4.40. (-)-(S)-Methyl 2-((2S,5S,6S)-5-methyl-6-((2R,3R,4R,5S,6S,7R)-3,5,7-tris(tert-butyldimethylsilyloxy)-4,6-dimethyl-10-(1-phenyl-1H-tetrazol-5-ylthio)decan-2-yl)tetra-hydro-2H-pyran-2-yl)propanoate (55) To a cooled (0C) solution of PPh3 (1.4 equiv, 7.7 mg) and 1-phenyl-1H-tetrazole-5-thiol 54 (1.5 equiv, 5.5 mg) in dry THF(0.05 M, 220 pL) was added dropwise DIAD (1.5 equiv, 6.2 pL). Theresulting yellow mixture was stirred for 10 min at 0 °C beforedropwise addition of primary alcohol 53 (16.0 mg, 21 umol) in dryTHF (0.05 M, 220 pL) and stirring for 3 h at rt The reaction mixturewas then treated with water (1 mL) and diluted with Et20 (3mL). Theaqueous layer was extracted with Et20 (3×) and the combined or-ganic fractions were washed with a saturated brine solution, thendried (MgSO4), filtered and concentrated in vacuo. The residue waspurified by flash chromatography on silica gel (hexanes/EtOAc, 90:10)to yield product 55 as a colorless oil (13.6 mg, yield=70%). R0.39(hexanes/EtOAc, 90:10);[c]65-1.0 (c1.36, CHzCl2); C47H8gN406SSis;MW 921.55 g/mol; IR (liquid film) Vmax 2953,2930,2886,2857,17411501, 1462,1387,1253,1052 cm-1; 1H NMR(500 MHz, CDCl;)n7.60-7.51(m, 5H), 3.93 (dt,J=6.7, 4.1 Hz,1H), 3.88 (dd,J=7.5,3.4 Hz,1H), 3.84(dd,J=8.4, 3.7 Hz,1H), 3.67 (s,3H), 3.69-3.62(m,1H), 3.55(dd,J=9.6,1.1 Hz,1H),3.45-3.35 (m,2H), 2.51 (dq,J=7.0,7.0Hz, 1H),2.24-2.16(m,1H),1.94(ddq,J=3.7,7.3, 7.3Hz,1H),1.89-1.73(m,4H),1.70-1.62 (m, 3H), 1.49-1.40(m, 3H),1.08 (d,J=7.1Hz, 3H), 1.06 (d,J=7.1 Hz, 3H), 0.92 (d,J=7.1 Hz, 3H), 0.91 (s,9H), 0.852 (s, 9H), 0.849(s,9H), 0.845 (d,J=7.2Hz,3H), 0.82(d,J=7.4Hz,3H), 0.11 (s,3H), 0.09(s,3H), 0.07 (s,3H), 0.05 (s,3H), 0.034 (s, 3H), 0.027(s,3H) ppm; cNMR(125 MHz,CDCl3)oc 175.9,154.5,133.9,130.2,129.9,124.0,79.6,77.4, 74.1,71.9,71.2,51.7,45.7,43.9,39.7,35.7,33.9,27.8,26.3,26.22,26.21,25.5,25.3,24.7,23.2,18.7,18.5,18.43,18.38,13.2,12.2,11.0,10.2,-3.0,-3.3,-3.6,-3.7,-3.8-3.9 ppm; MS (ESI) m|z 247.0 (7), 338.3(6),515.4(56),614.5(42),657.4(81),789.5(29),921.6(79,M+H*),938.6(15,M+NH4),943.6(26,M+Na+),1020.7(100); HRMS calcd forC47H89N406SSis [M+H+]: 921.5805, found: 921.5804 (-0.1 ppm);calcd for C47H92N5O6SSi3 [M+NH4]: 938.6071, found: 938.6066(-0.4 ppm); calcd for C47H88N406NaSSi3[M+Na*]:943.5625,found:943.5620(-0.5 ppm). 4.41. (+)-(S)-Methyl 2-((2S,5S,6S)-5-methyl-6-((2R,3R,4R,5S,6S,7R)-3,5,7-tris(tert-butyldimethylsilyloxy)-4,6-dimethyl-10-(1-phenyl-1H-tetrazol-5-ylsulfonyl)decan-2-yl)tetrahydro-2H-pyran-2-yl)propanoate (9) Oxidation reagent was prepared at 0°C by the dropwise additionof a 35% wt. solution of H202 in water (10 equiv, 17 pL) to(NH4)6Mo70244H20 (0.3 equiv, 5.5 mg) forming a bright yellowsolution. The mixture was added dropwise to a cooled(0°C)solutionof sulfide 55(13.6mg,15 umol) in 95% EtOH(0.1M, 200 pL)and wasstirred for 18 h at rt,resulting in the formation of a yellow precipitate.The reaction mixture was then treated with water (1 mL) and dilutedwith EtOAc (3 mL). The aqueous layer was extracted with EtOAc(3×)and the combined organic fractions were washed with a saturatedbrine solution, then dried (MgSO4), filtered and concentrated invacuo.The residue was purified by flash chromatography on silica gel(hexanes/EtOAc, 90:10) to yield sulfone 9 as a colorless oil (14.9 mg,quantitative yield). Rr0.38 (hexanes/EtOAc, 90:10);[c]6+0.5(c1.12,CH2Cl2); C47H88N4OgSSi3; MW 953.55 g/mol; IR (liquid film) Vmax ( 2954,2930,2886,2857,1741,1498,1463,1344,1257,1152,1050cm-; 'HNMR (500 MHz, CDCl3) oH 7.71-7.67 (m, 2 H), 7.65-7.57 (m,3H),3.93 ( dd,J=10.2, 4.9 Hz, 1H), 3 .90 (dd,J=7.3,3.3 Hz, 1H), 3.84 (dd, J = 8 .3, 3.4 H z,1H), 3 .73(appt,J=7 . 9 Hz, 2H), 3.67 (s, 3H),3.69-3.62 (m,1 H ), 3 . 56 (dd,J=9 .8 , 1.2 H z ,1H ) , 2. 5 2 (d q ,J=7.2 , 7.2 Hz , 1H) , 2.26-2.17 ( m,1H), 2.03-1.90(m, 3H), 1.89-1.77 (m, 2H),1.76-1.65(m,3H), 1.50-1.4 0 (m,3H), 1.08 (d,J=6. 9 Hz, 3H), 1.07 (d,J=6.8 Hz, 3H),0.93 (d,J=6 . 9 Hz, 3H), 0.91 ( s , 9 H), 0.86 (s, 9H), 0.88-0.85 (m, 3H),0.85(s,9H),0.84(d,J=7.1Hz,3H), 0.12(s,3H),0.10(s,3H),0.09(S, 3H), 0.06 (s, 3H), 0.05 (s,2×3H) ppm; 13c NMR(125MHz, CDCl3)oc 175.9, 1 53.6,133.2,131.6,129.9,125.2,79.7,74.8,74.2,71.6,71.3,56.4, 51.7,45.6,44.0,39.7,35.3,27.8,26.3,26.21,26.18(2C),25.3,23.2,18.7, 18.6, 18.39,18.36,17.8,13.2,12.7,11.0,10. 3, -3. 1, -3.4 , -3.66, - 3.71, -3.81, -3.82 p pm; MS (ESI) mjz 1 8 9.0 (1 1 ),247.0(15),262.0(1 1 ),338.3(20),515.4(61),532.4(37),588.5(10),614.5(100),953.6(1 1 , M+H+), 970.6 (14,M+NH4), 975.5(7,M+Na+),1020.7(10 ) ,10 5 2.7 (26); HRMS calcd for C47H89N40:SSi3 [ M+H+]: 953.5703, fou n d: 953.5676( - 2.8 p p m); calcd for C 4 7H92N50: S Si3 [M+ N H4]: 970.5969, found: 970.5942(-2.8ppm); calcd forC47H88 N 40 8 NaSSis ) [M+Na+]: 975.5523, found: 975.5496(-2.7ppm). 4.42.(-)-(R)-4-Benzyl-3-((2S,3R,6R,E)-2,4,6-trimethyl-3-((tri-methylsilyl)oxy)non-4-enoyl)oxazolidin-2-one (58) To a solution of crude aldehyde 1128(1.50g, 11 mmol) in dry EtOAc(0.25 M, 40 mL) at rt was4aaddedsuccessively (R)-4-benzyl-3-propionyloxazolidin-2-one 57(1.2 equiv, 2.99 g), dried MgCl2(0.2 equiv, 204 mg), Et3N (2.4 equiv, 3.6 mL) and TMSCl (2 equiv,mL). The pale orange mixture was stirred for 18 h at rt before fil-tration onto a pad of Celite(conditioned with Et20) and washingwith Et20(2x15mL).Filtrate was concentrated in vacuo to yield 58 asan orange oil (3.48g,yield=73% over 2 steps).Rf0.27 (hexanes/EtOAc,85:15);[a]-42 (c1.4, CDCl3); C25H39NO4Si; MW 445.67 g/mol; IR(liquid film) "max 2958, 1784, 1669,1386, 1212 cm-1; 1H NMR(400MHz, CDCl3) oH 7.37-7.24(m,5H),5.16 (ddd,J=9.5, 2.4, 1.4 Hz,1H),4.72 (ddt,=9.6,7.8,3.3 Hz,1H),4.29(d,J=9.6Hz,1H),4.20-4.08(m,3H), 3.33 (dd,J=13.4, 3.3 Hz, 1H), 2.71 (dd,J=13.4, 9.7 Hz, 1H),2.48-2.35(m,1H), 1.62 (d,J=1.3 Hz, 3H), 1.31-1.17(m, 4H), 0.96(d,J=6.8 Hz,2×3H), 0.90-0.84 (m, 3H), 0.05 (s, 9H) ppm; cNMR(100MHz, CDCl3)8c 176.8,153.4,136.8,135.7,133.3,129.6,129.1,127.4,82.6,65.8,55.3,41.6,39.9,38.2,32.0,20.9,20.7,14.5,14.3, 10.6,0.4 ppm; MS (ESI) m|z 356.2(80),396.2(75,M-TMS+Na+),468.2(8,M+Na+); HRMS calcd for C22H31NO4Na [M-TMS+Na+]: 396.2151,found: 396.2137 (3.5 ppm); Analysis calcd for C25H39NO4Si: C, 67.37;H, 8.82; N, 3.14; found: C, 67.16; H, 9.17; N, 3.11. 4.43. (-)-(R)-4-Benzyl-3-((2S,3R,6R,E)-3-hydroxy-2,4,6-trimethylnon-4-enoyl)oxazolidin-2-one (59) To a cooled (0 °C) solution of silylated aldol adduct 58 (3.48 g,7.8 mmol)in MeOH (0.1 M, 80 mL) was added TFA (1 drop). Afterstirring for1 hat O°C,the mixture was concentrated in vacuo and TFAwas co-evaporated with toluene (3×5mL). The pale yellow residuewas then purified by flash chromatography on silica gel (hexanes/EtOAc, 80:20) to yield alcohol 59 as a colorless oil (2.53 g,yield=87%).R0.26(hexanes/EtOAc, 75:25);[x]2-70(c0.28,CDCl3);C22H31NO4;MW 373.49 g/mol; IR (liquid film) Vmax 3510,2957,2871,1780,1698,1388,1212,1012 cm-1; 1H NMR(400 MHz, CDCl3) H 7.36-7.24 (m,5H), 5.24(dq,J=9.6, 1.3 Hz, 1H), 4.70 (dtd,J=3.2, 6.6, 7.1 Hz, 1H),4.24-4.06 (m, 4H), 3.33 (dd,J=3.4, 13.5 Hz, 1H), 2.80 (dd,J=9.4,13.5 Hz, 1H), 2.52(brs, 1H), 2.47-2.36(m,1H),1.68(d,J=1.3 Hz, 3H),1.33-1.18 (m, 4H), 1.05 (d,J=6.5 Hz, 3H), 0.95 (d,J=6.7 Hz, 3H),0.89-0.85 (m,3H) ppm;13c NMR (100 MHz, CDCl3) òc 176.9,154.0,136.9,135.5,132.8,129.7,129.1,127.4,81.9,66.2,55.8,40.8,39.9,37.9,32.1,21.0,20.8,14.9,14.3,10.9 ppm;MS (ESI) m/z 356.1 (100,M+H+-H2O), 396.2 (45, M+Na*); HRMS calcd for C22H31NO4Na 耐士科技 www.rysstech.com 400-188-0725 4.45. (+)-(2R,3R,6R,E)-3-(4-Methoxybenzyloxy)-2.4,6trimethylnon-4-en-1-ol (S6) To a cooled (0°C) solution of product 60 (358 mg, 0.725 mmol)in dry Et2O (0.1 M, 7.2 mL) was added successively MeOH (4 equiv,120 pL) and a 2 M solution of LiBH4 in THF (4 equiv, 1.5 mL). Afterstirring for 18 h at 0°C, the mixture was treated with a 1 N solutionofHCl at 0°C, followed by separation of the organic phase at rt. Theaqueous layer was extracted with Et2Q (3x) and the combinedorganic fractions were washed with a saturated brine solution, thendried (MgSO4), filtered and concentrated in vacuo. The residue waspurified by flash chromatography on silica gel (hexanes/EtOAc,75:25) to yield product S6 as a colorless oil (117 mg,yield=50%).R0.31 (hexanes/EtOAc, 80:20);[a]6+32.4(c1.16,CH2Cl);20H3203;MW 320.24 g/mol; IR (liquid film) "max 3447,2957,2927,2870,1613,1514,1456,1302,1248,1173,1037 cm-1;1H NMR(500 MHz, CDCl3)oH 7.22(d,J=8.6 Hz, 2H), 6.87 (d,J=8.7 Hz, 2H), 5.11 (d,J=9.6 Hz,1H), 4.42(d,J=11.4Hz, 1H), 4.16(d,J=11.5 Hz,1H), 3.80 (s,3H), 3.57(d,J=5.9 Hz, 2H), 3.46(d,J=9.7 Hz, 1H), 3.40 (br s,1H), 2.53-2.42(m,1H), 2.02-1.93(m,1H), 1.60 (d,J=1.2Hz,3H), 1.33-1.18(m, 4H),1.01 (d,J=6.7 Hz,3H), 0.87 (t,J=6.8 Hz,3H),0.66 (d,J=7.0 Hz, 3H)ppm; 13c NMR(125 MHz, CDCl3) oc159.3,138.6,130.7,130.4,129.7,114.0,91.9,69.1,68.8,55.4,39.8,37.1,32.1,21.5,20.9,14.3,14.0,10.8 ppm; MS (ESI) m/z 303.2(3),321.2 (1,M+H+), 343.2 (100,M+Na+), 344.2(21);HRMS calcd for C20H3303[M+H+]: 321.2424,found: 321.2419 (-1.5 ppm); calcd for C20H3203Na [M+Na+]:343.2244, found: 343.2239(-1.4ppm). 4.46.(+)-(2S,3R,6R,E)-3-(4-Methoxybenzyloxy)-2,4,6- trimethylnon-4-enal(10) Aldehyde 10 (54 mg,yield=81%) as a colorless oil was obtainedfrom alcohol S6 (68 mg, 0.21 mmol) according to general procedureC, and purification by flash chromatography on silica gel (hexanes/EtOAc, 90:10). 1H and 13c NMR chemical shift were identical tothose previously reported for the same compound by Leightonet a1.16d R0.66(hexanes/EtOAc, 80:20);[α]5+32.3 (c 4.13,CDCl3); C20H3003; MW 318.45 g/mol; IR (liquid film) Vmax 2957, 2927,2870,1729,1613,1513,1456,1302,1248,1173,1064,1036 cm-1;1H NMR(500 MHz, CDCl3)8H9.68(d,J=2.8Hz, 1H), 7.18 (d,J=8.2 Hz, 2H),6.86(d,J=8.3 Hz,2H), 5.18(d,J=9.6 Hz, 1H), 4.42 (d,J=11.6 Hz, 1H),4.15 (d, J=11.6 Hz, 1H), 3.80 (s, 3H), 3.71 (d, J=10.0 Hz, 1H),2.65-2.57 (m, 1H),2.53-2.43 (m, 1H), 1.60 (d, J=1.3 Hz, 3H),1.34-1.17(m,4H), 1.02(d,J=6.6 Hz,3H), 0.87 (t,J=6.3 Hz, 3H), 0.84(d, J=7.1 Hz, 3H) ppm; 13c NMR (125 MHz, CDCl3) 6c 205.2,159.3,139.5,130.4,129.7,129.4,113.9,85.7,69.2,55.4,48.3,39.8,32.3,21.4,20.9,14.3,11.0,10.7 ppm; MS (ESI) m/z 193.4(2),301.2(5),319.2(2,M+H+),341.2(35,M+Na*),342.2(21),373.2(100),403.2(8),493.3(6),723.5(6); HRMS calcd for C20H3103[M+H+]:319.2268,found:319.2271 (1.0 ppm); calcd for C20H3003Na [M+Na+]: 341.2087,found: 341.2092 (1.5 ppm). 4.47. (-)-(S)-Methyl 2-((2S,5S,6S)-5-methyl-6-((2R,3R,4R,5S,6S,7R,10E,12R,13R,14E,16R)-3,5,7-tris(tert-bu-tyldimethylsilyloxy)-13-(4-methoxybenzyloxy)-4,6,12,14,16-pentamethylnonadeca-10,14-dien-2-yl)tetrahydro-2H-pyran-2-yl)propanoate (61a) To a cooled (-55°C) solution of sulfone 9 (25.5 mg, 27 umol) inanhydrous DME (0.05 M, 540 pL) was added a 0.5 M solution ofKHMDS in toluene (1.1 equiv, 59 uL), followed immediately with0.5 M solution of aldehyde 10 in anhydrous DME (1.2 equiv,64 uL). The reaction was stirred for 1 h at -55 °C, then 30 min at-440 °C before the mixture was treated with a saturated aqueoussolution ofNH4Clat-40°C. After separation of the organic phase atrt, the aqueous layer was extracted with 20% EtOAc/hexanes andthe combined organic fractions were dried (MgSO4), filtered andconcentrated in vacuo. H NMR analysis of the crude product in-dicated a ratio 9:1 of isomers E (61a): Z (61b). The residue waspurified by flash chromatography on silica gel (hexanes/EtOAc,95:5 to 90:10) to yield sulfone 9 (6.2 mg, yield=24%), aldehyde 10(3.7 mg,yield=43%) and an inseparable mixture of product 61a,b(9.5 mg, yield=34%, 45% brsm) as colorless oils. Rr 0.60 (hexanes/EtOAc, 90:10);[α]2 -3.6 (c 0.93, CDCl3); C60H112OgSis; MW1045.78 g/mol; IR (liquid film) Vmax 2955,2929,2857,1742,1513,1459,1375,1249,1171 cm-1;1H NMR(500 MHz, CDCl3) oH 7.21 (d,J=8.5 Hz, 2Ha+2Hb), 6.84 (d,J=8.6 Hz, 2Ha+2Hb), 5.44-5.34 (m,2Ha+2Hb),5.04 (d,J=9.5 Hz,1Ha+1Hb), 4.412 (d,J=12.2 Hz,1Hb),4.406 (d, J=11.8 Hz, 1Ha), 4.26-4.18 (m, 1Ha+1Hb), 4.14 (d,J=11.9 Hz,1Ha), 4.13 (d,J=12.1 Hz, 1Hb),3.98-3.92(m,1Ha+1Hb),3.92-3.85 (m, 2Ha+2Hb), 3.80 (s, 3Hb), 3.79 (s, 3Ha), 3.67 (s,3Ha+3Hb),3.57(d,J=9.6Hz,1Ha+1Hb),3.24(d,J=8.7Hz,1Hb),3.23(d,J=9.1 Hz, 1Ha), 2.70-2.60 (m,1Hb), 2.55-2.49 (m,1Ha+1Hb),2.49-2.41 (m, 1Ha+1Hb), 2.35-2.28 (m, 1Ha), 2.24-2.18(m,1Ha+1Hb), 2.06-1.93 (m, 3Ha+3Hb), 1.92-1.77 (m, 2Ha+2Hb),1.76-1.66(m,2Ha+2Hb), 1.56 (s,3Ha), 1.55 (s,3Hb),1.47-1.40 (m,4Ha+4Hb), 1.37-1.15(m, 7Ha+7Hb), 1.08 (d,J=7.3 Hz, 3Ha+3Hb),1.07 (d,J=7.5 Hz,3Ha+3Hb), 0.99 (d,J=6.6 Hz, 3Ha+3Hb), 0.94 (d,J=6.8 Hz, 3Ha), 0.93 (d,J=7.3 Hz, 3Hb), 0.92 (s, 9Ha), 0.913 (d,J=7.0 Hz, 3Ha+3Hb), 0.912 (s,9Hb), 0.89 (s, 2×9Ha), 0.88 (s,9Hb),0.87 (s,9Hb),0.85 (d,J=7.1 Hz,3Ha+3Hb), 0.79 (d,J=6.9 Hz,3Ha),0.75(d,J=6.9Hz, 3Hb), 0.12(s,3Ha+3Hb),0.11(s,3Ha+3Hb),0.09(s,3Ha), 0.09 (s, 3Ha+3Hb),0.08(s, 3Hb), 0.07 (s, 3Ha), 0.05 (s,3Ha+3Hb),0.04 (s,3Hb) ppm; 13c NMR(125 MHz, CDCl3)òc 175.9,159.0,137.6,134.0,131.5,131.0,129.4,129.0,113.7,89.3,79.7,74.1,72.5,71.2,69.2,68.3,55.4,51.7,39.9,39.0,38.9,32.1,30.5,29.1,27.9,26.4, 26.34,26.31,25.28,23.9,23.1,21.61,21.58,20.9,18.7,18.52,18.45,18.1,17.5,14.4,14.2,13.2,11.7,11.23,11.17,11.12,-3.0,-3.2,-3.5, -3.6,-3.8,-3.9 ppm; MS (ESI) m|z 159.0(7),227.0(19),250.2 (5), 338.3(10),360.3(100),413.3(53),441.3(9),566.9(4),697.7(7),750.6(10),803.5(3),1067.8(9,M+Na+),1117.4(5); HRMScalcd for C60H1120gNaSi3 [M+Na+]: 1067.7557, found:1067.7586(2.7ppm). ((2R,3R,4R,5S,6S,7R,10E,12R,13R,14E,16R)-3,5,7-tris(tert-butyldi-methylsilyloxy)-13-hydroxy-4,6,12,14,16-pentamethylnonadeca-10,14-dien-2-yl)tetrahydro-2H-pyran-2-yl)propanoate (62) To a solution of PMB ether 61a,b (9.5 mg, 9 umol) in a solventmixture of CH2Cl2 and sodium phosphate buffer pH 7 (10:1, 0.02 M,450 pL) at rt, was added DDQ (4 equiv, 8.2 mg) in 2 portions over10min. After stirring for 30 min at rt, the aqueous layer was extractedwith 20% EtOAc/hexanes and the combined organic fractions werewashed with a saturated NaHCO3 solution, then dried(MgSO4), fil-tered and concentrated in vacuo. The residue was purified by flashchromatography on silica gel (hexanes/EtOAc, 95:5) to yield C19-alcohol 62 as a colorless oil (7.5 mg, yield=89%). Rf 0.31 (hexanes/Et0Ac,95:5);[x]+3.8(c0.53, CDCl;); C52H104O7Si3; MW: 925.63 g/mol; IR (liquid film) Vmax 3549,2956,2929,2857,1743,1463,1378,1256,1168,1051 cm-1;1H NMR(500 MHz, CDCl3) 8n 5.63-5.54 (m,1H), 5.31-5.17 (m, 1H), 5.17-5.10 (m, 1H), 3.97-3.92 (m, 1H),3.92-3.84 (m,2H), 3.68 (s, 3H), 3.69-3.62 (m, 2H), 3.59-3.52 (m,2H), 2.55-2.47 (m, 1H), 2.46-2.36 (m, 1H), 2.25-2.18 (m, 2H),2.06-1.99 (m, 1H), 1.99-1.92 (m, 1H), 1.91-1.86(m, 1H), 1.84-1.78(m, 1H), 1.75-1.66 (m, 2H), 1.59 (s,3H), 1.48-1.42(m,4H), 1.30-1.17(m,8H),1.08(d,J=7.0 Hz, 3H), 1.07 (d,J=7.0 Hz, 3H),0.94(d,J=6.6 Hz,3H), 0.94 (d,J=6.9 Hz, 3H), 0.91 (s, 9H), 0.89-0.87 (m, 3H), 0.88 (s,9H), 0.88 (s,9H), 0.86(d,J=7.2 Hz, 3H), 0.84 (d,J=6.6 Hz, 3H), 0.12 (s,3H), 0.11 (s, 3H), 0.10 (s, 3H), 0.08 (s, 3H), 0.06 (s,3H), 0.05 (s,3H)ppm; 13c NMR (125 MHz, CDCl3) òc 175.9, 136.2, 133.4, 133.1,132.882.8,82.0,79.7,74.2,72.3,71.2,51.7,41.5,40.0,36.7,36.0,32.0,30.5,29.9,29.1,27.9,26.4,26.30,26.28,25.3,23.9,23.2,20.8,18.7,18.53,18.49,18.4,17.6,17.5,14.4,13.2,11.9,11.1,11.0,10.9,-3.0,3.3, 3.5-3.6,-3.8,-3.9 ppm; MS (ESI) m/z 227.0(3),360.3(4),413.3 (8),511.4(5),643.5(6),833.6(4),925.7 (4,M+H+), 942.7(4,M+NH4),947.77 (100, M+Na+); HRMS calcd forr C52H10507Si3 [M+H+]:925.7163, found: 925.7149(-1.5 ppm); caled for C52H10807NSi3[M+NH4]:942.7428, found: 942.7415 1.4Pppm);calcd forC52H10407SizNa [M+Na+]: 947.6982, found: 947.6993(1.2 ppm). 4.49. (S)-Methyl 2-((2S,5S,6S)-5-methyl-6-((2S,3S,4S,5S,6S,7R,10E,12R,13R,14E,16R)-3,5,7,13-tetrahydroxy-4,6,12,14,16-pentamethylnonadeca-10,14-dien-2-yl)tetrahy-dro-2H-pyran-2-yl)propanoate (1b) Following a reported procedure,30 the tris-TBS ether 62 (7.5 mg,8 umol) was solubilized in dry THF (0.05 M, 160 pL) and was treatedwith a 1 M solution of TBAF in THF (8 equiv, 49 pL). After stirring for68 h at rt(or until all starting material was consumed), the mixturewas treated with CaCO3(25 mg), DOWEX 50WX8 100-200 mesh(80 mg, used as supplied) and MeOH (1 mL). The suspension wasstirred for 18 h at rt and then filtered onto a pad of Celite, washedwith MeOH thoroughly(~20 mL). The filtrate was concentrated invacuo and the pale yellow residue was purified by flash chroma-.1tography on silica gel (hexanes/EtOAc,60:40) to yield zincophorinmethyl ester 1b (3.2 mg, yield=68%) as a colorless oil. 1H chemicalshift were identical to those previously reported for the samecompound by Cossy et al.1.16b Rf 0.49 (hexanes/EtOAc, 60:40);C34H6207; MW:582.85g/mol;H NMR (500 MHz, CDCl3) 0H 5.93 (s,1H), 5.61 (app dt,J=15.4,6.9 Hz, 1H), 5.34 (dd,J=15.3, 8.8 Hz, 1H),5.11(d,J=9.9Hz,1H), 4.43 (d,J=8.2Hz,1H), 4.12-4.06(m, 3H), 3.76(d,J=9.7 Hz, 1H), 3.72 (s, 3H), 3.63 (dd,J=8.8, 1.6 Hz, 1H), 3.55(d,J=9.0 Hz, 1H), 3.43 (app dt,J=10.5, 2.2 Hz, 1H), 3.23 (dq,J=10.8,6.9 Hz,1H), 2.45-2.37(m,1H), 2.26-2.17(m,3H), 2.12 (d,J=1.8 Hz,1H),2.06-1.96(m,2H), 1.79-1.67 (m, 4H), 1.60 (d,J=1.1 Hz, 3H),1.38-1.15 (m, 6H), 1.10 (d,J=7.1 Hz, 3H),1.08 (d,J=7.0 Hz, 3H), 1.06(d,J=7.5 Hz,3H), 0.93 (d,J=6.6 Hz, 3H), 0.90-0.85(m,5H), 0.84(d,J=6.8Hz, 3H), 0.82 (d,J=6.5 Hz, 3H), 0.66 (d,J=6.8 Hz,3H)ppm;13cNMR (125 MHz, CDCl3) ǒc 175.7, 134.8, 133.6,133.42, 133.37, 84.6, 84.2,82.0,76.2,74.7,69.2,52.6,42.0,41.2,40.1,38.5,37.6,34.6,34.1,32.0,31.8,29.9,26.4,25.2,21.2,20.8,17.9, 17.6,15.0,14.4,13.4,11.44,11.37, 10.9 ppm; MS (ESI) m/z 193.3(4), 227.0(7),296.2(3), 338.3(3),360.3(11),413.3(4),565.4(7),583.5(12,M+H+), 605.4(100,M+Na+), 606.4(37); HRMS calcd for C34H6307[M+H+]: 583.4568,found: 583.4559 (-1.6 ppm); calcd for C34H6207Na [M+Na*]:605.4388, found: 605.4389 (0.2 ppm). Acknowledgements The authors wish to express their gratitude to the Natural Sci-ences and Engineering Research Council of Canada (EG #1504) forits financial support. Fellowship support (B2) from Fonds Quebecoisde la Recherche sur la Nature et les Technologies (FQRNT) to F.G. isalso gratefully acknowledged. Supplementary data Supplementary data (experimental procedures, spectroscopicdata, copies of lH and 13c spectra for all reported compounds) re-lated to this article can be found at http://dx.doi.org/10.1016/j.tet.2014.11.061. References and notes ( 1. ( a ) O Ha g an, D. Nat. Prod. R e p . 1992, 9, 4 4 47 4 - 7 9; ( b ) K oskinen, A . M. P; Kar- i sal m i, K. Chem. Soc. Rev 20 05, 3 4, 6 7 7- 6 9 0. ) ( a) D [ utton, C . J .; B anks, B . J ; Cooper , C. B . N at. Prod. R ep. 1 995, 1 2 , 165-181;(b) K evin, D . A . , II ; M eu j o , D . A . F ; Ha m a n n, M. T. Expert Opin . Drug D isc. 2009,4,109 - 1 4 6 . ) ( 3. P r essman, B . C . Ann u . R ev. 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