a concise synthesis of mupirocin h using a cross-metathesis-based strategy

FULL PAPER

DOI: 10.1002/ejoc.201402442

A Concise Synthesis of Mupirocin H Using a Cross-Metathesis-Based Strategy

Sandip Sengupta[a] and Taebo Sim*[a,b]

Keywords: Total synthesis / Natural products / Polyketides / Metathesis / Reformatsky reaction

A highly efficient (10.1% overall yield) and convergent(longest linear sequence of 16 steps) synthesis of mupirocinH has been achieved, starting from commercially available(+)-(R)-Roche ester. The route relies on an efficient Grubbs

Introduction

Mupirocin, a mixture of naturally occurring polyketidesisolated from Pseudomonas fluorescens (a soil isolate, NCIB10586), is active against Gram-positive bacteria, includingmethicillin-resistant Staphylococcus aureus (MRSA),[1] andis clinically used for the treatment of bacterial skin infec-tions. The mixture consists mainly of pseudomonic acids,with its main constituents being pseudomonic acid A (90%)along with pseudomonic acids B–D (Figure 1).[2] The 74 kbmupirocin gene cluster that is responsible for the biosynthe-sis of these substances has been sequenced, and many of itsopen reading frames have been assigned putative func-tions.[3] Mutagenesis of the HMG-CoA synthase (HCS) en-

Figure 1. Structure of pseudomonic acids and mupirocin H (1).

[a] Chemical Kinomics Research Center, Korea Institute of Scienceand Technology,Hwarangro 14-gil 5, Seongbuk-gu, Seoul 136-791, Republic ofKorea

[b] KU-KIST Graduate School of Converging Science andTechnology,145, Anam-ro, Seongbuk-gu, Seoul, 136-713, Republic of KoreaE-mail: [email protected] information for this article is available on theWWW under http://dx.doi.org/10.1002/ejoc.201402442.

Eur. J. Org. Chem. 2014, 5063–5070 © 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 5063

cross-metathesis reaction to generate a key, late-stage E-ole-fin intermediate, and a cobalt-catalysed diastereoselectiveReformatsky reaction to produce a β-hydroxy ester thatserves as a late-stage intermediate.

coding gene in Pseudomonas fluorescens perturbs the nor-mal mupirocin biosynthetic pathway, and gives rise to theproduction of a new metabolite, mupirocin H (Figure 1).[4]

The structure of mupirocin H was determined by exten-sive analysis of spectroscopic data, and confirmed by a re-cent total synthesis.[5a] Its fascinating truncated pseu-domonic acid structure and the important biological activi-ties of members of the pseudomonic acid family have at-tracted the attention of several synthetic groups. To date,three total syntheses of mupirocin H have been reported.The first, completed by Chakraborty and co-workers in2011,[5a] used d-glucose as the source of the three ste-reogenic hydroxymethine groups at C-3–C-5 of the targetcompound, and Still–Barrish hydroboration and Julia–Kocienski olefination as key processes. The synthesis, whichhad an overall yield of 5 %, started from a known d-gluc-ose-derived intermediate, and required 26 steps, with alongest linear sequence of 19 steps. The second total synthe-sis of mupirocin H, described by Willis and co-workers[5b,5c]

in 2012, was based on a strategy involving conversion of asix-membered lactone into a five-membered analogue. Theroute, which started from a substance prepared by resolu-tion of a bisulfite adduct,[5d] used a 16-step linear sequenceto produce the target in a 3% overall yield from a commer-cially sourced starting material. Another synthesis of mupi-rocin H by the She group,[5e] which appeared during thepreparation of this manuscript, used a Suzuki–Miyauracoupling and a Mukaiyama aldol reaction as key steps, andwas accomplished in a total of 11 steps (longest linear se-quence of 7 steps) and a 39% overall yield from known butnot commercially available starting materials.

As part of an ongoing program focussing on naturalproducts with unique biological activities, we have devel-oped a concise and efficient asymmetric synthesis of mupir-ocin H. Our route starts from commercially available (+)-(R)-Roche ester (2), and follows the design shown in retro-synthetic format in Scheme 1. The salient features of thestrategy include a Sharpless asymmetric epoxidation and abase-catalysed enantioselective epoxide-opening protocol to

S. Sengupta, T. SimFULL PAPERintroduce the C-3–C-5 triol array in fragment B, and aBrown crotylboration process to prepare the blocked meth-ylpentenol fragment A. Coupling of these two fragmentswas accomplished using a Grubbs cross-metathesis reactionto generate a key E-olefin intermediate, and a cobalt-cata-lysed, diastereoselective Reformatsky reaction was used to

Scheme 1. TBS = tert-butyldimethylsilyl; TBDPS = tert-butyldi-phenylsilyl.

Scheme 2. 2,2-DMP = 2,2-dimethoxypropane; PTSA = p-toluenesulfonic acid.

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form the β-hydroxy ester that serves as the precursor of theγ-lactone moiety in the target compound. This route for thepreparation of mupirocin H is much more efficient thanthose reported previously.

Results and Discussion

The sequence developed for the synthesis of fragment B,which serves as an important intermediate in the route tomupirocin H, began with conversion of commercially avail-able (+)-(R)-Roche ester 2 into monoprotected diol 3 byprotection of the alcohol and reduction of the ester (77%over two steps; Scheme 2).[6] Swern oxidation[7] of the pri-mary alcohol in 3, followed by two-carbon Wittig elong-ation[8] produced intermediate α,β-unsaturated ester 4 (E/Z= 98:2; 84% over two steps). Chemoselective reduction of4 using DIBAL-H (diisobutylaluminium hydride)[9] thengave the corresponding allylic alcohol (i.e., 5)[9d,9e] (95%),which underwent Sharpless asymmetric epoxidation[10]

using (–)-DIPT (diisopropyl tartrate), Ti(OiPr)4 (TIP), andTBHP (tert-butyl hydroperoxide) in CH2Cl2 at –20 °C togive an inseparable mixture of diastereomeric epoxyalcohols 6 (87%, dr = 4:1; determined by 1H and 13C NMRspectroscopy). Regioselective opening of the epoxide ring in6 using NaOH in DMSO yielded triol 7 (78 %),[11] and en-abled separation of the minor undesired diastereomer. Se-lective monoprotection of the primary alcohol group in en-antiomerically and diastereomerically pure triol 7 was car-ried out using TBDPSCl to generate diol 8 (90%), which

A Concise Synthesis of Mupirocin H

was then transformed to acetonide 9 (96%). Finally, re-moval of the benzyl protecting group in 9 by hydrogenolysis(Pd/C in EtOAc) yielded primary alcohol 10 (92 %). Ph3P/I2 in diethyl ether was used to transform the primaryalcohol moiety in 10 into the corresponding iodide, which,without purification, was subjected to a vinyl Grignard cou-pling reaction[12] in presence of CuI to give fragment B(75% over two steps).

Fragment A, with a simple 3-methylpent-1-en-4-ol struc-ture, was constructed using a Brown crotylboration reaction(Scheme 3). In this process, trans-2-butene was metallatedusing a modification of the Schlosser procedure involvingtreatment with potassium tert-butoxide and n-butyllithium(THF at –45 °C). (E)-Crotylpotassium, generated in thismanner, was first treated with (–)-B-methoxydiisopinocam-phenylborane (Ipc2BOMe) at –78 °C in Et2O, and then withacetaldehyde. The resulting addition reaction produced en-antiomerically pure threo-3-methyl-4-penten-2-ol, whosesecondary alcohol moiety was protected using TBSCl withimidazole to generate fragment A (60% over two steps).[13]

Scheme 3.

We next focussed on joining fragments A and B using aGrubbs cross-metathesis (CM) process. Earlier studies ofCM[14] reactions have demonstrated that Grubbs’ 2nd gener-ation catalyst would be appropriate for this reaction. Anexamination of the process showed that CM between frag-ments A and B with 5 mol-% catalyst did not take place inCH2Cl2, even at reflux, but that reactions in both benzeneand toluene occurred efficiently to produce the desired E-alkene 11 (Table 1). A higher yield of 11 was achieved whentoluene rather than benzene was used as solvent with a cat-alyst loading of 5–10 mol-%, and the optimal reaction tem-perature was determined to be 110 °C. Consequently, forthe most efficient CM reaction of fragments A and B toform 11 (90%, 95:5 E/Z) a solution of the reactants andGrubbs II catalyst was heated in refluxing toluene at 110 °Cfor 24 h.

Owing to its volatility and homo-cross-metathesis issues,fragment A was used in a sevenfold excess over fragment B.Pure E-11, obtained using silica gel column chromatog-raphy was then subjected to selective TBDPS-group re-moval using NH4F in MeOH to liberate the primaryalcohol moiety in 12 (85 %). DMP (Dess–Martinperiodinane) oxidation of 12 formed the corresponding al-dehyde, which, without purification, was submitted to Re-formatsky reaction with ethyl α-bromoacetate. As data inTable 2 shows, reaction of the freshly prepared aldehydewith ethyl α-bromoacetate using activated Zn and freshlyprepared Zn–Cu couple[15] resulted in the formation of un-

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Table 1. Screening of the cross-metathesis reaction[a] between frag-ments A and B using Grubbs’ 2nd generation catalyst.

Entry Catalyst loading [mol-%] Solvent Yield[b] [%]

1 5 CH2Cl2 no reaction2 15 CH2Cl23 5 benzene 71%4 15 benzene 74%6 5 toluene 82%7 10 toluene 90%8 15 toluene 90%

[a] All reactions were carried out under reflux for 24 h. [b] Isolatedyields.

wanted by-products (Table 2, entries 1 and 2). In addition,a reaction with lithium diisopropyl amide and EtOAc,[16]

and a CrCl2/LiI-catalysed Reformatsky reaction[17] wereboth sluggish, and a significant amount of unreacted alde-hyde was recovered in both cases (Table 2, entries 3 and 4).SmI2-mediated Reformatsky reaction[18] of the substrates at–78 °C generated the desired β-hydroxy ester (i.e., 13) withmodest efficiency, but with an unsatisfactory level of dia-stereoselectivity (Table 2, entry 5).

Table 2. Trial Reformatsky reactions and aldol reaction to form β-hydroxy ester 13.

[a] Isolated yields over two steps. [b] Diastereomeric ratio was de-termined by 1H NMR spectroscopic analysis of the crude reactionmixtures. LHMDS = lithium hexamethyldisilazide; DIPEA = diiso-propylethylamine.

As a result of these problems, we explored the cobalt-trimethylphosphine-catalysed Reformatsky process[19] de-scribed by Orsini et al.[20] Treatment of a sub-stoichiometricamount (5:1 molar ratio of the organic reagents to cobalt)of in-situ-generated [Co{P(CH3)3}4] with the aldehyde de-rived from 12 and ethyl bromoacetate led to the productionof 13 in high yield (68% over two steps) and with highdiastereoselectivity (9:1; Table 2, entry 6). It should benoted that the use of chiral auxiliaries is not effective inpromoting higher levels of diastereoselectivity in cobalt-cat-

S. Sengupta, T. SimFULL PAPER

Scheme 4.

alysed Reformatsky reactions.[21] Moreover, an attempt toincrease the diastereoselectivity by using an acetate aldolreaction[22] following Crimmins’ procedure was not success-ful (Table 2, entry 7). The assignment of the relative stereo-chemistry[20b] of 13 was aided by 1H NMR spectroscopicdata, but ultimately it was made based on the use of thissubstance to complete the synthesis of mupirocin H.

In the final stage of the synthesis, key intermediate 13was subjected to simultaneous removal of the acetonide andTBS ether groups using HCl in MeOH (Scheme 4). Thisprocess, carried out at 60 °C was accompanied by lactone-ring formation, and, as a result, produced mupirocin H (1)in 60 % yield. The analytical data (1H and 13C NMR spec-troscopy, IR spectroscopy, HRMS) and optical rotation ofsynthetic 1 are in full agreement with those reported for thesubstance isolated from the natural source.[4,5]

Conclusions

The route developed for the synthesis of mupirocin H isshort and highly efficient in terms of number of syntheticsteps and overall yield (16 steps in its longest linear se-quence, 17 steps overall, and 10.1% overall yield from com-mercially available starting materials). Moreover, the sim-plicity of the strategy should enable it to be used for thelarge-scale production of mupirocin H. Finally, the conver-gent strategy developed in this investigation, relying on aGrubbs cross-metathesis process, should be applicable tothe synthesis of other members of the mupirocin family,including mupirocin W, the thiomarinols, and the pseu-domonic acids.

Experimental SectionGeneral Remarks: All reactions were carried out under an inertatmosphere of argon or nitrogen using standard syringe, septa, andcannula techniques unless otherwise mentioned. Reactions weremonitored by TLC using precoated silica gel plates (E. Merck, 60F254, 0.25 mm). TLC plates were visualized using a UV lamp, orusing ninhydrin or p-anisaldehyde stains. Commercially available


reagents were used without further purification. All solvents werepurified by standard techniques. Reaction products were purifiedby silica gel column chromatography using Kieselgel 60 Art. 9385(230–400 mesh). The purity of all compounds was �95% and wasanalysed using a Waters LCMS system (Waters 2998 PhotodiodeArray Detector, Waters 3100 Mass Detector, Waters SFO SystemFluidics Organizer, Waters 2545 Binary Gradient Module, WatersReagent Manager, Waters 2767 Sample Manager) with a Sun-FireTM C18 column (4.6�50 mm, 5 μm particle size) [solvent gra-dient: 60% (or 95%) A at 0 min, 1% A at 5 min. Solvent A: 0.035 %TFA in H2O; Solvent B: 0.035% TFA in MeOH; flow rate: 3.0 (or2.5) mL/min]. 1H and 13C NMR spectra were obtained using aBruker 400 MHz NMR (400 MHz for 1H, and 100 MHz for 13C)spectrometer. Chemical shifts were calibrated to the CHCl3 (δ =7.26 ppm) signal for 1H NMR spectra, and the CDCl3 (δ =77.0 ppm) signal for 13C NMR spectra. Infrared spectra were mea-sured with an FTIR Nicolet iS10 spectrometer. Samples were re-corded neat or as KBr discs. High-resolution mass spectra (HRMS)were recorded with a QTOF mass spectrometer. Optical rotationswere measured with a Rudolph Autopol III polarimeter at thewavelength of sodium d-line (589 nm) at room temperature.

Ethyl (E,4S)-5-(Benzyloxy)-4-methyl-2-pentenoate (4): DMSO(3.54 mL, 49.8 mmol) was added to a cold (–78 °C) solution ofoxalyl chloride (3.56 mL, 41.5 mmol) in CH2Cl2 (50 mL). The mix-ture was stirred for 10 min at –78 °C, then a solution of primaryalcohol 3 (5.0 g, 27.7 mmol) in CH2Cl2 (50 mL) was added drop-wise. The solution was stirred for 15 min at the same temperature,and then Et3N (23.2 mL, 166.2 mmol) was added dropwise. Thereaction mixture was stirred at that same temperature for 45 min,then it was poured into saturated aqueous NH4Cl solution(50 mL). The organic phase was separated and washed with satu-rated aqueous NaHCO3 solution (20 mL). The aqueous phase waswashed with CH2Cl2 (3� 50 mL), and the combined organic ex-tracts were dried with MgSO4, and concentrated in vacuo. Thecrude aldehyde was submitted to the C2 Wittig reaction withoutany further purification.

A solution of the crude aldehyde in CH2Cl2 was treated with C2

Wittig ylide (13.1 g, 37.7 mmol), and the mixture was stirred for6 h at room temperature. After TLC showed that the reaction wascomplete, the organic phase was washed with H2O (30 mL), thelayers were separated, and the aqueous layer was extracted withCH2Cl2 (3� 30 mL). The combined organic extracts were washedwith brine, dried with MgSO4, and concentrated under reduced


pressure. The resulting crude product was purified by silica gel col-umn chromatography (EtOAc/hexane, 1:10) to give compound 4(5.7 g, 84% over two steps) as a yellow oil. Rf = 0.2 (EtOAc/hexane,1:9). [α]D25 = –4.9 (c = 1.15, CHCl3). 1H NMR (400 MHz, CDCl3):δ = 7.37–7.26 (m, 5 H), 6.94 (dd, J = 15.8, 7.0 Hz, 1 H), 5.88 (dd,J = 15.8, 1.4 Hz, 1 H), 4.51 (s, 2 H), 4.18 (q, J = 7.1 Hz, 2 H),3.44–3.36 (m, 2 H), 2.70–2.61 (m, 1 H), 1.29 (t, J = 7.1 Hz, 3 H),1.08 (d, J = 6.7 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =166.6, 151.0, 138.1, 128.3, 127.5, 127.4, 120.9, 73.8, 73.0, 60.1, 36.7,15.9, 14.2 ppm. HRMS (ESI): calcd. for C15H20O3Na [M + Na]+

271.1310; found 271.1317.

(E,4S)-5-(Benzyloxy)-4-methyl-2-penten-1-ol (5): DIBAL-H (20%solution in toluene; 64.5 mL, 90 mmol) was added slowly over15 min to a cooled (0 °C) solution of 4 (11 g, 44.35 mmol) in anhy-drous CH2Cl2 (120 mL). The reaction mixture was stirred for 1 hat 0 °C, then it was quenched with methanol (3 mL) and saturatedaqueous sodium potassium tartarate solution (50 mL). The mixturewas passed through a small pad of Celite. The organic layer wasseparated, and the aqueous layer was extracted with CH2Cl2 (3�

50 mL). The combined organic extracts were dried with MgSO4,and concentrated under reduced pressure. The residue was purifiedby silica gel column chromatography (EtOAc/hexane, 1:4) to giveallylic alcohol 5 (8.67 g, 95%) as a colourless liquid. Rf = 0.4(EtOAc/hexane, 3:7). [α]D26 = –3.5 (c = 1.10, CHCl3). IR (Neat): ν̃= 3444, 2925, 2856, 1637, 1094, 756, 698 cm–1. 1H NMR(400 MHz, CDCl3): δ = 7.38–7.26 (m, 5 H), 5.71–5.64 (m, 2 H),4.51 (s, 2 H), 4.10–4.09 (m, 2 H), 3.41–3.29 (m, 2 H), 2.57–2.47 (m,1 H), 1.03 (d, J = 6.7 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3):δ = 138.3, 134.9, 128.8, 128.2, 127.5, 127.4, 74.9, 72.8, 63.4, 36.7,16.8 ppm. HRMS (ESI): calcd. for C13H18O2Na [M + Na]+

229.1204; found 229.1203.

(2R,3R)-3-[(1R)-2-(Benzyloxy)-1-methylethyl]oxiran-2-ylmethanol(6): Ti(OiPr)4 (2.44 mL, 8.25 mmol) and TBHP (5 m in toluene;16.5 mL, 82.52 mmol) were sequentially added to a solution of(–)-DIPT (1.72 mL, 8.25 mmol) in dry CH2Cl2 (100 mL) at –30 °Ccontaining molecular sieves (4 Å; 3.5 g). The reaction mixture wasstirred for 30 min, then a solution of alcohol 5 (8.5 g, 41.26 mmol)in CH2Cl2 (30 mL) was added. The mixture was then stirred for anadditional 12 h at –30 °C. The reaction mixture was quenched withwater (45 mL) and NaOH solution (30% aq.) saturated with NaCl(20 mL), and the resulting mixture was stirred vigorously for anadditional 30 min at room temperature. The mixture was then vac-uum filtered through a pad of Celite, and the filter cake was washedwith CH2Cl2 (100 mL). The organic phase was separated, and theaqueous phase was extracted with CH2Cl2 (3� 100 mL). The com-bined organic extracts were washed with brine, dried with MgSO4,and concentrated under reduced pressure. The resulting crudeproduct was purified by silica gel column chromatography (EtOAc/hexane, 3:7) to give compound 6 (7.96 g, 87%) as a viscous liquid.Rf = 0.3 (EtOAc/hexane, 3:7). [α]D25 = +20.5 (c = 0.83, CHCl3). IR(Neat): ν̃ = 3442, 1638, 1455, 1365, 1092, 741, 699 cm–1. 1H NMR(400 MHz, CDCl3, data for major diastereomer): δ = 7.36–7.27 (m,5 H), 4.53 (d, J = 1.5 Hz, 2 H), 3.92–3.86 (m, 1 H), 3.60 (dd, J =12.4, 3.8 Hz, 1 H), 3.52–3.41 (m, 2 H), 3.00 (m, 1 H), 2.96 (dd, J

= 6.9, 2.4 Hz, 1 H), 1.85–1.68 (m, 2 H), 1.01 (d, J = 7.0 Hz, 3 H)ppm. 13C NMR (100 MHz, CDCl3, data for major diastereomer):δ = 138.4, 128.4, 128.3, 127.5, 127.4, 73.1, 72.5, 61.8, 57.7, 56.9,35.7, 13.3 ppm. HRMS (ESI): calcd. for C13H18O3Na [M + Na]+

245.1154; found 245.1157.

(2S,3R,4R)-5-(Benzyloxy)-4-methylpentane-1,2,3-triol (7): NaOH(0.5 n; 10 mL) was added to a solution of epoxy alcohol 6 (5 g,22.5 mmol) in 1,4-dioxane (30 mL). The mixture was stirred under


reflux for 12 h, then it was cooled to room temperature, and con-centrated to a volume of 15 mL. The mixture was diluted withCH2Cl2 (60 mL), and the layers were separated. The aqueous phasewas extracted with CH2Cl2 (3� 50 mL), and the combined organicextracts were washed with brine, dried with MgSO4, and filteredthrough a pad of Celite. The filtrate was concentrated under re-duced pressure, and the resulting crude product was purified bysilica gel column chromatography (EtOAc/hexane, 1:1) to give com-pound 7 (4.2 g, 78%) as a viscous liquid. Rf = 0.2 (EtOAc/hexane,1:1). [α]D27 = –7.1 (c = 1.62, CHCl3). IR (KBr): ν̃ = 3405, 1652,1073 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.38–7.24 (m, 5 H),4.52 (s, 2 H), 3.82–3.72 (m, 2 H), 3.70–3.63 (m, 2 H), 3.63–3.53 (m,2 H), 2.65 (br. s, 3 H), 2.13–2.04 (m, 1 H), 0.98 (d, J = 7.0 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3): δ = 137.4, 128.5, 127.8,127.7, 76.5, 73.5 73.1, 72.2, 63.6, 34.9, 14.2 ppm. HRMS (ESI):calcd. for C13H20O4Na [M + Na]+ 263.1260; found 263.1260.

(2S,3R,4R)-5-(Benzyloxy)-1-(tert-butyldiphenylsilyloxy)-4-methyl-pentane-2,3-diol (8): Imidazole (1.70 g, 25.0 mmol) and TBDPS-Cl(5.50 g, 19.9 mmol) were added to a stirred solution of triol 7(4.0 g, 16.66 mmol) in dry CH2Cl2 (50 mL) at 0 °C, and the reac-tion mixture was stirred at room temperature for 30 min. After thereaction was complete, the reaction mixture was diluted withCH2Cl2 (20 mL) and washed with water (10 mL) and brine(10 mL), dried with anhydrous MgSO4, and filtered through a padof Celite. The filtrate was concentrated under reduced pressure, andthe resulting crude product was purified by silica gel columnchromatography (EtOAc/hexane, 3:7) to give compound 8 (7.56 g,95 %) as a colourless liquid. Rf = 0.2 (EtOAc/hexane, 3:7). [α]D27 =+0.7 (c = 0.66, CHCl3). IR (KBr): ν̃ = 3484, 2959, 2930, 2857,1471, 1427, 1112, 1028, 823 cm–1. 1H NMR (400 MHz, CDCl3): δ= 7.68–7.66 (m, 4 H), 7.46–7.36 (m, 6 H), 7.35–7.26 (m, 5 H), 4.49(s, 2 H), 3.85 (d, J = 5.5 Hz, 2 H), 3.73–3.67 (m, 1 H), 3.63–3.57(m, 3 H), 3.19 (d, J = 5.6 Hz, 1 H), 3.10 (d, J = 4.9 Hz, 1 H), 2.12–2.03 (m, 1 H), 1.07 (s, 9 H), 1.01 (d, J = 7.1 Hz, 3 H) ppm. 13CNMR (100 MHz, CDCl3): δ = 137.6, 135.5, 132.9, 132.8, 129.8,128.4, 127.7, 127.6, 76.1, 73.4, 72.6, 72.1, 65.7, 34.5, 26.8, 19.1,14.6 ppm. HRMS (ESI): calcd. for C29H38O4SiNa [M + Na]+

501.2437; found 501.2436.

({(4S,5R)-5-[(R)-1-(Benzyloxy)propan-2-yl]-2,2-dimethyl-1,3-di-oxolan-4-yl}methoxy)(tert-butyl)diphenylsilane (9): 2,2-Dimeth-oxypropane (3.8 mL, 30 mmol) and PTSA (catalytic amount) weresuccessively added to a stirred solution of compound 8 (5.0 g,10.46 mmol) in CH2Cl2 (30 mL) at room temperature. The reactionmixture was stirred for 30 min at room temperature, then it wasquenched with saturated aqueous NaHCO3 (10 mL). The mixturewas diluted with CH2Cl2 (30 mL). The aqueous layer was extractedwith CH2Cl2 (3� 30 mL), and the combined organic extracts weredried with MgSO4, and filtered through a pad of Celite. The filtratewas concentrated under reduced pressure, and the resulting crudeproduct was purified by silica gel column chromatography (EtOAc/hexane, 1:20) to give compound 9 (5.2 g, 96%) as a colourless li-quid. Rf = 0.6 (EtOAc/hexane, 1:9). [α]D24 = +9.3 (c = 0.72, CHCl3).IR (KBr): ν̃ = 2931, 2857, 1495, 1428, 1274, 1112, 1071, 824 cm–1.1H NMR (400 MHz, CDCl3): δ = 7.71–7.66 (m, 4 H), 7.44–7.35(m, 6 H), 7.34–7.23 (m, 5 H), 4.50 (q, J = 12.0 Hz, 2 H), 4.19 (q,J = 5.4 Hz, 1 H), 3.98 (dd, J = 10.0, 5.3 Hz, 1 H), 3.80 (dd, J =10.8, 6.1 Hz, 1 H), 3.63 (dd, J = 9.2, 3.4 Hz, 1 H), 3.60 (dd, J =10.8, 5.3 Hz, 1 H), 3.46 (dd, J = 9.0, 6.9 Hz, 1 H), 2.15–2.03 (m, 1H), 1.32 (d, J = 6.3 Hz, 6 H), 1.08 (s, 9 H), 1.06 (d, J = 6.8 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3): δ = 139.1, 135.7, 135.6,133.6, 133.5, 129.6, 128.2, 127.7, 127.4, 127.3, 107.6, 79.3, 78.3,73.2, 73.1, 63.4, 33.1, 28.2, 26.9, 25.7, 19.2, 14.9 ppm. HRMS

S. Sengupta, T. SimFULL PAPER(ESI): calcd. for C32H42O4SiNa [M + Na]+ 541.2750; found541.2756.

(2R)-2-{(4R,5S)-5-[(tert-Butyldiphenylsilyloxy)methyl]-2-methyl-1,3-dioxolan-4-yl}propan-1-ol (10): Palladium on activated carbon(10 wt.-%; 200 mg) was added to a solution of benzyl ether 9 (5.0 g,9.65 mmol) in ethyl acetate (20 mL) under a nitrogen atmosphere.The reaction mixture was flushed with nitrogen, and then stirredunder a hydrogen atmosphere for 6 h until the consumption of thestarting material was complete. The reaction mixture was dilutedwith diethyl ether (60 mL), and filtered through a pad of Celite.The filtrate was concentrated under reduced pressure, and the re-sulting crude product was purified by silica gel column chromatog-raphy (EtOAc/hexane, 1:5) to give compound 10 (3.80 g, 92%) asa colourless oil. Rf = 0.3 (EtOAc/hexane, 1:4). [α]D25 = –40.9 (c =1.75, CHCl3). IR (KBr): ν̃ = 3448, 2931, 2857, 1472, 1427, 1112,1070, 824 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.69–7.66 (m, 4H), 7.46–7.36 (m, 6 H), 4.25–4.21 (m, 1 H), 3.97 (dd, J = 10.2,5.3 Hz, 1 H), 3.79 (dd, J = 10.8, 7.0 Hz, 1 H), 3.67–3.57 (m, 2 H),3.55 (dd, J = 10.8, 4.5 Hz, 1 H), 2.84 (dd, J = 9.0, 2.6 Hz, 1 H),2.23–2.10 (m, 1 H), 1.34 (s, 6 H), 1.06 (s, 9 H), 0.91 (d, J = 6.6 Hz,3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 135.6, 135.5, 133.2,133.1, 129.7, 127.7, 108.2, 82.9, 78.3, 68.1, 63.1, 34.2, 28.1, 26.8,25.7, 19.1, 14.1 ppm. HRMS (ESI): calcd. for C25H36O4SiNa [M +Na]+ 451.2281; found 451.2271.

tert-Butyl({(4S,5R)-2,2-dimethyl-5-[(R)-pent-4-en-2-yl]-1,3-dioxol-an-4-yl}methoxy)diphenylsilane (Fragment B): Triphenylphosphine(1.46 g, 5.59 mmol), imidazole (475 mg, 6.99 mmol), and then io-dine (1.89 g, 7.46 mmol) were added successively to a solution ofalcohol 10 (2.0 g, 4.66 mmol) in diethyl ether (20 mL) at 0 °C. Thereaction mixture was stirred for 6 h at 0 °C, then it was quenchedwith saturated aqueous sodium thiosulfate solution (10 mL), anddiluted with Et2O (30 mL). The aqueous layer was extracted withEt2O (3� 30 mL). The combined extracts were dried with MgSO4,filtered, and concentrated under reduced pressure. to give the crudeiodo compound as a colourless liquid. This was used for the nextGrignard reaction without any further purification.

Vinyl Grignard (1 m in THF; 14 mL) was slowly added to a suspen-sion of CuI (895 mg, 4.66 mmol) in diethyl ether (20 mL) at 0 °C.The resulting mixture was stirred for 30 min, and then a solutionof the crude iodo compound in Et2O (20 mL) was added slowly at0 °C. The reaction mixture was stirred for 5 h at the same tempera-ture, and then it was quenched with saturated NH4Cl solution(10 mL). The reaction mixture was diluted with EtOAc (30 mL),and the aqueous layer was extracted with EtOAc (3� 30 mL). Thecombined organic extracts were washed with brine, dried withMgSO4, filtered, and concentrated under reduced pressure. The re-sulting crude product was purified by silica gel column chromatog-raphy (EtOAc/hexane, 1:25) to give fragment B (1.53 g, 75% overtwo steps) as a colourless liquid. Rf = 0.8 (EtOAc/hexane, 1:9).[α]D25 = –13.1 (c = 0.75, CHCl3). IR (KBr): ν̃ = 2983, 2959, 2931,2857, 1428, 1379, 1275, 1112, 1072, 914 cm–1. 1H NMR (400 MHz,CDCl3): δ = 7.69–7.64 (m, 4 H), 7.46–7.35 (m, 6 H), 5.83–5.70 (m,1 H), 5.07–4.97 (m, 2 H), 4.24–4.15 (m, 1 H), 3.85–3.75 (m, 2 H),3.55 (dd, J = 10.8, 5.0 Hz, 1 H), 2.47–2.41 (m, 1 H), 1.99–1.84 (m,2 H), 1.33 (d, J = 9.0 Hz, 6 H), 1.05 (s, 9 H), 0.89 (d, J = 6.4 Hz,3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 136.1, 135.6, 135.5,133.4, 133.2, 129.6, 127.6, 116.5, 107.4, 81.5, 78.2, 63.3, 38.1, 31.5,27.1, 26.8, 25.7, 19.1, 16.2 ppm. HRMS (ESI): calcd. for C27H38O3-SiNa [M + Na]+ 461.2488; found 461.2500.

tert-Butyldimethyl[(2S,3R)-3-methylpent-4-en-2-yloxy]silane (Frag-ment A): trans-2-Butene (12 mL, 120 mmol) was added by cannulato a solution of tBuOK (1.0 m in THF; 60 mL, 60 mmol) in THF


(100 mL) at –78 °C. The reaction mixture was stirred for 5 min,and then a cooled (–78 °C) solution of nBuLi (2.5 m in hexane;25 mL, 63 mmol) in THF (30 mL) was added slowly by cannula.The reaction mixture was warmed to –55 °C, stirred for 45 minand then recooled to –78 °C. A cooled (–40 °C) solution of (–)-Ipc2BOMe (23 g, 72 mmol) in THF (50 mL) was then slowly addedby cannula, and the mixture was stirred for 1 h at –78 °C. BF3·Et2O(1.23 mL, 10 mmol) was then added dropwise, and then a cooled(–78 °C) solution of acetaldehyde (10 g, 50 mmol) in THF (25 mL)was added dropwise by cannula. The reaction mixture was stirredat –78 °C for 4 h, and then NaOH solution (3 m aq.; 30 mL,85 mmol) and H2O2 (30% solution; 30 mL, 85 mmol) were addedslowly at –78 °C. The reaction mixture was warmed to room tem-perature and then heated at reflux for 4 h. The layers were thenseparated, and the aqueous layer was extracted with diethyl ether(3 � 70 mL). The combined organic extracts were washed withbrine (30 mL), dried with MgSO4, filtered, and concentrated invacuo. The resulting crude volatile allylic alcohol was directly pro-tected as its TBS ether.

Imidazole (3.57 g, 52.5 mmol) was added to a solution of the crudevolatile allylic alcohol in CH2Cl2 (100 mL) at 0 °C. The reactionmixture was stirred for 10 min, and then TBSCl (6.3 g, 42 mmol)was added slowly. The mixture was stirred for 6 h at room tempera-ture until the reaction was complete, and then it was quenched bythe addition of saturated NH4Cl solution (20 mL). The layers wereseparated, and the aqueous layer was extracted with EtOAc (3�

30 mL). The combined organic extracts were washed with brine,dried with MgSO4, filtered, and concentrated under reduced pres-sure. The resulting crude product was purified by silica gel columnchromatography (EtOAc/hexane, 1:30) to give fragment A (6.4 g,60% over two steps) as a colourless liquid. Rf = 0.8 (EtOAc/hexane,1:19). [α]D26 = +8.2 (c = 2.31, CHCl3). IR (KBr): ν̃ = 2944, 2929,2886, 2858, 1472, 1421, 1255, 1103, 1039, 912 cm–1. 1H NMR(400 MHz, CDCl3): δ = 5.85–5.74 (m, 1 H), 5.01–4.96 (m, 2 H),3.74–3.69 (m, 1 H), 2.21–2.12 (m, 1 H), 1.05 (d, J = 6.1 Hz, 3 H),0.99 (d, J = 6.9 Hz, 3 H), 0.89 (s, 9 H), 0.04 (s, 6 H) ppm. 13CNMR (100 MHz, CDCl3): δ = 141.1, 114.2, 71.7, 45.5, 25.9, 20.6,18.1, 15.5, –4.3, –4.8 ppm.

tert-Butyl({(4S,5R)-5-[(2R,6R,7S,E)-7-(tert-butyldimethylsilyloxy)-6-methyloct-4-en-2-yl]-2,2-dimethyl-1,3-dioxolan-4-yl}methoxy)di-phenylsilane (11): A solution of fragment B (300 mg, 0.7 mmol) inanhydrous toluene (2 mL) was added to a solution of fragment A(1 g, 4.67 mmol) in anhydrous toluene (0.5 mL) under N2. GrubbsII catalyst (60 mg, 10 mol-%) was added, and the mixture washeated for 24 h at 110 °C, and then concentrated under reducedpressure. The resulting crude product was purified by silica gel col-umn chromatography (EtOAc/hexane, 1:25) to give compound 11(393 mg, 90 %) as a colourless liquid. Rf = 0.8 (EtOAc/hexane,1:19). [α]D26 = –10.8 (c = 0.52, CHCl3). IR (KBr): ν̃ = 3071, 2958,2931, 2857, 1429, 1462, 1378, 1249, 1112, 1040, 836 cm–1. 1H NMR(400 MHz, CDCl3): δ = 7.70–7.67 (m, 4 H), 7.46–7.36 (m, 6 H),5.45–5.22 (m, 2 H), 4.24–4.14 (m, 1 H), 3.87–3.74 (m, 2 H), 3.74–3.66 (m, 1 H), 3.59–3.54 (m, 1 H), 2.41–2.30 (m, 1 H), 2.21–2.08(m, 1 H), 1.99–1.80 (m, 2 H), 1.34 (d, J = 7.1 Hz, 6 H), 1.06 (s, 9H), 1.03 (dd, J = 7.5, 6.2 Hz, 3 H), 0.98 (d, J = 6.9 Hz, 3 H), 0.95(d, J = 6.5 Hz, 3 H), 0.90 (s, 6 H) ppm. 13C NMR (100 MHz,CDCl3): δ = 135.6, 134.8, 133.5, 133.3, 129.6, 127.6, 107.4, 83.4,81.6, 78.2, 71.9, 63.3, 44.3, 31.9, 28.2, 26.8, 25.9, 25.8, 20.4, 19.9,19.2, 18.1, –4.8, –4.4 ppm. HRMS (ESI): calcd. for C37H60O4Si2Na[M + Na]+ 647.3928; found 647.3930.

{(4S,5R)-5-[(2R,6R,7S,E)-7-(tert-Butyldimethylsilyloxy)-6-methyl-oct-4-en-2-yl]-2,2-dimethyl-1,3-dioxolan-4-yl}methanol (12): NH4F


(145 mg, 3.85 mmol) was added to a stirred solution of 11 (300 mg,0.5 mmol) in anhydrous MeOH (2 mL) at 25 °C. The reaction mix-ture was stirred for 12 h at room temperature, then saturatedNH4Cl solution (4 mL) was added, and the mixture was concen-trated under reduced pressure. The concentrated reaction mixturewas diluted with EtOAc (10 mL). The layers were separated, andthe aqueous layer was extracted with EtOAc (3 � 10 mL). The com-bined organic extracts were washed with brine, dried with MgSO4,filtered, and concentrated under reduced pressure. The resultingcrude product was purified by silica gel column chromatography(EtOAc/hexane, 1:5) to give compound 12 (164 mg, 85 %) as acolourless oil. Rf = 0.3 (EtOAc/hexane, 1:4). [α]D24 = –21.2 (c = 1.3,CHCl3). IR (KBr): ν̃ = 3441, 2958, 2929, 2856, 1668, 1462, 1378,1251, 1064, 1034, 971 cm–1. 1H NMR (400 MHz, CDCl3): δ = 5.48–5.29 (m, 2 H), 4.18–4.08 (m, 1 H), 3.83 (q, J = 5.5 Hz, 1 H), 3.71–3.66 (m, 1 H), 3.62–3.56 (m, 2 H), 2.42–2.32 (m, 1 H), 2.19–2.07(m, 1 H), 2.05–1.98 (m, 1 H), 1.98–1.86 (m, 1 H), 1.47 (m, 3 H),1.36 (s, 3 H), 1.04 (d, J = 6.1 Hz, 3 H), 0.95 (d, J = 6.9 Hz, 3 H),0.88 (m, 12 H), 0.02 (s, 6 H) ppm. 13C NMR (100 MHz, CDCl3):δ = 135.2, 126.5, 108.1, 80.9, 77.7, 71.9, 61.5, 44.3, 36.9, 31.8, 28.5,25.8, 20.6, 18.1, 16.0, 15.7, –4.4, –4.8 ppm. HRMS (ESI): calcd. forC21H42O4SiNa [M + Na]+ 409.2750; found 409.2748.

(S)-Ethyl 3-((4S,5S)-5-{(2R,6R,7S,E)-7-[(tert-Butyldimethylsilyl)-oxy]-6-methyloct-4-en-2-yl}-2,2-dimethyl-1,3-dioxolan-4-yl)-3-hydroxypropanoate (13): Dess–Martin periodinane (65 mg,0.15 mmol) was added to a stirred solution of primary alcohol 12(43 mg, 0.11 mmol) in anhydrous CH2Cl2 (2 mL) at 0 °C. The reac-tion mixture was warmed to room temperature and stirred for30 min. The reaction mixture was then filtered through a small padof Celite, and the filtrate was washed with saturated NaHCO3 andbrine. The separated aqueous layer was extracted with CH2Cl2 (3�

10 mL). The combined organic extracts were dried with MgSO4,filtered, and concentrated under reduced pressure. The crude alde-hyde was used in the next step without any further purification.

Trimethylphoshine (1 m solution in THF; 0.04 mL) was added to amixture of activated magnesium turnings (20 mg) and anhydrousCOCl2 (2.5 mg, 0.02 mmol) in THF (0.2 mL) at room temperature.The reaction mixture was stirred for 3 h at room temperature, andthe yellow-brown colour of the low-oxidation-state cobalt complexdeveloped. The reaction mixture was then cooled to 0 °C and thentreated slowly with a THF solution (1 mL) containing ethyl bromo-acetate (0.05 mL, 0.5 mmol) and the freshly prepared aldehydefrom 12. The addition rate was modulated so as to preserve theoriginal brown colour and reduce to a minimum the time of devel-opment of the blue colour (CoII complex). Completion of the reac-tion was indicated by the persistence of the brown colour for a fewminutes (low-oxidation-state cobalt complex). After TLC showedthat the reaction was complete, the mixture was diluted with EtOAc(5 mL) and poured into crushed ice. The layers were separated, andthe aqueous layer was extracted with ethyl acetate (3� 10 mL).The combined organic extracts were dried with MgSO4, filtered,and concentrated under reduced pressure. The resulting crudeproduct was purified by silica gel column chromatography (EtOAc/hexane, 1:10) to give compound 13 (35 mg, 68% over two steps) asa pale yellow oil. Rf = 0.5 (EtOAc/hexane, 1:4). [α]D24 = –10.3 (c =0.9, CHCl3). IR (KBr): ν̃ = 3357, 2958, 2925, 2853, 1734, 1653,1634, 1457, 1373, 1255, 836 cm–1. 1H NMR (400 MHz, CDCl3): δ= 5.46–5.31 (m, 2 H), 4.17 (q, J = 7.1 Hz, 2 H), 4.10 (m, 1 H),3.97–3.90 (m, 1 H), 3.89–3.83 (m, 1 H), 3.73–3.67 (m, 1 H), 2.78(dd, J = 16.9, 2.4 Hz, 1 H), 2.51 (dd, J = 17.1, 8.9 Hz, 1 H), 2.35(m, 1 H), 2.18–2.09 (m, 1 H), 2.05–1.91 (m, 2 H), 1.39 (s, 3 H),1.32 (s, 3 H), 1.29–1.25 (m, 6 H), 1.03 (d, J = 6.1 Hz, 3 H), 0.95(d, J = 6.7 Hz, 3 H), 0.88 (s, 9 H), 0.03 (s, 6 H) ppm. 13C NMR


(100 MHz, CDCl3): δ = 173.6, 134.8, 127.2, 107.4, 82.0, 78.9, 71.9,66.8, 60.7, 44.2, 38.1, 36.9, 31.8, 27.7, 25.9, 25.4, 20.4, 18.1, 16.6,14.1, –4.4, –4.8 ppm. HRMS (ESI): calcd. for C25H48O6SiNa [M +Na]+ 495.3118; found 495.3120.

(4S,5S)-5-[(1R,2R,6R,7S,E)-1,7-Dihydroxy-2,6-dimethyloct-4-enyl]-4-hydroxydihydrofuran-2(3H)-one (mupirocin H, 1): Concd. HCl(0.1 mL) was added to ester compound 13 (20 mg, 0.04 mmol) inmethanol (2 mL) . The reaction mixture was stirred at 65 °C for8 h, then it was cooled to room temperature, and treated withCH2Cl2 (10 mL) and half-saturated aqueous NaCl solution(10 mL). The layers were separated, and the aqueous layer was ex-tracted with CH2Cl2 (3� 10 mL). The combined organic extractswere dried with MgSO4, filtered, and concentrated under reducedpressure. The resulting crude product was purified by silica gel col-umn chromatography (MeOH/CH2Cl2, 1:8) to give mupirocin H(1; 6.5 mg, 60%) as a colourless oil. Rf = 0.3 (SiO2, MeOH/chloro-form, 1:9). [α]D24 = +28.3 (c = 0.18, CHCl3) (ref.[4] [α]D24 = +30.5 (c= 1.3, CHCl3). IR (KBr): ν̃ = 3407, 2960, 2922, 2853, 1742, 1668,1457, 1376, 1259, 1195, 1070 cm–1. 1H NMR (400 MHz, CDCl3):δ = 5.60 (ddd, J = 14.9, 8.4, 6.0 Hz, 1 H), 5.38 (dd, J = 15.4, 8.6 Hz,1 H), 4.59 (m, 1 H), 4.41 (dd, J = 5.6, 3.4 Hz, 1 H), 3.58 (dd, J =6.6, 6.2 Hz, 1 H), 3.51 (m, 1 H), 2.93 (dd, J = 18.1, 7.5 Hz, 1 H),2.51 (dd, J = 18.1, 4.4 Hz, 1 H), 2.34–2.18 (m, 2 H), 2.10–1.99 (m,1 H), 1.93–1.84 (m, 1 H), 1.18 (d, J = 6.3 Hz, 3 H), 1.03 (d, J =7.0 Hz, 3 H), 0.98 (d, J = 6.8 Hz, 3 H) ppm. 13C NMR (100 MHz,CDCl3): δ = 175.3, 135.0, 129.5, 87.2, 75.7, 71.5, 68.8, 45.3, 38.2,35.4, 34.8, 20.7, 16.8, 16.0 ppm. HRMS (ESI): calcd. forC14H24O5Na [M + Na]+ 295.1521; found 295.1535.

Supporting Information (see footnote on the first page of this arti-cle): Copies of the 1H and 13C NMR spectra for all compounds.

Acknowledgments

This research was supported by the Korea Institute of Science andTechnology and the National Research Foundation of Korea (grantnumber NRF-2011-0028676 from the creative/challenging researchprogram, and grant number NRF-220-2011-1-C00042 from theglobal research network research program.

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Received: April 18, 2014Published Online: July 11, 2014

a concise synthesis of mupirocin h using a cross-metathesis-based strategy

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