DOI: 10.1002/ajoc.201300067

Total Synthesis of Both Spiroketal Diastereomers of the Reported Structureof Cephalosporolide H

Rodney A. Fernandes* and Mahesh B. Halle[a]

Introduction

The 5,5-spiroketal moiety is encountered in many naturalproducts, such as halichondrin B (1),[1a,b] symbiospirol A(2),[1c] ascospiroketal B (3)[1d] penisporolides A (4) and B(5)[1e] and cephalosporolides 6–8[1f,g] (Scheme 1).

The rigid spiroketal structure with various functionalgroups in the vicinity imposes great challenges in target-ori-ented stereoselective synthesis. Metal-mediated alkynediolspiroketalization and acid-catalyzed spiroketalization arecommon approaches in the synthesis of these molecules.The latter method offers approximately 1.5–2:1 mixtures ofspiroketal diastereomers.[2] A recent chelation-controlledepimerization approach to spiroketals that involves Zn saltsraised the selectivity to as high as a 20:1 diastereomericmixture and is praiseworthy.[3] Whereas the direct acid-cata-lyzed ketalization of suitably placed ketone and hydroxygroups occurs with moderate diastereoselectivity, it offersa rapid access to both spiroketal diastereomers, as they aremostly separable.[2] This approach is apparently attractivewhen both spiroketal diastereomers are natural products, asin the case of cephalosporolides E and F.[1g,2] A recent simi-lar approach involved silver(I)-promoted alkylation of hem-iacetals with moderate diastereoselectivity.[4] In continua-tion of our interest in total synthesis of natural productsand our recent synthesis[2a] of cephalosporolides E and F,we became interested in the synthesis of cephalosporoli-de H. The latter is isolated as a single spiroketal diastereo-mer from the lyophilized culture broth of the marine-de-rived fungus Penicillium sp.[1f] Cephalosporolide H is

a potent anti-inflammatory agent as it inhibits the enzyme3 a-hydroxysteroid dehydrogenase (3a-HSD).[5] Whereasthe related diastereomers, cephalosporolides E and F havebeen synthesized four times,[2,4,6] there is only one reportedsynthesis of both spiroketal diastereomers of the reportedstructure of cephalosporolide H, that by Dudley and co-workers.[3] Considering the mismatch of spectral data of thereported structure of natural cephalosporolide H and thesynthesized molecules, the authors suggested that the ste-reochemistry of the spiroketal should be revised in the nat-ural cephalosporolide H and related molecules. Herein, wereport the synthesis of both spiroketal diastereomers of thereported structure of cephalosporolide H.

Our retrosynthetic disconnection of both spiroketal dia-stereomers of cephalosporolide H, 6 a and 6 b, based ona late stage spiroketalization is shown in Scheme 2. The spi-roketalization precursor 9 could be derived through dihy-droxylation of 10. The latter can be deconstructed to cross-metathesis precursors 11 and 12 b. Compound 11 can be vi-sualized as being derived through sequential allylation reac-tions from n-octanal (14, through intermediate compound13).

Results and Discussion

The forward synthesis started from n-octanal (14) as depict-ed in Scheme 3. A modified asymmetric Keck�s allylation[7]

of octanal catalyzed by (S)-BINOL provided the homoallylalcohol 13 in 83 % yield and 95 % ee.[7c] Protection of thehydroxy group as the TBDMS ether (92 % yield) and sub-sequent hydroboration-oxidation gave the primary alcohol15 in 72 % yield. Further, Swern oxidation and allyl-Grignard addition gave homoallyl alcohol 11 in 82 % yield.

The cross-metathesis[8] of olefin 11 with ethyl 2,2-dime-thylbut-3-enoate (12 a) catalyzed by readily availableGrubbs� catalysts G-I, G-II and G-H-II failed to providethe corresponding product 16 a (Scheme 4). This could be

Keywords: asymmetric dihydroxy-lation · cephalosporolides · crossmetathesis · Keck�s allylation ·spiroketalization

Abstract: A total synthesis of both spiroketal diastereomers of the reportedstructure of cephalosporolide H is accomplished in 12 steps and 9 % overallyield. The key steps involve Keck�s allylation, cross metathesis (to get the de-sired b,g-unsaturated ester), Sharpless asymmetric dihydroxylation (to install theb-hydroxy-g-lactone moiety), and spiroketalization to access both spiroketal dia-stereomers of the reported structure of the natural product.

[a] Prof. R. A. Fernandes, M. B. HalleDepartment of ChemistryIndian Institute of Technology BombayPowai, Mumbai 400076, Maharashtra (India)Fax: (+91) 22-25767152E-mail : rfernand@chem.iitb.ac.in

Supporting information for this article is available on the WWWunder http://dx.doi.org/10.1002/ajoc.201300067.

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attributed to steric crowding in the vicinity of the olefinbond by the dimethyl group in 12 a. Hence, the cross meta-thesis was executed with 12 b catalyzed by Grubbs� secondgeneration (G-II) catalyst to provide the b,g-unsaturatedester 16 b in approximately a 7:1 ratio (E/Z by 1H NMRspectroscopy) in 75 % yield. Further 2-iodoxybenzoic acid(IBX) oxidation of 16 b to give ketone (95 % yield) and ke-

talization furnished 17 in 78 % yield. Subsequent asymmet-ric dihydroxylation of 17 cleanly afforded the g-lactone 18as a single diastereomer isolated in 75 % yield. The acid-catalyzed deprotection of the TBDMS ether and the ketalgroup resulted in trans-ketalization to give a diastereomericmixture of 19 a and 19 b, which were isolated in 33 % and55 % yields, respectively.[9]

To complete the synthesis, the a-gem dimethylation wasattempted on isolated 19 a with either lithium diisopropyla-mide (LDA) or lithium bis(trimethylsilyl)amide(LiHMDS).[10] All attempts to obtain the dimethylatedproduct were unsuccessful. A partial isomerization of 19 ato 19 b occurred, as the latter was isolated from the reactionmixture. This is possible through base-catalyzed opening ofthe central furan ring in I to give intermediate II and subse-quent ring closure involving conjugate addition (Scheme 4)to give the more stable diastereomer 19 b. We next attempt-ed the dimethylation on compound 18 as shown inScheme 5. The use of excess LDA (7 equiv.) and methyl

Scheme 1. Natural products containing the 5,5-spiroketal structure.

Scheme 2. Retrosynthesis for both spiroketal diastereomers of cephalo-sporolide H. TBDMS = tert-butyldimethylsilyl.

Scheme 3. Synthesis of homoallylalcohol 11. MS=molecular sieves.

Asian J. Org. Chem. 2013, 2, 593 – 599 � 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim594

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iodide (10 equiv.) gave mostly monomethylated compound20[11] in an optimized 72 % yield along with 21, which wasisolated in 14 % yield. Repeating the methylation reactionon isolated compound 20 now afforded the gem-dimethylat-ed product 21 in 75 % yield (based on 9 % recovery of un-reacted 20). Treatment of 21 with aq. 4 n HCl resulted indeprotection of the TBDMS and ketal groups with concom-itant trans-ketalization, which afforded the spiroketal dia-stereomers of cephalosporolide H, 6 a and 6 b, in 54 % and34 % isolated yield, respectively.[12] The 1H NMR, 13C NMR,and IR spectra of these compounds were in good agree-ment with those reported in the literature.[3a]

Comparison of NMR data and optical rotation of 6 a,[a]25

D =�4.6 (c 0.5, MeOH) (with the same stereochemistryas assigned to the natural isolate), to that of the naturalproduct, [a]25

D = ++57.6 (c 0.7, MeOH),[1f] indicated a com-plete mismatch. However this data matches with that re-ported by Dudley and co-workers,[3a] [a]25

D =�5 (c 0.7,MeOH) for the synthesized compound. The NMR data andoptical rotation of 6 b, [a]25

D = ++59.8 (c 0.5, MeOH) are ingood agreement with that of the natural isolate[1f] and thepreviously synthesized compound, [a]25

D = ++65 (c 0.5,MeOH).[3a]

Dudley and co-workers[3a] developed a strategy in whichthe diastereomeric diols that have the requisite stereochem-istry through chelation of metal salts across the two ringscontrol the stereochemistry at the spirocenter. Thus, thechelation between a free -OH group and the spiroketaloxygen of the adjacent ring will dominate steric effects anddetermine which diol diastereomer prevails in the chelation

Scheme 4. Cross metathesis, spiroketalization, and attempted a-gem dimethylation. Ts=4-toluenesulfonyl.

Scheme 5. Synthesis of spiroketal diastereomers of the reported struc-ture of cephalosporolide H. HMPA=hexamethylphosphoramide.

Asian J. Org. Chem. 2013, 2, 593 – 599 � 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim595

www.AsianJOC.org Rodney A. Fernandes and Mahesh B. Halle.

step. With this diastereoselective method to obtain the dia-stereomeric diol, they were still uncertain about the stereo-chemistry of the spirocenter. The stereochemical assign-ment for the spirocenter of the synthesized diastereomersby Dudley and co-workers[3a] was based on NMR correla-tions with the spiroketal resonances of cephalosporolides Eand F, for which X-ray crystallographic data is available.The synthesized compounds in this paper match in all re-spects with those synthesized by Dudley and co-workers.[3a]

However, the assignment of the correct structure and abso-lute stereochemistry to the isolated natural product is notpossible at this stage. By comparison of spectral data withthose of cephalosporolides E and F we also believe thatthere is a need to revise the reported structure of the natu-ral product and related molecules as suggested earlier byDudley and co-workers.[3a]

Conclusions

In summary, we have accomplished the total synthesis ofboth spiroketal diastereomers of the reported structure ofcephalosporolide H, 6 a and 6 b, starting from commerciallyavailable n-octanal by using Keck�s allylation, cross meta-thesis, asymmetric dihydroxylation, and spiroketalization asthe key steps. The synthesis was completed in 12 steps andan overall yield of 9 % for 6 a and 6 b. This study describesthe second synthesis of both spiroketal diastereomers ofcephalosporolide H and indicates that the spiroketal stereo-chemistry may need revision. The strategy can be readilyadopted for synthesis of related spiroketal natural products.

Experimental Section

General Information

Flasks were oven or flame dried and cooled in a desiccator. Anhydrousreactions were carried out under an atmosphere of Ar or N2. Solventsand reagents were purified by standard methods. Thin layer chromatog-raphy was performed on EM 250 Kieselgel 60 F254 silica gel plates. Thespots were visualized by staining with KMnO4 or by UV lamp. 1H NMRand 13C NMR spectra were recorded at 400 and 100 MHz, respectively,and chemical shifts are based on the tetramathylsilane (TMS) signal atd=0.00 pm for 1H NMR and the CDCl3 signal at d =77.00 ppm (t) for13C NMR. IR samples were prepared by evaporation from CHCl3 onCsBr plates or as KBr pallets. High-resolution mass spectra were ob-tained by positive electrospray ionization.

(4R)-Undec-1-en-4-ol (13)[7]

Ti ACHTUNGTRENNUNG(iPrO)4 (123 mg, 0.434 mmol, 1.25 mol %) was added to a mixture of(S)-(�)-BINOL (0.248 g, 0.868 mmol, 2.5 mol %) and activated 4 � mo-lecular sieves (0.7 g) in anhydrous toluene (65 mL). The reaction mix-ture was stirred at room temperature for 2.5 h and then cooled to�15 8C and allyltributyltin (17.21 g, 52.06 mmol, 1.5 equiv.) and n-octanal(14, 4.45 g, 34.71 mmol) were added. After 36 h at �15 8C, saturated aq.NaHCO3 (25 mL) was added, and the contents were stirred for 3 h. Thereaction mixture was filtered through a pad of Celite. The filtrate wasconcentrated and the crude material was purified by chromatography ona silica gel column with petroleum ether/EtOAc (4:1) as the eluent togive (R)-undec-1-en-4-ol (13, 4.49 g, 83%) as a colorless oil: [a]25

D = ++7.0(c= 0.6, CHCl3), lit. [7]; [a]27

D = ++ 6.9 (c =1.0, CHCl3); IR (CHCl3): n=

3402, 2929, 2857, 1641, 1466, 995, 916, 668 cm�1; 1H NMR (400 MHz,CDCl3/TMS): d=5.88–5.78 (m, 1H, 2-H), 5.16–5.10 (m, 2H, 1-H), 3.65–3.63 (m, 1H, 4-H), 2.33–2.27 (m, 1H, 3-Ha), 2.18–2.10 (m, 1H, 3-Hb),1.67 (br s, 1H, OH), 1.49–1.37 (m, 2H, 5-H), 1.37–1.29 (m, 10 H, 6-, 7-,8-, 9-, 10-H), 0.88 ppm (t, J =6.9 Hz, 3 H, 11-CH3); 13C NMR (100 MHz,CDCl3): d =134.9, 117.8, 70.6, 41.8, 36.7, 31.8, 29.6, 29.2, 25.6, 22.6,14.0 ppm.

(4R)-4-(tert-Butyldimethylsilyloxy)undecan-1-ol (15)[13]

Imidazole (0.240 g, 3.53 mmol, 1.2 equiv.) and TBDMSCl (0.665 g,4.41 mmol, 1.5 equiv.) were added to a solution of (R)-undec-1-en-4-ol(13, 0.5 g, 2.94 mmol) in CH2Cl2 (20 mL) at 0 8C and the mixture wasstirred for 12 h at room temperature. Water (5 mL) was added and thereaction mixture was extracted with CH2Cl2 (3 � 30 mL). The combinedorganic layers were washed with water and brine, then dried (Na2SO4)and concentrated. The crude product was purified by chromatographyon a silica gel column with petroleum ether/EtOAc (9:1) as the eluentto afford (R)-tert-butyldimethyl(undec-1-ene-4-yloxy)silane (0.768 g,92%) as a colorless oil: [a]25

D = ++12.7 (c =0.64, CHCl3), lit. [13]; [a]26D =

+13.6 (c=1.03, CHCl3); IR (CHCl3): n =3078, 2957, 2930, 2857, 1641,1472, 1362, 1256, 1075, 1005, 939, 913, 836, 808, 668 cm�1; 1H NMR(400 MHz, CDCl3/TMS): d =5.86–5.76 (m, 1H, 2-H), 5.05–5.00 (m, 2 H,1-H), 3.67 (quint, J=5.8 Hz, 1 H, 4-H), 2.24–2.16 (m, 2 H, 3-H), 1.43–1.36 (m, 2 H, 5-H), 1.33–1.26 (m, 10 H, 6-, 7-, 8-, 9-, 10-H), 0.89–0.87 (m,12H, 11-CH3, -CACHTUNGTRENNUNG(CH3)3), 0.041 ppm (s, 6 H, -Si ACHTUNGTRENNUNG(CH3)2); 13C NMR(100 MHz, CDCl3): d= 135.5, 116.5, 72.0, 41.9, 36.8, 31.9, 29.7, 29.3, 25.9,25.3, 22.7, 18.2, 14.1, �4.4, �4.5 ppm.

BH3·SMe2 (0.35 mL, 3.69 mmol, 1.5 equiv.) was added dropwise to a solu-tion of (R)-tert-butyldimethyl(undec-1-ene-4-yloxy)silane (0.7 g,2.46 mmol) in anhydrous THF (15 mL) at 0 8C. The solution waswarmed to room temperature and stirred for 3 h. EtOH (1 mL), aq.NaOH (4 n, 1 mL), and 30 % H2O2 (1 mL) were sequentially added at0 8C, then the reaction mixture was warmed to room temperature andstirred for additional 2 h. After evaporation of the volatiles, water(5 mL) was added and the solution was extracted with EtOAc (3 �30 mL). The combined organic layers were washed with brine, dried(Na2SO4), and concentrated. The residue was purified by chromatogra-phy on a silica gel column with petroleum ether/EtOAc (9:1) as theeluent to give alcohol 15 (0.535 g, 72%) as a colorless oil: [a]25

D =�4.2(c= 0.86, CHCl3); IR (CHCl3): n=3364, 3011, 2930, 2858, 1471, 1378,1256, 1051, 936, 837, 668 cm�1; 1H NMR (400 MHz, CDCl3/TMS): d=

3.74–3.69 (m, 1H, 4-H), 3.64–3.57 (m, 2H, 1-H), 2.19 (br s, 1 H, OH),1.65–1.60 (m, 2H, 3-H), 1.57–1.53 (m, 2 H, 2-H), 1.47–1.44 (m, 2H, 5-H),1.32–1.27 (m, 10H, 6-, 7-, 8-, 9-, 10-H), 0.89 (m, 12 H, 11-CH3, -CACHTUNGTRENNUNG(CH3)3),0.05 ppm (s, 6 H, -Si ACHTUNGTRENNUNG(CH3)2); 13C NMR (100 MHz, CDCl3): d =72.1, 63.2,36.5, 33.4, 31.8, 29.7, 29.3, 28.1, 25.9, 25.5, 22.6, 18.1, 14.1, �4.5 ppm;HRMS: m/z : calcd for C17H39O2Si: 303.2719 [M+H+]; found: 303.2719.ACHTUNGTRENNUNG(7R,4R/S)-7-(tert-Butyldimethylsilyloxy)tetradec-1-en-4-ol (11)

Oxalyl chloride (0.26 mL, 2.97 mmol, 1.5 equiv.) was gradually added toa solution of dimethyl sulfoxide (0.465 g, 5.95 mmol, 3.0 equiv.) inCH2Cl2 (25 mL) at �78 8C over a period of 2 min. After stirring for15 min, a solution of 15 (0.6 g, 1.98 mmol) in CH2Cl2 (10 mL) was addedand the reaction mixture stirred for 45 min. A solution of Et3N (1.1 mL,7.92 mmol, 4.0 equiv.) in CH2Cl2 (5 mL) was added and the reactionmixture was stirred for 30 min and then gradually warmed to room tem-perature over 1 h. After addition of water (30 mL), the organic layerwas separated and the aqueous layer extracted with CH2Cl2 (3 � 30 mL).The combined organic extracts were washed with water and brine, thendried (Na2SO4) and concentrated to give the crude aldehyde (0.530 g)which was used directly in the next reaction.

Allylmagnesium bromide (2.6 mL, 2.64 mmol, 1 m solution in Et2O) wasadded to a solution of above aldehyde in THF (20 mL) at 0 8C. The reac-tion mixture was stirred for 1 h at 0 8C and 1 h at room temperature. Sa-turated aq. NH4Cl was added and the mixture was extracted withEtOAc (3 � 30 mL). The combined organic layers were washed withbrine, dried (Na2SO4), and concentrated. The residue was purified bychromatography on a silica gel column with petroleum ether/EtOAc

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(4:1) as the eluent to give alcohol 11 (0.557 g, 82% yield) as a colorlessoil: IR (CHCl3): n =3377, 3019, 2928, 2852, 1733, 1602, 1454, 1043, 925,669 cm�1; 1H NMR data for both diastereomers with some peaks over-lapping, 1H NMR (400 MHz, CDCl3/TMS): d=5.89–5.78 (m, 2H, 2-H),5.16–5.10 (m, 4H, 1-H), 3.73–3.58 (m, 4H, 4-, 7-H), 2.33–2.12 (m, 4H, 3-H), 1.78 (br s, 2 H, OH), 1.65–1.50 (m, 8 H, 5-, 6-H), 1.50–1.41 (m, 4 H,8-H), 1.30–1.24 (m, 20H, 9-, 10-, 11-, 12-, 13-H), 0.90–0.86 (m, 24 H, 14-CH3, -C ACHTUNGTRENNUNG(CH3)3), 0.06 (s, 6H, -Si ACHTUNGTRENNUNG(CH3)2), 0.05 ppm (s, 6H, -Si ACHTUNGTRENNUNG(CH3)2);13C NMR (100 MHz, CDCl3): d=135.1, 134.9, 117.9, 117.6, 72.4, 72.1,71.1, 70.7, 42.0, 41.8, 36.8, 36.5, 33.2, 32.4, 32.2, 31.9, 31.8, 29.8, 29.7,29.3, 25.9, 25.86, 25.4, 25.3, 22.6, 18.1, 14.1, �4.46, �4.47, �4.53,�4.54 ppm; HRMS: m/z : calcd for C20H43O2Si: 343.3032 [M+H+];found: 343.3024.

(9R,6R/S,E)-Ethyl 9-(tert-butyldimethylsilyloxy)-6-hydroxyhexadec-3-enoate (16b)

Ethyl 3-butenoate (12 b, 0.333 g, 2.92 mmol, 5 equiv.) and Grubbs�-II cat-alyst (1 mg, 0.00117 mmol, 0.2 mol %) were added to a solution of 11(0.2 g, 0.584 mmol) in anhydrous and degassed CH2Cl2 (10 mL). Themixture was heated to reflux for 48 h in a nitrogen atmosphere and thencooled and concentrated. The residue was purified by chromatographyon a silica gel column with petroleum ether/EtOAc (4:1) as the eluentto give ester 16 b (0.187 g, 75 % yield) as a colorless oil: (1H NMR of iso-lated compound indicated a ca. 7:1, E/Z mixture): IR (CHCl3): n =3437,2951, 2930, 2857, 1735, 1642, 1464, 1371, 1256, 1159, 1031, 971, 939, 836,667 cm�1; 1H NMR data for major E diastereomer with some peaksoverlapping, (400 MHz, CDCl3/TMS): d=5.65–5.59 (m, 4 H, 3-,4-H),4.13 (q, J=7.1 Hz, 4H, -OCH2), 3.71–3.59 (m, 4H, 6-, 9-H), 3.05 (d, J =

6.3 Hz, 4H, 2-H), 2.28–2.12 (m, 4 H, 5-H), 1.58–1.42 (m, 16H, 7-, 8-, 10-,11-H), 1.27–1.23 (m, 22H, 12-, 13-, 14-, 15-H, -CH3), 0.91–0.86 (m, 24H,16-CH3, -CACHTUNGTRENNUNG(CH3)3), 0.05 (s, 6 H, -Si ACHTUNGTRENNUNG(CH3)2), 0.04 ppm (s, 6H, -Si ACHTUNGTRENNUNG(CH3)2);13C NMR (100 MHz, CDCl3): d=171.94, 171.9, 130.8, 130.7, 125.2, 124.9,72.3, 72.1, 71.2, 70.9, 60.62, 60.6, 40.6, 40.5, 38.1, 36.8, 36.6, 33.2, 32.4,32.2, 31.9, 31.8, 29.73, 29.7, 29.3, 25.9, 25.8, 25.4, 25.3, 22.6, 18.1, 14.14,14.1, �4.48, �4.54 ppm; HRMS: m/z : calcd for C24H49O4Si: 429.3400[M+H+]; found: 429.3391.ACHTUNGTRENNUNG(3R,E)-Ethyl 5-[2-(3-tert-butyldimethylsilyloxy)decyl-1,3-dioxolan-2-yl]pent-3-enoate (17)

IBX (0.185 g, 0.662 mmol, 1.5 equiv.) was added to a solution of 16b(0.190 g, 0.441 mmol) in EtOAc (10 mL) and the mixture was heated toreflux for 6 h. Then the reaction mixture was filtered through a pad ofsilica gel and the filtrate was concentrated. The residue was purified bychromatography on a silica gel column with petroleum ether/EtOAc(4:1) as the eluent to give the corresponding ketone (0.179 g, 95 %yield) as a colorless oil: [a]25

D =�4.7 (c =0.46, CHCl3); IR (CHCl3): n=

2956, 2930, 2857, 1740, 1717, 1646, 1588, 1464, 1407, 1373, 1302, 1256,1181, 1077, 1029, 972, 939, 837, 809, 775, 667 cm�1; 1H NMR (400 MHz,CDCl3/TMS): d=5.74–5.56 (m, 2H, 3-, 4-H), 4.15 (q, J =7.1 Hz, 2H,-OCH2), 3.80–3.73 (m, 1H, 9-H), 3.19 (d, J =5.5 Hz, 2 H, 5-H), 3.09 (d,J =5.5 Hz, 2 H, 2-H), 2.55–2.45 (m, 2H, 7-H), 1.81–1.72 (m, 1H, 8-Ha),1.65–1.62 (m, 1H, 8-Hb), 1.48–1.22 (m, 15 H, 10-, 11-, 12-, 13-, 14-, 15-H,-CH3), 0.99–0.89 (m, 12H, 16-CH3, -C ACHTUNGTRENNUNG(CH3)3), 0.04 (s, 3 H, -SiCH3),0.03 ppm (s, 3 H, -SiCH3); 13C NMR (100 MHz, CDCl3): d =208.9, 171.5,126.2, 126.1, 71.1, 60.6, 46.4, 37.92, 37.9, 37.0, 31.8, 30.2, 29.7, 29.2, 25.8,25.2, 22.6, 18.0, 14.1, 14.05, �4.47, �4.59 ppm; HRMS: m/z : calcd forC24H47O4Si: 427.3244 [M+H+]; found: 427.3235.

Ethylene glycol (0.650 g, 10.48 mmol, 30 equiv.) was added to a solutionof the above ketone (0.149 g, 0.35 mmol) and pTsOH (catalytic, 4 mg) inanhydrous benzene (30 mL) and the reaction mixture was heated toreflux for 48 h with removal of water though Dean–Stark apparatus.After cooling to room temperature, NaHCO3 (10 mg) was added andthe mixture was stirred for 15 min. Water (10 mL) was added and the or-ganic layer was separated. The aqueous layer was extracted with EtOAc(3 � 25 mL). The combined organic layers were washed with water andbrine, then dried (Na2SO4) and concentrated. The residue was purifiedby chromatography on a silica gel column with petroleum ether/EtOAc(4:1) as the eluent to give ester 17 (0.128 g, 78 % yield) as a colorless

oil: [a]25D = ++4.4 (c =0.3, CHCl3); IR (CHCl3): n =2956, 2929, 2856, 1739,

1635, 1464, 1370, 1305, 1256, 1160, 1076, 1034, 973, 836, 810, 774,666 cm�1; 1H NMR (400 MHz, CDCl3/TMS): d=5.75–5.52 (m, 2 H, 3-, 4-H), 4.13 (q, J =7.1 Hz, 2H, -OCH2), 3.96–3.85 (m, 4 H, -(OCH2)2), 3.64–3.58 (m, 1 H, 3’-H), 3.04 (d, J =6.1 Hz, 2H, 2-H), 2.35 (d, J =6.3 Hz, 2H,5-H), 1.70–1.23 (m, 19 H, 1’-, 2’-, 4’-, 5’-, 6’-, 7’-, 8’-, 9’-H, -CH3), 0.94–0.87 (m, 12H, 10’-CH3, -CACHTUNGTRENNUNG(CH3)3), 0.03 ppm (s, 6H, -Si ACHTUNGTRENNUNG(CH3)2);13C NMR (100 MHz, CDCl3): d=171.8, 129.0, 125.2, 111.1, 72.1, 65.0,60.5, 40.6, 38.2, 37.1, 32.7, 31.8, 30.6, 29.8, 29.3, 25.9, 25.3, 22.6, 18.1,14.2, 14.1, �4.4, �4.5 ppm; HRMS: m/z : calcd for C26H51O5Si: 471.3506[M+H+]; found: 471.3498.ACHTUNGTRENNUNG(4R,5R)-5-{2-[(R)-3-(tert-Butyldimethylsilyloxy)decyl]-1,3-dioxolan-2-yl}methyl-4-hydroxydihydrofuran-2(3H)-one (18)

tBuOH (0.4 mL) and water (1.4 mL) were added to a mixture ofK3Fe(CN)6 (0.263 g, 0.798 mmol, 3.0 equiv.), K2CO3 (0.110 g,0.798 mmol, 3.0 equiv.), MeSO2NH2 (25.3 mg, 0.266 mmol, 1.0 equiv.),hydroquinidine 1,4-phthalazinediyl diether ((DHQD)2PHAL, 2.1 mg,0.00266 mmol, 1.0 mol %), and K2OsO4·2H2O (0.4 mg, 0.00106 mmol,0.4 mol %). The mixture was stirred for 5 min and cooled to 0 8C in icebath. To the cooled mixture, a solution of the b,g-unsaturated ester 17(0.125 g, 0.266 mmol, 1.0 equiv.) in tBuOH (1 mL) was added. The reac-tion mixture was stirred at 0 8C for 12 h then at room temperature for6 h. The mixture was then quenched with solid Na2SO3 (20 mg) andstirred for 30 min. The solution was extracted with EtOAc (3 � 30 mL)and the combined organic layers were washed with KOH (10 mL, 1m),water (20 mL), and brine, then dried (Na2SO4) and concentrated. Theresidue was purified by chromatography on a silica gel column with pe-troleum ether/EtOAc (3:2) as the eluent to give the lactone 18 (91.3 mg,75% yield) as a colorless oil: [a]25

D = ++ 7.3 (c =0.24, CHCl3); IR(CHCl3): n= 3444, 2951, 2929, 2857, 1778, 1464, 1361, 1256, 1162, 1076,949, 836, 667 cm�1; 1H NMR (400 MHz, CDCl3/TMS): d= 4.61–4.56 (m,1H, 5-H), 4.39–4.30 (m, 1H, 4-H), 4.03–3.96 (m, 4H, -(OCH2)2), 3.66–3.63 (m, 1H, 3’-H), 3.45 (br s, 1 H, OH), 2.75 (dd, J=17.8, 5.8 Hz, 1 H, 3-Ha), 2.56 (d, J =17.8 Hz, 1H, 3-Hb), 2.40–2.26 (m, 2H, 1’’-CH2), 1.63–1.26 (m, 16H, 1’-, 2’-, 4’-, 5’-, 6’-, 7’-, 8’-, 9’-H), 0.88 (m, 12H, 10’-CH3,-C ACHTUNGTRENNUNG(CH3)3), 0.04 (s, 3 H, -SiCH3), 0.03 ppm (s, 3 H, -SiCH3); 13C NMR(100 MHz, CDCl3): d= 175.3, 110.3, 80.9, 71.6, 68.4, 64.6, 64.1, 37.6, 37.0,34.1, 32.2, 31.8, 31.1, 29.7, 29.3, 25.8, 25.3, 22.6, 18.1, 14.1, �4.4,�4.5 ppm; HRMS: m/z : calcd for C24H47O6Si: 459.3142 [M+H+]; found:459.3150.

(2R,3a’R,5R,6a’R)-5-Heptyltetrahydro-3 H,3’H-spiro[furan-2,2’-furo ACHTUNGTRENNUNG[3,2-b]furan]-5’ ACHTUNGTRENNUNG(3a’H)-one (19a) and (2S,3a’R,5R,6a’R)-5-heptyltetrahydro-3H,3’H-spiro[furan-2,2’-furo ACHTUNGTRENNUNG[3,2-b]furan]-5’ ACHTUNGTRENNUNG(3a’H)-one (19b)

Aqueous HCl (4 n, 0.3 mL) was added to a solution of 18 (90 mg,0.20 mmol) in CH3OH (3 mL) at 0 8C. The reaction mixture was warmedto room temperature and stirred for 3h. After evaporation of the vola-tiles, water (5 mL) was added and the solution was extracted withEtOAc (3 � 20 mL). The combined organic layers were washed withwater and brine, then dried (Na2SO4) and concentrated. The residue waspurified by chromatography on a silica gel column with petroleumether/EtOAc (3:2) as the eluent to give 19 a (18.3 mg, 33 %) as a colorlessoil. Further elution with petroleum ether/EtOAc (1:1) gave 19b(30.5 mg, 55 %) as a colorless oil.

Data for 19a : [a]25D = ++39.8 (c =0.4, CHCl3); IR (CHCl3): n =3019, 2929,

2857, 1783, 1463, 1404, 1363, 1337, 1272, 1148, 1106, 1061, 968, 901, 869,667 cm�1; 1H NMR (400 MHz, CDCl3/TMS): d=5.11–5.08 (m, 1 H, 3a’-H), 4.78–4.73 (m, 1 H, 6a’-H), 4.06–4.00 (m, 1H, 5-H), 2.75 (dd, J =18.4,5.3 Hz, 1 H, 6’-Ha), 2.67 (d, J=14.7 Hz, 1H, 6’-Hb), 2.55 (dd, J =14.9,6.8 Hz, 1H, 3’-Ha), 2.35 (dd, J =14.9, 2.1 Hz, 1H, 3’-Hb), 2.13–2.01 (m,2H, 3-H), 1.76–1.51 (m, 4 H, 4-, 1’’-H), 1.49–1.27 (m, 10 H, 2’’-, 3’’-, 4’’-,5’’-, 6’’-H), 0.88 ppm (t, J =6.8 Hz, 3 H, 7’’-H); 13C NMR (100 MHz,CDCl3): d =175.7, 115.4, 83.9, 78.9, 76.6, 42.2, 35.8, 35.4, 35.0, 31.7, 29.8,29.5, 29.2, 25.7, 22.6, 14.0 ppm; HRMS: m/z : calcd for C16H27O4:283.1909 [M+H+]; found: 283.1904.

Data for 19 b : [a]25D =�14.4 (c= 0.25, CHCl3); IR (CHCl3): n =2956,

2925, 2852, 1783, 1646, 1463, 1353, 1155, 1110, 1057, 905, 668 cm�1;

Asian J. Org. Chem. 2013, 2, 593 – 599 � 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim597

www.AsianJOC.org Rodney A. Fernandes and Mahesh B. Halle.

1H NMR (400 MHz, CDCl3/TMS): d =5.18–5.14 (m, 1H, 3a’-H), 4.92–4.86 (m, 1H, 6a’-H), 4.08–4.01 (m, 1H, 5-H), 2.76 (dd, J =18.7, 8.0 Hz,1H, 6’-Ha), 2.64 (dd, J =18.7, 1.5 Hz, 1H, 6’-Hb), 2.43 (d, J =14.2 Hz,1H, 3’-Ha), 2.13–1.99 (m, 4H, 3’-Hb, 3-H, 4-Ha), 1.77–1.54 (m, 3H, 4-Hb,1’’-H), 1.52–1.26 (m, 10 H, 2’’-, 3’’-, 4’’-, 5’’-, 6’’-H), 0.87 ppm (t, J=

6.8 Hz, 3 H, 7’’-H); 13C NMR (100 MHz, CDCl3): d=175.7, 114.7, 83.2,81.5, 77.5, 41.3, 37.7, 35.3, 33.7, 31.8, 30.4, 29.6, 29.2, 25.9, 22.6,14.1 ppm; HRMS: m/z : calcd for C16H27O4: 283.1909 [M+H+]; found:283.1901.ACHTUNGTRENNUNG(3R,4R,5R)-5-{2-[(R)-3-(tert-Butyldimethylsilyloxy)decyl]-1,3-dioxolan-2-yl}methyl-4-hydroxy-3-methyldihydrofuran-2(3H)-one (20) and (4R,5R)-5-{2-[(R)-3-(tert-butyldimethylsilyloxy)decyl]-1,3-dioxolan-2-yl}methyl-4-hydroxy-3,3-dimethyldihydrofuran-2 ACHTUNGTRENNUNG(3 H)-one (21)

nBuLi (0.525 mL, 0.84 mmol, 1.6 m solution in hexane, 7.0 equiv.) wasadded to a solution of diisopropylamine (85 mg, 0. 84 mmol, 7.0 equiv.)in THF (1.5 mL) at �78 8C. After stirring for 30min, a solution of b-hy-droxy lactone 18 (0.055 g, 0.12 mmol) in THF (2 mL) was added. The so-lution was stirred for 1h at �78 8C and then a solution of methyl iodide(0.08 mL, 0.170 g, 1.20 mmol, 10 equiv.) in HMPA (0.15 mL, 0.150 g,0.84 mmol, 7 equiv.) was added. After stirring for 2 h, a solution of satu-rated aq. NH4Cl (2 mL) was added and the mixture was warmed toroom temperature. All volatiles were removed under reduced pressureand the residue was extracted with EtOAc (3 � 20mL). The combinedorganic layers were washed with water and brine, then dried (Na2SO4)and concentrated. The residue was purified by chromatography ona silica gel column with petroleum ether/EtOAc (4:1) as the eluent toafford 21 (8.2 mg, 14 %) as a colorless oil. Further elution with petrole-um ether/EtOAc (7:3) gave 20 (40.8 mg, 72 %) as a colorless oil.

Data for 20 : [a]25D = ++4.5 (c=0.32, CHCl3); IR (CHCl3): n =3450, 2956,

2930, 2857, 1777, 1463, 1379, 1361, 1256, 1188, 1080, 1004, 948, 836, 774,669 cm�1; 1H NMR (400 MHz, CDCl3/TMS): d =4.68–4.63 (m, 1H, 5-H),4.04–3.96 (m, 5H, 4-H, -(OCH2)2), 3.67–3.62 (m, 1H, 3’-H), 3.44 (br s,1H, OH), 2.66–2.61 (m, 1H, 3-H), 2.37–2.30 (m, 1H, 1’’-Ha), 1.69–1.26(m, 17H, 1’’-Hb,1’-, 2’-, 4’-, 5’-, 6’-, 7’-, 8’-, 9’-H), 1.29 (d, J =7.9 Hz, 3 H,3-CH3), 0.90–0.85 (m, 12 H, 10’-CH3, -CACHTUNGTRENNUNG(CH3)3), 0.036 (s, 3 H, -SiCH3),0.029 ppm (s, 3 H, -SiCH3); 13C NMR (100 MHz, CDCl3): d =178.4,110.3, 78.6, 74.6, 71.6, 64.6, 64.2, 43.6, 37.1, 34.2, 32.2, 31.8, 31.0, 29.7,29.3, 25.9, 25.3, 22.6, 18.1, 14.1, 13.8, �4.4, �4.5 ppm; HRMS: m/z : calcdfor C25H49O6Si: 473.3298 [M+H+]; found: 473.3299.

Data for 21: [a]25D = ++4.9 (c= 0.25, CHCl3); IR (CHCl3): n =3449, 2951,

2919, 2851, 1731, 1464, 1375, 837, 667 cm�1; 1H NMR (400 MHz, CDCl3/TMS): d=4.68–4.64 (m, 1 H, 5-H), 4.17–3.88 (m, 4H, -(OCH2)2), 3.87 (d,J =2.8 Hz, 1 H, 4-H), 3.67–3.62 (m, 1H, 3’-H), 3.46 (br s, 1 H, OH), 2.42–2.24 (m, 2 H, 1’’-H), 1.78–1.17 (m, 22 H, 1’-, 2’-, 4’-, 5’-, 6’-, 7’-, 8’-, 9’-H,2� 3-CH3), 0.87 (m, 12 H, 10’-CH3, -C ACHTUNGTRENNUNG(CH3)3), 0.03 ppm (s, 6H, -Si-ACHTUNGTRENNUNG(CH3)2); 13C NMR (100 MHz, CDCl3): d= 180.6, 110.4, 77.4, 76.3, 71.6,64.6, 64.1, 44.9, 37.0, 34.3, 32.2, 31.8, 31.0, 29.7, 29.3, 25.9, 25.4, 23.2,22.6, 18.1, 17.8, 14.1, �4.4, �4.5 ppm; HRMS: m/z : calcd for C26H51O6Si:487.3455 [M+H+]; found: 487.3455.ACHTUNGTRENNUNG(4R,5R)-5-{2-[(R)-3-(tert-Butyldimethylsilyloxy)decyl]-1,3-dioxolan-2-yl}methyl-4-hydroxy-3,3-dimethyldihydrofuran-2 ACHTUNGTRENNUNG(3 H)-one (21)

nBuLi (0.57 mL, 0.91 mmol, 1.6 m in hexane, 7.0 equiv.) was added toa solution of diisopropylamine (92 mg, 0.91 mmol, 7.0 equiv.) in THF(1.0 mL) at �78 8C. After stirring for 30min, a solution of 20 (0.059 g,0.13 mmol) in THF (2 mL) was added. The solution was stirred for 1h at�78 8C, and then a solution of methyl iodide (0.081 mL, 1.3mmol,10 equiv.) in HMPA (0.16 mL, 0.163 g, 0.91 mmol, 7.0 equiv.) was added.The reaction mixture was warmed to �40 8C and stirred for 8h. Saturat-ed aq. NH4Cl (2 mL) was added and the mixture was warmed to roomtemperature. Volatiles were removed under reduced pressure and theresidue was extracted with EtOAc (3 � 20mL). The combined organiclayers were washed with water and brine, then dried (Na2SO4) and con-centrated. The residue was purified by chromatography on a silica gelcolumn with petroleum ether/EtOAc (3:1) as the eluent to afford 21(45.56 mg, 75 %) as a colorless oil. Further elution with petroleum ether/EtOAc (7:3) gave unreacted 20 (5.3 mg, 9%).

Data for 21: [a]25D = ++5.0 (c =0.32, CHCl3). Other spectral data is the

same as above.

Spiroketal diastereomers of cephalosporolide H, (6a) and (6b)

Aqueous HCl (4 n, 0.2 mL) was added to a solution of 21 (20 mg,0.041 mmol) in CH3OH (2 mL) at 0 8C. The reaction mixture waswarmed to room temperature and stirred for 2 h. After evaporation ofthe volatiles, water (5 mL) was added and the solution was extractedwith EtOAc (3 � 20 mL). The combined organic layers were washed withwater and brine, then dried (Na2SO4) and concentrated. The residue waspurified by flash silica gel column chromatography with petroleumether/EtOAc (3:2) to give 6 b (4.34 mg, 34%) as a colorless oil. Furtherelution gave 6 a (6.89 mg, 54%) as a colorless oil.

Data for 6 a : [a]25D =�4.6 (c= 0.5, MeOH); IR (CHCl3): n=2954, 2930,

2858, 1779, 1464, 1349, 1122, 1030, 885, 833, 669 cm�1; 1H NMR(400 MHz, CDCl3/TMS); d =5.07 (t, J= 4.9 Hz, 1 H, 3a’-H), 4.29 (d, J =

4.7 Hz, 1 H, 6a’-H), 4.02–3.93 (m, 1H, 5-H), 2.44 (d, J =14.1 Hz, 1H*),2.14–1.96 (m, 4H*), 1.72–1.60 (m, 2H*), 1.29 (s, 3 H, 6’-CH3), 1.28–1.25(m, 11H, 1’’-Hb, 2’’-, 3’’-, 4’’-, 5’’-, �6’’-H), 1.21 (s, 3 H, 6’-CH3), 0.87 ppm(t, J=6.9 Hz, 3 H, 7’’-H), *for 3-, 3’-, 4-H and 1’’-Ha ; 13C NMR(100 MHz, CDCl3) d=180.6, 115.1, 87.1, 81.9, 79.8, 44.5, 41.6, 37.4, 36.3,31.8, 30.8, 29.6, 29.2, 26.0, 24.8, 22.7, 18.3, 14.1 ppm; HRMS: m/z : calcdfor C18H31O4: 311.2222 [M+H+]; found: 311.2218.

Data for 6b : [a]25D = ++59.8 (c=0.5, MeOH); IR (CHCl3): n =2956, 2928,

2856, 1782, 1464, 1391, 1259, 1053, 905, 667 cm�1; 1H NMR (400 MHz,CDCl3/TMS) d =5.03 (ddd, J= 6.4, 3.8, 1.6 Hz, 1 H, 3a’-H), 4.29 (d, J =

3.8 Hz, 1H, 6a’-H), 4.10–3.99 (m, 1 H, 5-H), 2.53 (dd, J=15.0, 6.4 Hz,1H, 3’-Ha), 2.36 (dd, J =15.0, 1.5 Hz, 1H, 3’-Hb), 2.14–1.97 (m, 3H^),1.57–1.47 (m, 1H^), 1.31–1.21 (m, 15H, 1’’-, 2’’-, 3’’-, 4’’-, 5’’-, 6’’-H, 6’-CH3), 1.22 (s, 3 H, 6’-CH3), 0.88 ppm (t, J=6.9 Hz, 3H, 7’’-H), ^for 3-and 4-H ; 13C NMR (100 MHz, CDCl3) d= 181.0, 115.4, 85.2, 80.6, 79.0,44.5, 42.3, 35.7, 35.5, 31.8, 30.0, 29.6, 29.2, 25.8, 23.1, 22.6, 18.1,14.1 ppm; HRMS: m/z : calcd for C18H31O4: 311.2222 [M+H+]; found:311.2215.

Acknowledgements

This work was financially supported by the Industrial Research andConsultancy Centre (IRCC) and the Indian Institute of TechnologyBombay. M.B.H. thanks the Council of Scientific and Industrial Re-search (CSIR), New Delhi, for a senior research fellowship.

[1] a) D. Uemura, K. Takahashi, T. Yamamoto, C. Katayama, J.Tanaka, Y. Okumura, Y. Hirata, J. Am. Chem. Soc. 1985, 107,4796 – 4798; b) Y. Hirata, D. Uemura, Pure Appl. Chem. 1986, 58,701 – 710; c) Y. Tsunematsu, O. Ohno, K. Konishi, K. Yamada, M.Suganuma, D. Uemura, Org. Lett. 2009, 11, 2153 –2156; d) S. F. Sei-bert, A. Krick, E. Eguereva, S. Kehraus, G. M. Konig, Org. Lett.2007, 9, 239 – 242; e) X. Li, I. Sattler, W. Lin, J. Antibiot. 2007, 60,191 – 195; f) X. Li, Y. Yao, Y. Zheng, I. Sattler, W. Lin, Arch.Pharm. Res. 2007, 30, 812 –815; g) M. J. Ackland, J. R. Hanson,P. B. Hitchcock, A. H. Ratcliffe, J. Chem. Soc. Perkin Trans. 1 1985,843 – 847.

[2] a) R. A. Fernandes, A. B. Ingle, Synlett 2010, 158 – 160; b) M. A.Brimble, O. C. Finch, A. M. Heapy, J. D. Fraser, D. P. Furkert, P. D.O�Connor, Tetrahedron 2011, 67, 995 –1001.

[3] a) S. F. Tlais, G. B. Dudley, Org. Lett. 2010, 12, 4698 –4701; b) S. F.Tlais, G. B. Dudley, Beilstein J. Org. Chem. 2012, 8, 1287 –1292.

[4] S. Chang, R. Britton, Org. Lett. 2012, 14, 5844 –5847.[5] T. M. Penning, J. Pharm. Sci. 1985, 74, 651 – 654.[6] C. V. Ramana, S. B. Suryawanshi, R. G. Gonnade, J. Org. Chem.

2009, 74, 2842 –2845.[7] a) G. E. Keck, K. H. Tarbet, L. S. Geraci, J. Am. Chem. Soc. 1993,

115, 8467 –8468; b) G. E. Keck, L. S. Geraci, Tetrahedron Lett.

Asian J. Org. Chem. 2013, 2, 593 – 599 � 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim598

www.AsianJOC.org Rodney A. Fernandes and Mahesh B. Halle.

1993, 34, 7827 –7828; c) M. Kurosu, M. Lorca, Synlett 2005, 1109 –1112.

[8] For olefin cross metathesis see: a) S. J. Connon, S. Blechert, Angew.Chem. 2003, 115, 1944 – 1968; Angew. Chem. Int. Ed. 2003, 42,1900 – 1923; b) A. K. Chatterjee, T.-L. Choi, D. P. Sanders, R. H.Grubbs, J. Am. Chem. Soc. 2003, 125, 11360 – 11370; c) B. H. Lip-shutz, G. T. Aguinaldo, S. Ghorai, K. Voigtritter, Org. Lett. 2008,10, 1325 –1328, and references therein.

[9] The absolute configurations of the spiroketal stereocenters in 19 aand 19 b are tentatively assigned by comparison of 1H and13C NMR data to that of cephalosporolides E and F.[2a]

[10] For a representative a-gem dimethylation of a g-lactone see: M.-Y.Rios, F. Velazquez, H. Olivo, Tetrahedron 2003, 59, 6531 –6537.

[11] The anti configuration of the a-methyl group is assigned by analogyto similar a-alkylations known in the literature, see: a) A. R.Chamberlin, M. Dezube, Tetrahedron Lett. 1982, 23, 3055 –3058;b) C. Harcken, R. Br�ckner, Angew. Chem. 1997, 109, 2866 –2868;Angew. Chem. Int. Ed. Engl. 1997, 36, 2750 –2752. The stereochem-istry at this center is of no consequence as it is dimethylated subse-quently.

[12] The spiroketal stereochemistry for 6a and 6 b is assigned by com-parison of spectral data with that reported.[3]

[13] H. W. Yang, C. Zhao, D. Romo, Tetrahedron 1997, 53, 16471 –16488.

Received: April 15, 2013Revised: May 6, 2013

Published online: June 11, 2013

Asian J. Org. Chem. 2013, 2, 593 – 599 � 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim599

www.AsianJOC.org Rodney A. Fernandes and Mahesh B. Halle.