Tetrahedron: Asymmetry 24 (2013) 196–201

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Tetrahedron: Asymmetry

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A flexible enantioselective synthesis of (+)-centrolobine and5-epi-diospongin-A using asymmetric transfer hydrogenation/tandemGrubbs cross-metathesis/oxy-Michael reaction as key steps

Gullapalli Kumaraswamy ⇑, Dasa RambabuOrganic & Biomolecular Chemistry Division, CSIR—Indian Institute of Chemical Technology, Hyderabad 500 607, India

a r t i c l e i n f o

Article history:Received 20 November 2012Accepted 4 January 2013

0957-4166/$ - see front matter � 2013 Elsevier Ltd. Ahttp://dx.doi.org/10.1016/j.tetasy.2013.01.005

⇑ Corresponding author. Tel.: +91 40 27193154; faxE-mail address: gkswamy_iict@yahoo.co.in (G. Kum

a b s t r a c t

An efficient enantioselective synthesis of (+)-centrolobine and 5-epi-diospongin-A was achieved by theuse of asymmetric transfer hydrogenation (ATH)/tandem Grubbs cross-metathesis/oxy-Michael reaction.Furthermore, this strategy allows for diastereodivergent access to every representative member of thefamily.

� 2013 Elsevier Ltd. All rights reserved.

O

OH

O

O

OH

O

O

MeO OH

diospongin B 2diospongin A 1

O

OH

O

1. Introduction

The functionalized tetrahydropyran motif is prevalent in numer-ous biologically active natural products. Many of these naturalproducts have been reported to have potent biological activitywhich is attributed to the presence of the functionalized tetrahy-dropyran core.1 Among them, 2,6-disubstituted glycoside naturalproducts, such as (+)-centrolobine 4, diospongin-A 1 and B 2, haveshown an array of therapeutical activities such as anti-osteopo-rotic,2 anti-cancer,3 anti-inflammatory, anti-bacterial andanti-leishmanial activities.4

Moreover, regardless of their structural similarities, they exhibitnoteworthy differences in their biological profiles. Diospongin Bdisplays a potent inhibitory activity on bone resorption inducedby parathyroid hormone, while diospongin A does not show anyactivity for the same.5 (+)-Centrolobine 4 is an antibiotic, isolatedfrom the heartwood of Centrolobium robustum,6 while its enantio-mer with similar activity occurs in a different origin, that is,Centrolobium tomentosum (Fig. 1).7

2. Results and discussion

Due to the biological activity of 1–4, synthetic approaches havebeen recorded.8,9 To date, most strategies rely on asymmetricinduction resulting from either chiral auxiliaries, resident chiralityor catalytic asymmetric synthesis with privileged ligands with highcatalyst loading. Due to our interest in developing catalytic routesto bioactive small molecules,10 we recently developed a flexibleenantioselective synthesis for diospongin-A 1 and B 2, and theirenantiomers using a catalytic hetero-Diels–Alder/Rh-catalysed

ll rights reserved.

: +91 40 27193275.araswamy).

1,4-addition and asymmetric transfer hydrogenation strategy.11

Herein, we report another alternative unified synthetic strategyfor the synthesis of (+)-centrolobine and 5-epi-diospongin-A bymeans of asymmetric hydogenation/tandem Grubbs cross-metathesis/oxyMichael reactions. Our retrosynthetic approach isshown in Scheme 1.

In principle, 5-epi-diospongin-A 3, could be obtained from atandem Grubbs cross-metathesis/oxy-Michael reaction of 1,3-antidiol 5 and phenylvinylketone. The 1,3-anti diol 5 could be gener-ated via an indium catalysed allylation of b-hydroxyphenyl acetal-dehyde, which in turn could be obtained from 6. The stereogeniccentre in 6 could be accessed through a catalytic enantioselectiveasymmetric transfer hydrogenation that is either (S) or (R) by usingthe corresponding prochiral keto substrate. In a similar manner,(+)-centrolobine, 4 could be obtained by employing olefin tethered

centralobin 45-epi-diospongin A 3

Figure 1. Bioactive glycoside natural products 1–4.

OH

OH

OH

MeO OTBS

O

O

+

+

O

OH

O

diastereoselectiveallylation

catalytic asymmetrictransfer hydrogenaion

tandem Grubbs-crossmetathesis/Michael reaction

O

MeO OH

catalytic asymmetrictransfer hydrogenaion

tandem Grubbs-crossmetathesis/Michael reaction

3

4

5 6

7

OEt

OOH

Scheme 1. Retro synthetic analysis of 5-epi-diospongin-A 3 and (+)-centrolobine 4.

G. Kumaraswamy, D. Rambabu / Tetrahedron: Asymmetry 24 (2013) 196–201 197

secondary alcohol 7 and TBS-protected phenylvinylketone(Scheme 1).

Accordingly, the readily available b-ketoester 8 was subjectedto Noyori’s protocol using 1 mol % of (S,S)-RuCl[N-tosyl)-1,2-diphenylethylenediamine](p-cymene) in the presence of 10 mol %K2CO3 in 2-propanol and stirring at ambient temperature for 48 hto afford b-hydroxyl compound 6 in 98% yield and with 96%enantioselectivity.

The enantiopurity was analysed by HPLC (Chiralpak OD-H, 5%isopropanol in hexane at a flow rate of 0.8 mL/min) and the abso-lute configuration was assigned by chemical correlation.12b Next,the secondary hydroxyl in 6 was protected as a silyl ether to give9 in 99% yield. The reduction of 9 with DIBAL-H gave the aldehydeand the corresponding crude residue was subjected to deprotec-tion of the TBS group using PPTS in an aprotic solvent at 0 �C to givethe b-hydroxyl aldehyde. Next, without purification, the residue ofb-hydroxyl aldehyde, was submitted to a b-chelation-controlledindium-mediated allylation.13 After work-up purification, theanti-diol 5 (9:1) was obtained in 81% yield as the major compound(75% over three steps). Finally, after considerable experimentation,

O

10 mol% K2CO3

rt, 48 h

i) DIBAL-H-78 °C

DCM, 20 min

O

OEt

Grubbs 2nd gen

DCM, 12 h, reflux

ii) PPTS, MeOH0 °C,1 h

9, 99%

8

3

N

NH

Ru

Ph

Ph

Ts1 mol%

O

Briii) In0, H2O

rt, 4 h

2-propanol

OEt

OOTBS

Scheme 2. Synthesis of 5

the intended tandem Grubbs cross-metathesis-oxy-Michael reac-tion14 of 5 with vinylacetophenone employing a second-generationGrubbs catalyst led smoothly to the desired 5-epi-diospongin-A 3in 88% isolated yield and with >99% diastereomeric ratio.

The chirooptical data of 3 were in full agreement with those re-ported in the literature8f {½a�23

D ¼ �11:3 (c 0.6, CHCl3), lit.8f

½a�23D ¼ �11:6 (c 0.54, CHCl3)} (Scheme 2).Next, we initiated the synthesis of (+)-centrolobine, 4 employ-

ing strategic steps used in the above synthesis. The reduction of10 with 1 mol % of (R,R)-RuCl[N-tosyl)-1,2-diphenylethylenedi-amine](p-cymene) in the presence of 10 mol % K2CO3 in 2-propanoland stirring at ambient temperature for 48 h resulted in no trace ofthe desired compound 11 (Table 1, entry 1). The same reactionwith heating at 80 �C under otherwise identical conditions gavehydroxyl compound 11 in 10% yield with 65% ee (Table 1, entry2). When the reduction was carried out with 1 mol % of(R,R)-RuCl[N-tosyl)-1,2-diphenylethylenediamine](p-cymene) inthe presence of HCO2H:Et3N (5:2) in EtOAc and heating at 80 �Cfor 24 h, 11 was obtained in low yield and with moderate ee(Table 1, entry 3). However, when the same substrate was exposed

OH

O

O

imadazoleDCM, 12 h

98%yield; 96%ee

dr = > 99

5, 75% (over 3 steps)

88%

6,

,

TBSClOEt

OOH

OH

dr = 9:1OH

-epi-diospongin-A 3.

Table 1Asymmetric reduction of d-keto compound 10 employing various conditions

MeO

OH

OEt

O

MeO

O

OEt

O

10 11, 98%yield; 88%ee

N

NH

Ru

Ts1 mol%

Ph

Ph

Entry Conditions Time (h) % Yield %ee

1 10 mol % K2CO3

2-Propanol, rt48 No reaction

2 10 mol % K2CO3

2-Propanol, 80 �C48 10 65

3 HCO2H:Et3N (5:2)EtOAc, 80 �C

24 40 60

4 HCO2H:Et3N (5:2)80 �C

24 95 72

5 HCO2H:Et3N (5:2)40 �C

24 98 88

198 G. Kumaraswamy, D. Rambabu / Tetrahedron: Asymmetry 24 (2013) 196–201

to HCO2H:Et3N (5:2) as the hydrogen source as well as the solventand heating at 80 �C, the expected product 11 was obtained withgood yield and ee (Table 1, entry 4). Reducing temperature to40 �C gave the target compound 11 with acceptable ee (88%) andhigh yield (Table 1, entry 5).15

With the enantioenriched compound 11 in hand, we proceededfurther. The stereogenic secondary hydroxyl group in 11 was pro-tected as TBS–ether 12 (98%). Upon exposure of 12 to DIBAL-H inDCM at �78 �C the aldehyde was obtained, which without purifica-tion was submitted to Wittig olefination (Ph3P+CH3I�, t-BuOK, THF,�78 �C to rt) to give the terminal olefin 13 in 81% yield (over twosteps). Fluoride induced desilylation resulted in secondary alcohol7 in 90% isolated yield. Finally, the tandem Grubbs CM-oxyMichaelreaction between terminal olefin 7 and p-t-butyldimethylsilyloxyvinylacetophenone using Grubbs 2nd generation catalyst in DCM,heated at reflux for 12 h gave 2,6-disubstituted pyrone 14 in 90%yield with an 88:12 diastereomeric ratio. The major cis-configureddiastereomer 14 was separated by silica gel column chromatogra-

MeO

OH

O

O

MeO OTBDMS

imadazoleDCM, 12 h

dr = 88:12

TBAF, THF

12, 98%

7, 90%

90%14,

TBSCl11MeO

OTBS

CO2

0 °C to rt, 4 h

Scheme 3. Synthesis of

phy.16 Initially, the benzylic deoxygenation of 14 was attempted byemploying H2–Pd/C under balloon pressure with a trace of HCl.9k

However, the reaction mixture showed a multitude of productsand no trace amount of the desired compound 4 was observed.Consequently, the deoxygenation and deprotection of TBS groupwere achieved by reduction with NaBH4 following acid-catalysedelimination of the resulting secondary alcohol and subsequentreduction with NaBH4 to give (+)-centralobine 4 in 75% isolatedyield.9v The enantiomeric purity and analytical data (1H and 13CNMR) were in agreement with those reported for the natural prod-uct4b {½a�23

D ¼ þ95:3 (c 0.12, MeOH), lit.4b ½a�23D ¼ þ97:5 (c 0.1,

MeOH)} (Scheme 3).

3. Conclusion

In conclusion, we have accomplished a unified enantioselectiveroute for the synthesis of (+)-centrolobine and 5-epi-diospongin-Aby combining two efficient catalytic processes, that is, an asym-

MeO

OTBS

TBSO

O

i) DIBAL-H-78 °C

DCM, 20min

Grubbs 2nd gen

(+)-centrolobine

DCM, 12 h, reflux

ii) Ph3PCH3It-BuOK, THF

-78°C to rt; 12 h

i) NaBH4MeOH, 0 °C to rt,1 h

75%

4ii) THF, NaBH4

TFA, rt , 1 h

Et

13, 81% (over 2 steps)

(+)-centrolobine, 4.

G. Kumaraswamy, D. Rambabu / Tetrahedron: Asymmetry 24 (2013) 196–201 199

metric transfer hydrogenation (ATH) and tandem Grubbs cross-metathesis/oxy-Michael reaction. The genesis of chirality installedvia ATH offers an attractive alternative to high pressure molecularhydrogen methods. Additionally, this methodology uses a low levelof catalyst loading and gives high enantioselectivity with opera-tional simplicity. This is a flexible approach that provides accessto the synthesis of each representative member of diosponginand centrolobine family. Further work is currently in progress.

4. Experimental

4.1. General

All reactions were conducted under an atmosphere of nitrogen(IOLAR, Grade I). Apparatus used for reactions were oven dried.THF was distilled over sodium benzophenone ketyl before use,2-propanol and dichloromethane were distilled over calciumhydride. All other chemicals used were commercially available.Progress of the reactions was monitored by TLC on Silica Gel 60F-254 pre-coated. Evaporation of the solvents was performed at re-duced pressure on a rotary evaporator. Column chromatographywas carried out with silica gel grade 60–120, and 100–200 mesh.1H NMR spectra were recorded at 300 and 500 MHz and 13CNMR 75 MHz in CDCl3. J values are recorded in Hertz and abbrevi-ations used are s-singlet, d-doublet, t-triplet, q-quartet, m-multi-plet and br-broad. Chemical shifts (d) are reported relative toTMS (d = 0.0) as the internal standard. IR spectra were recordedon FT/IR-5700. Mass spectra data were compiled using MS (ESI),HRMS mass spectrometers. Optical rotations were recorded on ahighly sensitive polarimeter with 10 mm cell.

4.1.1. (S)-Ethyl 3-hydroxy-3-phenylpropanoate 6To a solution of 8 (500 mg, 2.60 mmol) in anhydrous 2-propanol

(5 mL) under argon was added (S,S)-Ru-catalyst (15.8 mg,0.026 mmol, 1 mol %), which was pre-dissolved in CH2Cl2

(2 � 1 mL). Then, K2CO3 (36 mg, 0.260 mmol) was added and theresulting reaction mixture was stirred at ambient temperaturefor 48 h. The reaction mixture was then diluted with water and ex-tracted with EtOAc (3 � 10 mL). The combined organic layers werewashed with brine (3 � 5 mL), dried over anhydrous Na2SO4, fil-tered and concentrated under reduced pressure to give the residuewhich was subjected to silica gel flash column chromatography(20% EtOAc in hexane) to afford 495 mg (98%) of compound 6 asa colourless liquid. ½a�23

D ¼ �43:0 (c 1, CHCl3) {lit.12b ½a�23D ¼ �50:1

(c 1.50, CHCl3)}; 1H NMR (300 MHz, CDCl3): 7.36–7.25 (m, 5H),5.12 (dd, J = 4.5, J = 8.4 Hz, 1H), 4.17 (q, J = 7.1 Hz, J = 14.3 Hz, 2H),2.74–2.70 (m, 2H), 1.23 (t, J = 6.9 Hz, J = 14.1 Hz, 3H); 13C NMR(75 MHz, CDCl3): 172.3, 142.4, 128.4, 127.7, 125.6, 70.2, 60.8,43.2, 14.0; IR m (cm�1): 3452, 3031, 2982, 1728, 1298, 1194,1161, 1033, 914, 760, 700, 539; ESI-MS: m/z 217 (M+Na)+; ESI-HRMS calcd for C11H14O3Na 217.08352, found 217.08324.

4.1.2. (S)-Ethyl 3-(tert-butyldimethylsilyloxy)-3-phenylpropan-oate 9

To a stirred solution of 6 (495 mg, 2.55 mmol) in CH2Cl2 (10 mL)was added imidazole (348 mg, 5.10 mmol) at 0 �C. After stirring thesolution for 15 min, tert-butyldimethyl silyl chloride (575 mg,3.82 mmol) and catalytic DMAP were added sequentially at thesame temperature. The resulting reaction mixture was stirred atambient temperature for 12 h, then quenched with a saturatedNH4Cl solution and extracted with CH2Cl2 (3 � 25 mL). Thecombined organic layers were dried over anhydrous Na2SO4 andconcentrated under reduced pressure. The crude residue was puri-fied by silica gel column chromatography (5% EtOAc in hexane) toafford the product 9 (780 mg, 99%) as a colourless oil. ½a�23

D ¼ �41:5

(c 1, CHCl3); 1H NMR (300 MHz, CDCl3): 7.30–7.24 (m, 5H), 5.14(dd, J = 4.1 Hz, J = 9.2 Hz, 1H), 4.10 (q, J = 7.1 Hz, J = 14.3 Hz, 2H),2.72 (dd, J = 9.2 Hz, J = 14.5 Hz, 1H), 2.67 (dd, J = 4.1 Hz,J = 14.5 Hz, 1H), 1.25 (t, J = 7.1 Hz, J = 14.3 Hz, 3H), 0.84 (s, 9H),0.01 (s, 3H), �0.17 (s, 3H); 13C NMR (75 MHz, CDCl3): 171.1,144.0, 128.2, 127.4, 125.8, 72.2, 67.7, 60.4, 45.4, 25.6, 21.8, 18.0,14.1, �2.9, �4.7, �5.3; IR m (cm�1): 3448, 3031, 2955, 2893,2857, 1738, 1467, 1092, 1049, 954, 834, 777, 699, 667, 533;ESI-MS: m/z 331 (M+Na)+; ESI-HRMS: calcd for C17H28O3NaSi331.16999, found 331.17031.

4.1.3. (1S,3R)-1-Phenylhex-5-ene-1,3-diol 5To a stirred solution of 9 (750 mg, 2.43 mmol) in CH2Cl2 (15 mL)

was added DIBAL-H (346 mg, 2.43 mmol, 1 M solution in toluene)at �78 �C. The reaction mixture was stirred for 30 min at the sametemperature and then quenched with a saturated sodium potas-sium tartarate solution. The aqueous layer was then extracted withCH2Cl2 (3 � 30 mL). The combined organic layers were washedwith brine solution, dried over anhydrous Na2SO4, and concen-trated under reduced pressure to give the corresponding crudealdehyde. The aldehyde was subjected to next step without furtherpurification. To a 0 �C cooled solution of aldehyde (574 mg) inMeOH (5 mL) was added PTSA (413 mg, 2.17 mmol), and then stir-red at 0 �C for 1 h, then quenched with water and extracted withEtOAc (3 � 20 mL). The combined organic layers were washed withNaHCO3 (3 � 10 mL) followed by brine (3 � 10 mL). The contentswere dried over anhydrous Na2SO4 and concentrated underreduced pressure, to give the crude hydroxy-aldehyde which wassubjected to next step without further purification.

To the above residue, water (14 mL) and indium powder(343 mg, 2.98 mmol) were sequentially added at 23 �C. To this, al-lyl bromide (0.25 mL, 2.98 mmol) was added and the reaction flaskwas sealed with a rubber septum. After vigorous stirring for 1 h atthe same temperature, the reaction mixture was concentrated. Tothe resulting residue, ethyl acetate (30 mL) was added and stirredand filtered. The filtrate was dried over Na2SO4 and concentratedunder reduced pressure. The crude residue was passed through asilica gel column chromatography (50% EtOAc in hexane) to affordthe separable diastereomers in a 9:1 ratio [major (311 mg) andminor (34 mg)]. The major isomer was found to be a white semisolid 5 (311 mg, 75% yield over three steps). ½a�23

D ¼ �31:0 (c 2.2,CHCl3); 1H NMR (300 MHz, CDCl3): 7.28–7.18 (m, 5H), 5.76–5.62(m, 1H), 5.07–4.94 (m, 3H), 3.87–3.81 (m, 1H), 2.64 (br s, 2H),2.21–2.16 (m, 2H), 1.84–1.73 (m, 2H); 13C NMR (75 MHz, CDCl3):144.3, 134.3, 128.3, 127.2, 125.4, 118.2, 71.4, 67.9, 43.9, 41.8; IRm (cm�1): 3380, 2927, 2852, 1717, 1453, 1054, 765, 700, 420;ESI-MS: m/z 215 (M+Na)+; ESI-HRMS: calcd for C12H16O2Na215.10425, found 215.10431.

4.1.4. 5-epi-Diospongin-A 3A 50 mL flame-dried two-neck round bottom flask equipped

with a magnetic stirrer bar and reflux condenser was charged with(1S,3R)-1-phenylhex-5-ene-1,3-diol 5 (50 mg, 0.26 mmol), 1-phe-nylprop-2-en-1-one (69 mg, 0.52 mmol) and anhydrous dichloro-methane (11 mL) under an atmosphere of argon, and degassedfor 5 min. Second generation Grubbs’ catalyst (23 mg, 0.026 mmol)was then added in a single portion resulting in an orange solution,which was refluxed for 12 h. The reaction mixture was then al-lowed to cool to room temperature, and concentrated in vacuo toafford a dark brown oil, which was purified by silica gel columnchromatography (eluting with 30% ethyl acetate/hexanes) fur-nished the title compound 3 as a white solid (68 mg, 88% yield).½a�23

D ¼ �11:3 (c 0.6, CHCl3) lit.8f ½a�23D ¼ �11:6 (c 0.54, CHCl3); 1H

NMR (500 MHz, CDCl3): d 7.97 (d, J = 7.8 Hz, 2H), 7.56 (t,J = 7.8 Hz, 1H), 7.45(t, J = 7.0 Hz, 2H), 7.30–7.29 (m, 5H), 4.37 (d,J = 12.0 Hz, 1H), 4.22–4.17 (m, 1H), 4.07–4.02 (m, 1H), 3.47 (dd,

200 G. Kumaraswamy, D. Rambabu / Tetrahedron: Asymmetry 24 (2013) 196–201

J = 5.2 Hz, J = 15.7 Hz, 1H), 3.10 (dd, J = 6.1 Hz, J = 16.6 Hz, 1H), 2.23(d, J = 11.3 Hz, 2H), 1.55(br, 1H), 1.36–1.29 (m, 3H); 13C NMR(150 MHz, CDCl3): d 198.0, 141.6, 137.2, 133.2, 128.5, 128.3,128.2, 127.5, 125.9, 77.5, 72.4, 68.1, 60.4, 44.7, 42.4, 40.9; IR m(cm�1): 3448, 2924, 2853, 1725, 1599, 1453, 1072, 750; ESI-MS:m/z 297 (M+H)+; ESI-HRMS: calcd for C19H20O3Na 319.13047,found 319.13037.

4.1.5. (R)-Ethyl 5-hydroxy-5-(4-methoxyphenyl)pentanoate 11To a mixture of ethyl 5-(4-methoxyphenyl)-5-oxopentanoate

10 (500 mg, 2 mmol) and HCOOH:Et3N (5:2) was added Ru-catalyst (12.2 mg, 0.02 mmol, 1 mol %) which was pre-dissolvedin DCM. The resulting reaction mixture was heated at 40 �C for24 h. After cooling the reaction mixture to room temperature,water was added and the aqueous layer extracted with EtOAc(3 � 10 mL). The organic solution was washed with aqueous NaH-CO3 and brine successively. The organic layer was dried over anhy-drous Na2SO4, and concentrated under reduced pressure. Theresulting residue was subjected to silica gel flash column chroma-tography (30% EtOAc in hexane) to afford 11 as a colourless liquid(497 mg, 98%). ½a�23

D ¼ þ22:5 (c 1, CHCl3); 1H NMR (300 MHz,CDCl3): d 7.19–7.18 (m, 2H), 6.8 (d, J = 7.9 Hz, 2H), 4.57–4.54 (m,1H), 4.04 (q, J = 6.9, 14.9 Hz, 2H), 3.73 (s, 3H), 2.25–2.23 (m, 2H),1.75–1.55 (m, 4H), 1.23 (t, J = 6.9, 13.9 Hz, 3H); 13C NMR(100 MHz, CDCl3): d 173.5, 158.8, 136.6, 126.9, 113.6, 73.5, 60.2,55.1, 38.1, 33.9, 21.1, 14.1; ESI-MS: m/z 275 (M+Na)+; ESI-HRMS:calcd for C14 H20O4Na 275.12538, found 275.12554.

4.1.6. (R)-Ethyl 5-(tert-butyldimethylsilyloxy)-5-(4-methoxyphen-yl)pentanoate 12

To a stirred solution of 11 (490 mg, 1.95 mmol) in CH2Cl2

(10 mL) was added imadazole (265 mg, 3.882 mmol) at 0 �C. Afterstirring the solution for 15 min, tert-butyldimethyl silyl chloride(0.438 mg, 2.91 mmol) and catalytic DMAP were added sequen-tially at the same temperature. The resulting reaction mixturewas stirred at room temperature for 12 h, and quenched with a sat-urated NH4Cl solution. Next, the aqueous layer was extracted withCH2Cl2 (3 � 20 mL) and the combined organic layers were driedover anhydrous Na2SO4. The contents were filtered and concen-trated under reduced pressure. The resulting crude residue waspurified by silica gel column chromatography (5% EtOAc in hexane)to afford the product 12 as a colourless oil (698 mg, 98%).½a�23

D ¼ þ29:5 (c 2.1, CHCl3); 1H NMR (300 MHz, CDCl3): d 7.35 (d,J = 7.9 Hz, 2H), 6.99 (d, J = 8.9 Hz, 2H), 4.77–4.75 (m, 1H), 4.25 (q,J = 6.9, 14.8 Hz, 1H), 3.94 (s, 3H), 2.4–2.41 (m, 2H), 1.87–1.74 (m,4H), 1.38 (t, J = 6.9, 14.8 Hz, 3H), 1.03 (s, 9H), 0.17 (s, 3H), 0.0 (s,3H); 13C NMR (75 MHz, CDCl3): d 173.6, 158.4, 137.5, 135.9,126.8, 113.3, 74.2, 60.1, 65.4, 55.1, 40.2, 34.1, 25.8, 21.8, 14.2,�4.6, �5.0; IR (neat): 3451, 2954, 2932, 2857, 1736, 1612, 1248,1088, 835, 554 cm�1; ESI-MS: m/z 389 (M+Na)+; ESI-HRMS: calcdfor C20H34O4NaSi 389.21186, found 389.21276.

4.1.7. (R)-tert-Butyl(1-(4-methoxyphenyl)hex-5-enyloxy)dimeth-ylsilane 13

To a stirred solution of 12 (698 mg, 1.90 mmol) in CH2Cl2

(10 mL) was added DIBAL-H (299 mg, 2.1 mmol, 1 M solution intoluene) at �78 �C. The resulting reaction mixture was stirred for30 min at the same temperature and then quenched with a satu-rated sodium potassium tartarate solution. The aqueous layerwas extracted with CH2Cl2 (3 � 25 mL). The combined organic lay-ers were washed with brine, dried over anhydrous Na2SO4, andconcentrated under reduced pressure to give the correspondingaldehyde. The aldehyde was subjected to the next step without fur-ther purification.

Potassium t-butoxide (443 mg, 3.94 mmol) and methyl triphen-ylphosphonium iodide (1.60 g, 3.94 mmol) were dissolved in dry

THF (15 mL) and stirred at room temperature for 4 h. The resultingyellow colour solid precipitate was allowed to settle down. Next,the clear supernatant orange-yellow liquid was cannulised intothe above crude aldehyde (552 mg), which was dissolved in dryTHF (5 mL) at �78 �C after which the reaction mixture was allowedto return to ambient temperature (�12 h). Next, the reaction mix-ture was quenched with an aq satd NH4Cl and the aqueous layerwas extracted with diethyl ether (3 � 30 mL). The combined or-ganic layers were dried over anhydrous Na2SO4 and concentratedunder reduced pressure. The crude residue was purified by silicagel column chromatography using (10% EtOAc in hexane) to affordproduct 13 as a colourless oil (496 mg, 81% over two steps).½a�23

D ¼ þ39:1 (c 1.2, CHCl3); 1H NMR (300 MHz, CDCl3): d 7.81 (d,J = 8.0 Hz, 2H), 6.82 (d, J = 8.0 Hz, 2H), 5.78–5.72 (m, 1H), 4.93(dd, J = 17.0 Hz, J = 28.0 Hz, 2H), 4.59–4.56 (m, 1H), 3.78 (s, 3H),2.04–2.0 (m, 2H), 1.71–1.66 (m, 1H), 1.60–1.57(m, 1H), 1.47–1.42(m, 1H), 1.36–1.25 (m, 1H), 0.87 (s, 9H), 0.00 (s, 3H), �0.15 (s,3H); 13C NMR (75 MHz, CDCl3): d 158.4, 138.8, 138.0, 126.8,114.3, 113.2, 74.5, 55.1, 40.4, 39.2, 33.6, 29.6, 25.8, 24.9, 18.2,�4.6, �4.9; IR (neat): 3451, 3074, 2931, 2857, 1639, 1511, 1248,1085, 910, 833, 774,667, 555 cm�1.

4.1.8. (R)-1-(4-Methoxyphenyl)hex-5-en-1-ol 7To a stirred solution of 13 (496 mg, 1.61 mmol) in THF (10 mL)

was added TBAF (2.42 mL, 2.42 mmol, 1 M solution in THF) at 0 �Cafter which the reaction mixture was allowed to return to ambienttemperature and stirred for further 4 h. The reaction mixture wasthen quenched with H2O and extracted with EtOAc (3 � 20 mL).The combined organic layers were washed with brine, dried overanhydrous Na2SO4, and concentrated under reduced pressure.The crude residue was purified by silica gel column chromatogra-phy using (20% EtOAc in hexane) to afford product 7 as a colourlessliquid (301 mg, 90%). ½a�23

D ¼ þ25:0 (c 0.7, CHCl3); 1H NMR(400 MHz, CDCl3): d 7.41 (d, J = 8.32 Hz, 2H), 7.03 (d, J = 8.32 Hz,2H), 5.97–5.88 (m, 1H), 4.78–4.75 (m, 1H), 3.90 (s, 3H), 2.20–2.0(m, 2H), 1.99–1.92 (m, 1H), 1.88–1.81 (m, 1H) 1.69–1.61 (m, 1H),1.53–1.46 (m, 1H) 13C NMR (75 MHz, CDCl3): d 158.9, 138.5,136.8, 127.0, 114.6, 113.7, 74.0, 55.2, 38.3, 33.5, 29.6. 25.1; IR m(cm�1): 3417, 3072, 2931, 2858, 1639, 1611, 1512, 1460, 1300,1246, 1176, 1034,831, 762, 638.

4.1.9. 1-(4-(tert-Butyldimethylsilyloxy)phenyl)-2-((2S,6R)-6-(4-methoxyphenyl)tetrahydro-2H-pyran-2-yl)ethanone 14

A 50-mL flame-dried two-neck round bottom flask equippedwith a magnetic stirrer bar and reflux condenser was charged with(R)-1-(4-methoxyphenyl) hex-5-en-1-ol (50 mg, 0.24 mmol), 11-(4-(tert-butyldimethylsilyloxy)phenyl)prop-2-en-1-one (128 mg,0.48 mmol) and anhydrous dichloromethane (10 mL) under an ar-gon atmosphere, and degassed for 5 min. Second generation Grub-bs’ catalyst (21 mg, 0.024 mmol) was then added in a singleportion resulting in an orange solution, which was refluxed for12 h. The reaction mixture was then allowed to return to roomtemperature, after which the reaction mixture was concentratedin vacuo to afford a dark brown oil, which was purified by silicagel column chromatography (10% ethyl acetate in hexanes) to givethe cyclic compound 14 (84 mg, major) in an 88:12 ratio of separa-ble diastereomers (12 mg, minor). ½a�23

D ¼ þ9:5 (c 1.1, CHCl3); 1HNMR (400 MHz, CDCl3): d 7.89 (d, J = 7.5 Hz, 2H), 7.21 (d,J = 7.5 Hz, 2H), 6.83 (dd, J = 8.8 Hz, J = 17.6 Hz, 4H), 4.36 (d,J = 11.3 Hz, 1H), 4.15–4.10 (m, 1H), 3.77 (s, 3H), 3.32 (dd,J = 6.3 Hz, J = 16.4 Hz, 1H), 2.97 (dd, J = 6.3 Hz, J = 16.4 Hz, 1H),1.96–1.93 (m, 1H), 1.84–1.81 (m, 2H), 1.75–1.70 (m, 1H),1.56–1.47 (m, 1H), 1.40–1.32 (m, 1H), 0.99 (s, 9H), 0.23 (s, 6H);13C NMR (75 MHz, CDCl3): d 197.1. 160.1, 158.6, 135.3, 131.0,130.5, 127.0, 119.7, 113.5, 79.4, 75.0, 55.1, 45.2, 32.9, 31.3, 29.6,25.5, 23.7, �4.4; IR m (cm�1): 3448, 2930, 2856, 1741, 1678,

G. Kumaraswamy, D. Rambabu / Tetrahedron: Asymmetry 24 (2013) 196–201 201

1598, 1511, 1252, 1168, 1078, 1037, 997, 911, 837, 783, 710, 673.545; ESI-MS: m/z 441(M+H)+; ESI-HRMS: calcd for C26H37O4Si441.24556, found 441.24448.

4.1.10. (+)-Centrolobine 4To a 0 �C cooled stirred solution of 1-(4-(tert-butyldimethylsi-

lyloxy)phenyl)-2-((2S,6R)-6-(4-methoxyphenyl)tetrahydro-2H-pyran-2-yl)ethanone 14 (80 mg, 0.18 mmol) in methanol (3 mL)was added NaBH4 (11 mg, 0.27 mmol) and while stirring it was al-lowed to return to room temperature (�1 h). After completion ofthe reaction, methonol was evaporated off under reduced pressure,and the residue was re-dissolved in THF (1 mL) after which NaBH4

(67 mg, 1.80 mmol) was added followed by the dropwise additionof trifluoroacetic acid (0.75 mL) over 30 min, which was carefullyneutralized with NaOH (5% aqueous, 0.5 mL). After this addition,the reaction mixture was extracted with Et2O. The combinedorganic phases were washed with NH4Cl (aq satd 5 mL), brine(5 mL), dried over Na2SO4, and concentrated under reducedpressure. The resulting residue was purified by silica gel columnchromatography using 30% EtOAc in hexane as eluent to give (+)-centrolobine as a white solid (42 mg, 75%). ½a�23

D ¼ þ95:3 (c 0.12,MeOH) {lit.4b ½a�23

D ¼ þ97:5 (c 0.1, MeOH)}; 1H NMR (400 MHz,CDCl3): 7.30 (d, J = 8.0 Hz, 2H), 7.05 (d, J = 9.0 Hz, 2H), 6.89 (d,J = 9.0 Hz, 2H), 6.73 (d, J = 9.0 Hz, 2H), 4.65 (br s, 1H), 4.29 (d,J = 10.0 Hz, 1H), 3.8 (s, 3H), 3.45–3.42 (m, 1H), 2.74–2.76 (m, 2H),1.93–1.81 (m, 2H), 1.74–1.7 (m, 1H), 1.64–1.59 (m, 2H),1.53–1.45 (m, 1H), 1.36–1.28 (m, 1H); 13C NMR (75 MHz, CDCl3):158.6, 153.4, 135.8, 134.6, 129.5, 127.0, 115.0, 113.6, 79.0, 77.1,55.2, 38.2, 33.3, 31.2, 30.7, 24.0 IR m (cm�1): 3406, 3013, 2931,2853, 1613, 1513, 1447, 1246, 1176, 1035, 828, 765, 544;ESI-MS: m/z 335 (M+Na)+; ESI-HRMS: calcd for C20H24O3Na335.16177, found 335.16237.

Acknowledgments

We are grateful to Dr. J. S. Yadav, Director, IICT, for his encour-agement. Financial support was provided by the DST, New Delhi,India (Grant No.: SR/S1/OC-08/2011) and the fellowship providedto D.R.B. by CSIR (New Delhi) is gratefully acknowledged. Thanksare also due to Dr. G. V. M. Sharma for his support.

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