Tetrahedron Letters 52 (2011) 3128–3130

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Tetrahedron Letters

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Titanocene(III) chloride mediated radical induced asymmetric synthesisof a-methylene bis-c-butyrolactone

Sumit Saha, Samir Kumar Mandal, Subhas Chandra Roy ⇑Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700 032, India

a r t i c l e i n f o

Article history:Received 4 March 2011Revised 28 March 2011Accepted 4 April 2011Available online 12 April 2011

Keywords:Radical cyclizationActive bromocompoudTitanocene(III) chloridea-Methylene bis-c-butyrolactoneNatural products

OO

O

O

R 1

2

33a

4

6a6 R = Et , xylobovide

R = nBu, canadensolideR = nHex, sporothriolide

A

H

H

O

O

R

4

6

0040-4039/$ - see front matter � 2011 Elsevier Ltd. Adoi:10.1016/j.tetlet.2011.04.023

⇑ Corresponding author. Tel.: +91 33 2473 4971; faE-mail address: ocscr@iacs.res.in (S.C. Roy).

a b s t r a c t

Asymmetric synthesis of a-methylene bis-c-butyrolactone has been synthesized using titanocene(III)chloride as a radical source. Titanocene(III) chloride (Cp2TiCl) was prepared in situ from commerciallyavailable titanocene dichloride (Cp2TiCl2) and zinc dust in THF.

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The pharmaceutical composition having bis-c-lactone deriva-tives containing a variety of substituents at C-3 and C-6 with alkyl,phenyl, alkoxycarbonyl, methylene groups show ulcer-healingproperties.1 The ulcer healing properties of these types of compo-sitions (A) are efficaciously applied for treatment of gastric or duo-denal ulcer. Naturally occurring optically active xylobovide,canadensolide, sporothriolide and its analogues are representativeclass of bis-lactone derivatives, showing anti-germinative antibac-terial, and fungicidal activity. They differ only at alkyl substitutionpattern at C-6 position. It is also reported that some of the epi-isomers (type B) also shows biological activities.2a

OO

1

2

33a

6aR = Et , epi-xylobovideR = nBu, epi-canadensolideR = nHex, epi-sporothriolide

B

H

H

Beside various biological activities, unique stereochemical fea-tures of the three stereo centres with dense functionality of theconcave bis-lactone skeleton attracted much attention to syntheticchemists towards the synthesis of bis-c-lactone derivatives.2b

Although there are several reports regarding the synthesis2 of

ll rights reserved.

x: +91 33 2473 2805.

bis-lactones in racemic as well as in optically forms, not a singlesynthesis is reported so far involving radicals generated by usingtitanocene(III) chloride as a radical source. We report herein thesynthesis of a-methylene bis-c-butyrolactone skeleton applyingradical induced Cp2TiCl mediated bromo-alkyne cyclization reac-tion3 starting from sugar derived (R)-2,3-O-cyclohexylideneglycer-aldehyde as a chiral precursor. Titanocene(III) chloride (Cp2TiCl)was prepared in situ from commercially available titanocenedichloride (Cp2TiCl2) and zinc dust in THF.4 The present strategy in-volves the construction of the second lactone ring via C–C bondforming radical cyclization reaction.

Thus, (R)-2,3-O-cyclohexylideneglyceraldehyde (1) was treatedwith diallyl zinc to furnish inseparable mixture of diasteromericalcohols 2a and 2b in a ratio of 9:1 (Scheme 1).

The erythro-selectivity of the addition of diallylzinc reagentwith the aldehyde 1 to afford 2a as the major product can be ex-plained with the analogy reported by Mulzer5 and from our labora-tory.6 Not only the bulky cyclohexylidene moiety but also themetal used (zinc) control the nucleophilic attack at Si face (Cram

OHH

O

O

R

M R

H

O

O

RH

OMR

. .M M

CRAM anti-CRAM

Figure 1.

O OHO

O

O OTBDMSO

OTBDMSCl / Imidazole

DMF90%

5a 6a

O OOTBDMS

O Br

LDA/ CBr4

THF

7a

O OTBDMSO

O

H

H H

Cp2TiCl

THF

8a

O OTBDMSO

O

H

H H

O

PDC / DMF

Mol Sieve 4A0 / 500C

30%

9a

H H

H24% from 6a

Scheme 3.

O O

O

H

ii) NH4Cl65%1

80%

NaHBr

+ O O

H OH

O O

H OH2a 2bratio 9:1

i) Zn / allyl bromide

+ O O

H O

O O

H O

3a 3bratio 9:1

Scheme 1.

S. Saha et al. / Tetrahedron Letters 52 (2011) 3128–3130 3129

direction) at the neighbouring prochiral carbonyl center of 1favouring the formation of 2a (Fig. 1).

The mixture of alcohols 2a and 2b was allowed to react withpropargyl bromide in the presence of NaH in THF to furnish aninseparable mixture of propargyl ethers 3a and 3b in the same ra-tio (Scheme 1).

The isomeric mixture of 3a and 3b was subjected to OsO4-oxonemediated oxidative cleavage7 of the olefinic bond to yield an insep-arable mixture of carboxylic acids 4a and 4b in almost 9:1 ratio inmoderate yield. Deprotection of the cyclohexylidene group in 4 fol-lowed by in situ lactonization was performed by using hydrochlo-ric acid in MeOH–H2O to produce a diasteomeric mixture of thelactones 5a and 5b (Scheme 2) in good yield. Both isomers 5a(R,S; 62%) and 5b (R,R; 8%) were separated by column chromatog-raphy. The major isomer of the lactone 5a was treated withTBDMS–Cl in the presence of imidazole yielding TBDMS protectedlactone 6a in 90% yield.

Now, at this stage a-bromination8 of 6a was carried out usingLDA–CBr4 at low temperature to produce brominated lactone 7a

+ O O

H O

O O

H O

3a 3b

OsO4 / Oxon

55%DMF

HOO OHO

O

H+ / MeOH

+70%

5a (62%)

H

RRR

S

R

S

Scheme

(Scheme 3). Due to instability of the compound 7a, it was usedfor the next step without further purification. The crude 7a wassubjected to radical cyclization reaction using Cp2TiCl in THF tofurnish the cyclized product 8a in 24% yield (from 6a).9 The cy-clized product 8a was treated with PDC in DMF6 in the presenceof molecular sieves (4 Å) for allylic oxidation to afford the opticallyactive core structure of bis-c-lactone 9a (30%),10 the basic skeletonof six-epimers of the natural products type B.

Now it is expected that the minor diastereomer of the lactone5b would produce the basic skeleton 9b of the natural productstype A following the same reaction sequences.

O OHO

O

5b

O OTBDMSO

O

H

H H

O9b

H

In conclusion, we have developed a radical cyclization strategy for thesynthesis of bis-c-lactone skeleton using Cp2TiCl as a radical source.Although the synthesis of the a-methylene bis-c-butyrolactonedescribed above has provided mainly compound with opposite

e

O O

O

5b (8%)

H

+ O O

H O

O O

H OCOOH COOH

4a 4b

R

R

2.

3130 S. Saha et al. / Tetrahedron Letters 52 (2011) 3128–3130

stereochemistry to that of the natural products (at the stereogeniccenter bearing the alkyl substituent at C-6), the work nevertheless of-fers a convenient and asymmetric route through the radicaltechnology.

Acknowledgments

We sincerely thank DST, New Delhi for financial support. S.S.and S.K.M. thank CSIR, New Delhi for research fellowships.

Supplementary data

Supplementary data associated with this article can be found, inthe online version, at doi:10.1016/j.tetlet.2011.04.023.

References and notes

1. (a) Aldridge, D. C.; Crawley, G. C.; Strawson, C. J. U.S. Patent DE 2543150 A119760415, 1976.; (b) Abate, D.; Abraham, W. R.; Meyer, H. Phytochemistry1997, 44, 1443; (c) Krohn, K.; Ludewig, K.; Aust, H.; Draeger, S.; Schultz, B. J.Antibiot. 1994, 47, 113.

2. (a) Lertvorachon, J.; Meepowpan, P.; Thebtaranonth, Y. Tetrahedron 1998, 54,14341; (b) Lertyvorachon, J.; Thebtaranonth, Y.; Thongpanchang, T.; Thongyoo,P. J. Org. Chem. 2001, 66, 4692; (c) Yu, M.; Lynch, V.; Pagenkopf, B. L. Org. Lett.2001, 3, 2563; (d) Chaiyanurakkul, A.; Jichati, R.; Kaewpet, M.; Rajviroongit, S.;Thebtaranonth, Y.; Thongyoo, P.; Watcharin, W. Tetrahedron 2003, 59, 9825; (e)Sharma, G. V. M.; Gopinath, T. Tetrahedron Lett. 2005, 46, 1307; (f) Varugese, S.;Thomas, S.; Haleema, S.; Puthiaparambil, T. T.; Ibnusaud, I. Tetrahedron Lett.2007, 48, 8209; (g) Mondal, S.; Ghosh, S. Tetrahedron 2008, 64, 2359.

3. Jana, S.; Guin, C.; Roy, S. C. Tetrahedron Lett. 2005, 46, 1155.4. (a) RajanBabu, T. V.; Nugent, W. A. J. Am. Chem. Soc. 1994, 116, 986. and

references cited therein.; (b) Gansauer, A.; Bluhm, H.; Pierobon, M. J. Am. Chem.Soc. 1998, 120, 12849; (c) Gansauer, A.; Pierobon, M.; Bluhm, H. Synthesis 2001,2500. and references cited therein.; (d) Justicia, J.; Oller-Lopez, J. L.; Campana,A. G.; Oltra, J. E.; Cuerva, J. M.; Bunuel, E.; Cardenas, D. J. J. Am. Chem. Soc. 2005,127, 14911; (e) Gansauer, A.; Bluhm, H. Chem. Rev. 2000, 100, 2771; (f)Monleón, L. M.; Grande, M.; Anaya, J. Synlett 2007, 1243.

5. (a) Mulzer, J.; Kappert, M.; Huttner, G. Angew. Chem., Int. Ed. Engl. 1984, 23, 704;(b) Mulzer, J.; Angermann, A. Tetrahedron Lett. 1983, 24, 2843.

6. Saha, S.; Roy, S. C. Tetrahedron 2010, 66, 4278.7. Travis, B. R.; Narayan, R. S.; Borhan, B. J. Am. Chem. Soc. 2002, 124, 3824.

8. Higuchi, Y.; Shimoma, F.; Ando, M. J. Nat. Prod. 2003, 66, 810.9. Synthesis of 8a: A solution of 6a (280 mg, 1 mmol) in THF (1.0 mL) was added

into a stirred solution of LDA [prepared from di-isopropylamine (0.28 mL,2.0 mmol and 1.6 M nBuLi in hexane (1.2 mL, 2.0 mmol)] in THF (1.0 mL) at�78 �C. The mixture was stirred at this temperature for 1 h, then CBr4 (660 mg,2 mmol) in THF (0.5 mL) was added dropwise at �78 �C. The mixture waswarmed to room temperature, stirred for 20 min and a saturated aqueoussolution of NH4Cl (1 mL) was added. It was extracted with ethyl acetate(4 � 20 mL). The combined extracts were washed with brine (10 mL) and thendried over Na2SO4. Solvent was removed under reduced pressure to affordcrude 7a which was used without further purification for the radical cyclizationreaction. A solution of titanocene dichloride (205 mg, 0.82 mmol) in dry THF(20 mL) was stirred with activated zinc dust (128 mg, 1.96 mmol) for 1 h underargon [activated zinc dust was prepared by washing 20 g of commerciallyavailable zinc dust with 60 mL of 4 M HCl and thorough washing with waterand finally with dry acetone and then drying in vacuo]. The resulting greensolution was then added dropwise to a stirred solution of the crude bromide 7ain dry THF (20 mL) at room temperature under argon during 1 h. The reactionmixture was stirred for overnight and was decomposed with saturated solutionof Na2HPO4 (2 mL). Most of the solvent was removed under reduced pressureand the residue was extracted with ethyl acetate (3 � 30 mL). The combinedorganic layer was washed with water (20 mL), brine (10 mL) and finally dried(Na2SO4). After removal of the solvent under reduced pressure the cruderesidue was purified by column chromatography over silica gel (20% ethylacetate in light petroleum) to afford the lactone 8a (69 mg, 24% from 6a) as lowmelting solid. a½ �26:0

D = +47.5 (c, 1.5 in CHCl3). IR (neat): 2956, 2930, 1777, 1459,1258, 1119 cm�1; 1H NMR (300 MHz, CDCl3): d 0.06 (s, 6H), 0.88 (s, 9H), 3.61-3.63 (m, 1H), 3.79–3.92 (m, 2H), 4.24–4.28 (m, 1H), 4.42–4.46 (m, 1H), 4.56 (s,1H), 4.72 (d, J = 6 Hz, 1H), 5.17 (s, 1H), 5.48 (s, 1H); 13C NMR (75 MHz, CDCl3): d18.2, 25.8, 50.6, 63.4, 71.4, 82.6, 83.9, 108.6, 143.3, 150.7; HRMS: calcd forC14H24O4SiNa [M+Na]+ 307.1342, found 307.1346.

10. Synthesis of 9a: To a stirred solution of 8a (80 mg, 0.28 mmol) in dry DMF(1 mL) was added molecular sieves (4 Å) and pyridinium dichromate (560 mg,1.4 mmol) at room temperature and was heated at 50 �C for 5 h. The solidswere filtered off and the filtrate was diluted with water (5 mL). It was extractedwith ethyl acetate (4 � 25 mL). The combined organic layer was washed withsaturated NaHCO3 (10 mL), water (4 � 5 mL) and finally dried (Na2SO4). Thesolvent was removed under reduced pressure and the residue obtained waschromatographed over silica gel (30% ethyl acetate in light petroleum) tofurnish the lactone 9a (25 mg, 30%) as a low melting solid. a½ �26:0

D = +10.0 (c, 1.5in CHCl3). IR (neat): 2958, 2928, 1781, 1462, 1256, 1119 cm�1; 1H NMR(500 MHz, CDCl3): d 0.07 (s, 6H), 1.26 (s, 9H) 3.70-3.75 (m, 1H), 4.12–4.13 (m,1H), 4.92–5.00 (m, 2H), 5.78–5.86 (m, 1H), 7.10 (d, J = 2.5 Hz, 1H), 7.38 (d,J = 2.5 Hz, 1H); 13C NMR (125 MHz, CDCl3): d 14.3, 29.2, 50.4, 56.6, 75.9, 81.3,124.5, 125.5, 167.4, 170.4; HRMS: calcd for C14H22O5SiNa [M+Na]+ 321.1134,found 321.1144.